ENTITYA TYPEA IDA DATABASEA ENTITYB TYPEB IDB DATABASEB EFFECT MECHANISM RESIDUE SEQUENCE TAX_ID CELL_DATA TISSUE_DATA MODULATOR_COMPLEX TARGET_COMPLEX MODIFICATIONA MODASEQ MODIFICATIONB MODBSEQ PMID DIRECT NOTES ANNOTATOR SENTENCE SIGNOR_ID APRT protein P07741 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 15196008 t miannu "In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP)" SIGNOR-280467 adenine smallmolecule CHEBI:16708 ChEBI AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "precursor of" 9606 15196008 t miannu "In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP)" SIGNOR-280468 "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "precursor of" 9606 15196008 t miannu "In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP)" SIGNOR-280469 FGF2 protein P09038 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15564063 f miannu "Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression." SIGNOR-255079 REN protein P00797 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT "up-regulates quantity" cleavage 9606 32201502 t miannu "Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10)." SIGNOR-260225 LPCAT2 protein Q7L5N7 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI "down-regulates quantity" "chemical modification" 9606 21498505 t miannu "Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. " SIGNOR-272767 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -1 31995776 t miannu "This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. ." SIGNOR-268733 DCAF1 protein Q9Y4B6 UNIPROT NF2 protein P35240 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 18332868 t miannu "VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation." SIGNOR-271673 SRC protein P12931 UNIPROT SH3PXD2A protein Q5TCZ1 UNIPROT "up-regulates activity" phosphorylation 20943948 t lperfetto " Recently, we have shown that tyrosine kinase c-Src substrate Tks4 and Tks5 proteins are novel members of the organizer superfamily" SIGNOR-264706 HPRT1 protein P00492 UNIPROT "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI "down-regulates quantity" "chemical modification" 9606 10338013 t miannu "Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#." SIGNOR-280470 PBK protein Q96KB5 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 26745678 t miannu "TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.|These data confirm the phosphorylation of c-Jun by TOPK at serine 63 and 73 during the development of resistance to EGFR-targeted TKIs." SIGNOR-278155 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI "up-regulates quantity" "precursor of" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267884 ANXA3 protein P12429 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001109;BTO:0000038 30998268 f miannu "ANXA3 downregulation evidently increased the apoptosis of HCT116 (Figure 2C) and SW480 (Figure 2D) cells, and Ox‐induced cell apoptosis was further aggravated by ANXA3 suppression." SIGNOR-262208 MSX2 protein P35548 UNIPROT DLX2 protein Q07687 UNIPROT "down-regulates activity" binding 10090 BTO:0000945 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240932 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Thr345 GADSDVEtPSNFGKY 9606 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262985 TM9SF4 protein Q92544 UNIPROT ATP6V1H protein Q9UI12 UNIPROT "up-regulates activity" binding 9606 BTO:0001109;BTO:0000038 25659576 t miannu "Here, we demonstrate that TM9SF4 represents a novel V-ATPase-associated protein involved in V-ATPase activation. We have observed in HCT116 and SW480 colon cancer cell lines that TM9SF4 interacts with the ATP6V1H subunit of the V-ATPase V1 sector. Suppression of TM9SF4 with small interfering RNAs strongly reduces assembly of V-ATPase V0/V1 sectors, thus reversing tumor pH gradient with a decrease of cytosolic pH, alkalization of intracellular vesicles and a reduction of extracellular acidity." SIGNOR-266885 PRKCI protein P41743 UNIPROT LLGL1 protein Q15334 UNIPROT "up-regulates activity" phosphorylation Ser659 RVKSLKKsLRQSFRR 9615 12725730 t miannu "This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner." SIGNOR-263179 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257372 DMC1 protein Q14565 UNIPROT SYCP3 protein Q8IZU3 UNIPROT "up-regulates activity" binding 10090 BTO:0001275 SIGNOR-C351 10525529 t miannu "The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process." SIGNOR-264206 HPRT1 protein P00492 UNIPROT guanine smallmolecule CHEBI:16235 ChEBI "down-regulates quantity" "chemical modification" 9606 10338013 t miannu "Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#." SIGNOR-280471 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 BTO:0000782 15623513 t lperfetto "Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus." SIGNOR-132894 EIF4B protein P23588 UNIPROT 48S_initiation_complex complex SIGNOR-C454 SIGNOR "form complex" binding 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269165 TFIIH complex SIGNOR-C457 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 30860024 f lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair." SIGNOR-269323 UBN1 protein Q9NPG3 UNIPROT "HIRA complex 1" complex SIGNOR-C461 SIGNOR "form complex" binding 9606 30285846 t miannu "H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex." SIGNOR-269433 guanine smallmolecule CHEBI:16235 ChEBI "guanosine 5'-monophosphate(2-)" smallmolecule CHEBI:58115 ChEBI "up-regulates quantity" "precursor of" 9606 10338013 t miannu "Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#." SIGNOR-280473 GHSR protein Q92847 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256925 AKT proteinfamily SIGNOR-PF24 SIGNOR TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Ser939 SFRARSTsLNERPKS 10090 BTO:0000944 12150915 t lperfetto "We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines." SIGNOR-244369 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-187184 "Succinate dehydrogenase-Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR "Respiratory electron transport chain" phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 f lperfetto "The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA)." SIGNOR-262138 MAPK1 protein P28482 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t llicata "Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo." SIGNOR-80092 TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 18635759 t gcesareni "Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades." SIGNOR-179476 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 18550549 t gcesareni "Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144." SIGNOR-178888 Ub:E2 complex SIGNOR-C497 SIGNOR HECTD1 protein Q9ULT8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271294 ULK1 protein O75385 UNIPROT HK1 protein P19367 UNIPROT "up-regulates activity" phosphorylation Ser124 NIVHGSGsQLFDHVA 9606 BTO:0000007 27153534 t done miannu "Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown)." SIGNOR-274034 POU2F1 protein P14859 UNIPROT MYH2 protein Q9UKX2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 15728583 t lperfetto "Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation" SIGNOR-238757 ACE protein P12821 UNIPROT bradykinin smallmolecule CHEBI:3165 ChEBI "down-regulates quantity by destabilization" binding 9606 16219810 t "The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin." SIGNOR-253341 TAC1 protein P20366 UNIPROT TACR2 protein P21452 UNIPROT up-regulates binding 9606 8925404 t gcesareni "The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag)." SIGNOR-44773 hsa-miR-199a-5p mirna URS0000554A4F_9606 RNAcentral ATG7 protein O95352 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000599 22713463 t Parnian "We further demonstrated that miR-199a-5p downregulation increased autophagy activation by targeting ATG7." SIGNOR-279818 AKT1 protein P31749 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Thr60 EYRRRRHtMDKDSRG 9606 16081417 t llicata "Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt." SIGNOR-252481 CSK protein P41240 UNIPROT EEF2 protein P13639 UNIPROT "down-regulates quantity" phosphorylation 9606 24648518 t miannu "C-terminal Src kinase (Csk)-mediated phosphorylation of eukaryotic elongation factor 2 (eEF2) promotes proteolytic cleavage and nuclear translocation of eEF2.|In this report, we show that eukaryotic elongation factor 2 (eEF2) is a new protein substrate of Csk and could locate in the nucleus." SIGNOR-279698 PBXIP1 protein Q96AQ6 UNIPROT PBX1 protein P40424 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 24488098 t miannu "This protein that we have termed hematopoietic PBX-interacting protein (HPIP) is mainly localized in the cytosol and in small amounts in the nucleus. The region of PBX that interacts with HPIP includes both the homeodomain and immediate N-terminal flanking sequences. Strikingly, electrophoretic mobility shift assays revealed that HPIP inhibits the ability of PBX-HOX heterodimers to bind to target sequences. " SIGNOR-273666 FASN protein P49327 UNIPROT Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 9356448 f miannu "Our model of the native fatty acid synthase (FAS) depicts it as a dimer of two identical multifunctional proteins (Mr approximately 272,000) arranged in an antiparallel configuration so that the active Cys-SH of the beta-ketoacyl synthase of one subunit (where the acyl group is attached) is juxtaposed within 2 A of the pantetheinyl-SH of the second subunit (where the malonyl group is bound). This arrangement generates two active centers for fatty acid synthesis and predicts that if we have two appropriate halves of the monomer, we should be able to reconstitute an active fatty acid-synthesizing site" SIGNOR-268159 ADRA2B protein P18089 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256714 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Thr785 SINEMLStQALRLDE 9606 17396146 t gcesareni "The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells." SIGNOR-154175 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1763 TPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248789 "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR CD4 protein P01730 UNIPROT "up-regulates activity" binding 9606 31001252 t scontino "Extracellular domain of¬†CD4, which is responsible for the recognition of its ligands, is composed of four globular Ig-like domains (D1-D4). The N-terminal D1 domain binds to a segment of the non-polymorphic Œ≤2 domain of MHC class II. CD4 is required for the recognition of most antigens in vivo. The presence of the CD4 coreceptor enhances T cell sensitivity to antigens" SIGNOR-267990 "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR PUM1 protein Q14671 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 31320642 t lperfetto "In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins" SIGNOR-268351 PCM1 protein Q15154 UNIPROT CEP250 protein Q9BV73 UNIPROT up-regulates relocalization 9606 15659651 t miannu "Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1" SIGNOR-133334 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto "AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬†" SIGNOR-244311 PAPOLB protein Q9NRJ5 UNIPROT "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity by stabilization" "chemical modification" 9606 19224921 t lperfetto "Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner." SIGNOR-268328 AMPD3 protein Q01432 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "down-regulates quantity" "chemical modification" 9606 26321268 t miannu "AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia." SIGNOR-280490 PRKACA protein P17612 UNIPROT RGS18 protein Q9NS28 UNIPROT "up-regulates activity" phosphorylation Ser216 PTNLRRRsRSFTCNE 9606 BTO:0000132 24244663 t done miannu "Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216. " SIGNOR-273786 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser192 VNSVRRKsCLVKEVE 9606 17567953 t lperfetto "Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres." SIGNOR-155898 MAPKAPK2 protein P49137 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates phosphorylation Ser323 KDLGRSEsLRVVCRP 9606 16456544 t lperfetto "Mk2 activated limk1 by phosphorylation at ser-323." SIGNOR-144333 HPRT1 protein P00492 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "chemical modification" 9606 10338013 t miannu "Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#." SIGNOR-280477 PRKAG1 protein P54619 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates binding 9606 16054041 t gcesareni "Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits." SIGNOR-139173 CDK1 protein P06493 UNIPROT SLC9A3R1 protein O14745 UNIPROT "down-regulates activity" phosphorylation Ser280 LAEAALEsPRPALVR 9606 20937695 t miannu "During the early stages of mitosis in HeLa cells, Cdc2 phosphorylates EBP50 on serine residues 280 and 302.|Phosphorylation by Cdc2 inhibits EBP50's role in forming microvilli in interphase but not mitotic cells. (A) Results from scoring JEG-3 cells for the presence of microvilli; error bars indicate mean \u00b1 SD. (B) Representative images from the microvillar rescue assay." SIGNOR-278305 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2366 MEQGHFAsPDQNSML 9606 17623675 t lperfetto "Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo." SIGNOR-244537 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT "up-regulates quantity" phosphorylation Thr267 KSNLKRVtLELGGKS 9606 28193222 t miannu "AURKA phosphorylates ALDH1A1 at T267, T442, and T493.|Our data revealed that AURKA increases ALDH1A1 levels by inhibiting its ubiquitylation; thus, we examined whether 3A-ALDH1A1 was impervious to AURKA mediated protein stability." SIGNOR-278166 ZBTB46 protein Q86UZ6 UNIPROT LIF protein P15018 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 30962287 t miannu "ZBTB46 binds directly to the LIF regulatory sequence and enhances its transcription. Our study confirmed a novel positive association between ZBTB46 activity and LIF levels in prostate cancer tissues and cells. Under androgen regulation, low levels of ZBTB46 are an essential transcriptional factor for maintaining LIF-STAT3 signaling, while the loss of androgen signaling or inhibition of AR signaling causes LIF-enhanced therapeutic resistance and CRPC characteristics through the upregulation of ZBTB46. We also found that LIF activation drives malignant progression and NE-like reprogramming in prostate cancer by activating STAT3 signaling." SIGNOR-277988 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT "up-regulates quantity" phosphorylation Thr442 KDIDKAItISSALQA 9606 28193222 t miannu "AURKA phosphorylates ALDH1A1 at T267, T442, and T493.|Our data revealed that AURKA increases ALDH1A1 levels by inhibiting its ubiquitylation; thus, we examined whether 3A-ALDH1A1 was impervious to AURKA mediated protein stability." SIGNOR-278167 NUP43 protein Q8NFH3 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262087 hypoxanthine smallmolecule CHEBI:17368 ChEBI IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "precursor of" 9606 10338013 t miannu "Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#." SIGNOR-280478 "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "precursor of" 9606 10338013 t miannu "Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#." SIGNOR-280479 MAPK1 protein P28482 UNIPROT LIMA1 protein Q9UHB6 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser362 PVHPKPLsPDSRASS 9606 BTO:0001033 23188829 t miannu "Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover." SIGNOR-263054 FGFR3 protein P22607 UNIPROT GLO1 protein Q04760 UNIPROT "up-regulates activity" phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu "We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D)." SIGNOR-276181 VTI1A protein Q96AJ9 UNIPROT "LE-TGN SNARE" complex SIGNOR-C157 SIGNOR "form complex" binding 9606 BTO:0000567 18195106 t lperfetto "We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport" SIGNOR-253081 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT "up-regulates activity" phosphorylation Ser616 EGDDRPEsPEYSGGN 10116 BTO:0000601 11080179 t miannu "We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP." SIGNOR-262934 CSNK1E protein P49674 UNIPROT TRAF3 protein Q13114 UNIPROT "up-regulates activity" phosphorylation Tyr446 SLYSQPFyTGYFGYK 9606 BTO:0002181 32779804 t miannu "We found that the interaction of CK1ε with TRAF3Y116F, TRAF3Y446F were markedly decreased compared with interactions with WT TRAF3 by Co‐IP (Figure 6C); as expected, TRAF3Y116F and TRAF3Y446F mutants exhibited reduced K63‐linked ubiquitination (Figure 6D). These data suggest that the phosphorylation of TRAF3 at Tyr 116 and Tyr 446 regulate CK1ε‐induced K63‐linked ubiquitination." SIGNOR-277524 AMP smallmolecule CHEBI:456215 ChEBI IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "precursor of" 9606 26321268 t miannu "AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia." SIGNOR-280484 AMPD2 protein Q01433 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "chemical modification" 9606 26321268 t miannu "AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia." SIGNOR-280487 RELA protein Q04206 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR "form complex" binding 9606 BTO:0000452;BTO:0002625 22223884 t alessandro "Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin" SIGNOR-254527 clemastine chemical CHEBI:3738 ChEBI P2RX7 protein Q99572 UNIPROT "up-regulates activity" "chemical activation" 9606 21262970 t Luana "Clemastine potentiates the human P2X7 receptor by sensitizing it to lower ATP concentrations." SIGNOR-257893 "Parathyroid hormone-related peptide (1-36)" smallmolecule CHEBI:80274 ChEBI PTH1R protein Q03431 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257575 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser272 RPRSKSQsSSNCSNP -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251290 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr239 APRSSDLtDRVKVWT 9606 BTO:0000671 17522053 t llicata "Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc)." SIGNOR-155106 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 12242151 t gcesareni "We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members." SIGNOR-92942 USF1 protein P22415 UNIPROT FMR1 protein Q06787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 "BTO:0001363; BTO:0000142" 11058604 f miannu "We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs." SIGNOR-254882 SMAD6 protein O43541 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates binding 9606 19352540 t gcesareni "Mad6-pellino-1 interaction abrogated signaling mediated by a complex of irak1." SIGNOR-185128 EGR1 protein P18146 UNIPROT SLC9A3 protein P48764 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 16464174 f "Transcriptional stimulation of the human NHE3 promoter activity by PMA: PKC independence and involvement of the transcription factor EGR-1|Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity" SIGNOR-254269 CDK1 protein P06493 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates phosphorylation Ser728 VVKQEQLsPKKKENN 9606 SIGNOR-C17 22163316 t gcesareni "We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase." SIGNOR-195233 IRF9 protein Q00978 UNIPROT STAT2 protein P52630 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9242679 t lperfetto "Coimmunoprecipitation assays demonstrate p48 association with STAT2 but not STAT1.The studies demonstrate the in vivo existence of a STAT2.p48 complex and a distinct STAT2.STAT1 complex after IFN-alpha stimulation. Data suggest that distinct bipartite complexes STAT2.p48 and STAT2.STAT1 translocate to the nucleus and associate on the DNA target site as ISGF3." SIGNOR-217806 MC1R protein Q01726 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268697 JAG1 protein P78504 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 10551863 t "Binding Calcium-dependent." gcesareni "Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch." SIGNOR-269936 ARRB2 protein P32121 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000971 12488444 t miannu "Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination." SIGNOR-272592 AMP smallmolecule CHEBI:456215 ChEBI IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "precursor of" 9606 26321268 t miannu "AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia." SIGNOR-280489 FZR1 protein Q9UM11 UNIPROT SKIL protein P12757 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 11741538 t miannu " We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC. " SIGNOR-272621 PRKD2 protein Q9BZL6 UNIPROT SSH1 protein Q8WYL5 UNIPROT "down-regulates activity" phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 t lperfetto "Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase" SIGNOR-275937 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser175 EEEEDLSsPPGLPEP 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120467 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-34669 MAPDA protein Q6DHV7 UNIPROT methylammonium smallmolecule CHEBI:59338 ChEBI "up-regulates quantity" "chemical modification" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. " SIGNOR-280504 MAPDA protein Q6DHV7 UNIPROT "2'-deoxyinosine 5'-phosphate(2-)" smallmolecule CHEBI:61194 ChEBI "up-regulates quantity" "chemical modification" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. " SIGNOR-280505 N(6)-methyl-dAMP(2-) smallmolecule CHEBI:169976 ChEBI "2'-deoxyinosine 5'-phosphate(2-)" smallmolecule CHEBI:61194 ChEBI "up-regulates quantity" "precursor of" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. " SIGNOR-280506 SMAD1/4 complex SIGNOR-C85 SIGNOR PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18854943 f fferrentino "This Smad1/4 complex can directly interact with Shn-2 and C/EBP a on the PPAR g promoter thus, resulting in the transcriptional activation of PPAR g" SIGNOR-253551 TRIM32 protein Q13049 UNIPROT DTNBP1 protein Q96EV8 UNIPROT "down-regulates quantity" ubiquitination 9534 BTO:0000298 19349376 t miannu "TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation." SIGNOR-265658 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT "down-regulates activity" phosphorylation Ser898 SECDPTPsHRGQLNK 9606 BTO:0000567 31167143 t miannu "Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations. " SIGNOR-276729 atropine chemical CHEBI:16684 ChEBI CHRM4 protein P08173 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 2704370 t miannu "In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium." SIGNOR-258390 "Immunoglobulin kappa light chain" protein P0DOX7 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR "form complex" binding 9606 BTO:0000776 20176268 t scontino "Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes." SIGNOR-268194 MAPDA protein Q6DHV7 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "chemical modification" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group." SIGNOR-280498 MRGPRX2 protein Q96LB1 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257327 PBX1 protein P40424 UNIPROT HOXB1 protein P14653 UNIPROT "up-regulates activity" binding -1 10052460 t 2 miannu "Pbx1 and exd act as cofactors that enhance the DNA binding specificity of Hox proteins. The structure of the HoxB1–Pbx1–DNA ternary complex shows that HoxB1 and Pbx1 bind to overlapping binding sites located on opposite faces of the DNA." SIGNOR-241219 Ub:E2 complex SIGNOR-C497 SIGNOR PML protein P29590 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270992 cisapride chemical CHEBI:3720 ChEBI KCNH2 protein Q12809 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9395068 t miannu "A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. cisapride displays specific, high affinity block of the human cardiac K+ channel HERG. It is likely that this interaction underlies the proarrhythmic effects of the drug observed under certain clinical settings." SIGNOR-258672 NCOA1 protein Q15788 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 9427757 t miannu "Steroid receptor co-activator (src1) is one of a number of transcriptional co-activators that are capable of potentiating the activity of nuclear receptors including the oestrogen receptor (er)." SIGNOR-54442 GPR119 protein Q8TDV5 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257040 CREB1 protein P16220 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001379 34751390 t scontino "CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription." SIGNOR-267137 MCRS1 protein Q96EZ8 UNIPROT "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR "form complex" binding 9606 BTO:0000007 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex." SIGNOR-267161 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto "Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1." SIGNOR-217586 SMARCE1 protein Q969G3 UNIPROT "Muscle cell-specific SWI/SNF ARID1B variant" complex SIGNOR-C482 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270704 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9262330 t miannu "We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine." SIGNOR-258663 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser761 DSLGRRSsLSRLEPS 9606 25009260 t lperfetto "Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome" SIGNOR-205238 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Thr356 PLEEERQtQRSKPQP 9606 BTO:0000130 17217339 t lperfetto "Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation." SIGNOR-152027 RRAGA protein Q7L523 UNIPROT RAGAC complex SIGNOR-C113 SIGNOR "form complex" binding 9606 20381137 t gcesareni "Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant" SIGNOR-228164 MAP3K7 protein O43318 UNIPROT TNFAIP8L2 protein Q6P589 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser3 sFSSKSLA 9606 BTO:0000007 32188758 t done miannu " TAK1 phosphorylated the Ser3 in the noncanonical degron motif of TIPE2 to trigger its interaction with β-TrCP for subsequent ubiquitination and degradation." SIGNOR-273668 MAPK3 protein P27361 UNIPROT AMPH protein P49418 UNIPROT "down-regulates activity" phosphorylation Ser293 PAPARPRsPSQTRKG 9606 15262992 t lperfetto "Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2." SIGNOR-126867 KLHL25 protein Q9H0H3 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0002552 27664236 t miannu "Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. " SIGNOR-272334 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "up-regulates activity" binding 9606 21084559 t miannu "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1." SIGNOR-256186 KLF4 protein O43474 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 17308127 t lperfetto "Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element." SIGNOR-270544 MAPK8 protein P45983 UNIPROT ARHGAP8 protein P85298 UNIPROT "up-regulates activity" phosphorylation Ser455 TKPTLPPsPLMAARR 28092672 t lperfetto "Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation." SIGNOR-275550 SYNE1 protein Q8NF91 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR "up-regulates activity" binding 9606 BTO:0001950 24781983 t miannu "Nesprin-1 is involved in the DNA Damage Response network. The Nesprin-1 interaction with MSH2 and MSH6 (MutSα complex) is a constitutive cellular event required for proper DNA repair." SIGNOR-261823 CDK1 protein P06493 UNIPROT SKA3 protein Q8IX90 UNIPROT "up-regulates activity" phosphorylation Thr360 ENLLRTPtPPEVTKI 9606 28479321 t miannu "Cdk1 treatment further enhanced the binding of Ska3 2D to Ndc80, suggesting that phosphorylation of other Cdk1 sites in Ska3 further contributes to the Ndc80C-Ska3 interaction, although this contribution is not apparent in our kinetochore localization assay.We next purified the GST-Ndc80C Bonsai construct that lacks the loop region of Ndc80 as well as the coiled coil regions of Ndc80C [17].|Thus, Ska3 can be phosphorylated by Cdk1 on T358 and T360 sites in vitro.We next tested whether Ska3 was required for Ska1 or Ska2 localization." SIGNOR-278375 ROCK1 protein Q13464 UNIPROT PFN1 protein P07737 UNIPROT down-regulates phosphorylation Ser138 MASHLRRsQY 9606 22479341 t lperfetto "We previously identified pfn1 as a huntingtin aggregation inhibitor, and others have implicated it as a tumor-suppressor. Rho-associated kinase (rock) directly phosphorylates pfn1 at ser-137 to prevent its binding to polyproline sequences. This negatively regulates its anti-aggregation activity." SIGNOR-196820 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273152 AURKB protein Q96GD4 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-70420 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-70436 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Thr87 GVPAEGRtPPPFPGE 9606 22721717 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-197936 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT unknown phosphorylation Ser34 PEVTGRSsVLRVSQK -1 26134678 t lperfetto "To address whether the phosphorylation state of TACC3 influenced Aurora-A binding and activation, we generated TACC3 variants in which all three Aurora-A phosphorylation sites (S34, S552 and S558)| The SA mutant had strongly reduced levels of phosphorylation compared to the individual mutations|" SIGNOR-263697 SH3GLB1 protein Q9Y371 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates binding 9606 21311563 t gcesareni "Bif-1 forms a complex with beclin1 through uvrag and promotes the activation of the class iii pi3 kinase, vps34, in mammalian cells." SIGNOR-171899 FFAR2 protein O15552 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257276 TGFBI protein Q15582 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 SIGNOR "up-regulates activity" binding 26387839 t lperfetto "BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers" SIGNOR-253271 CDK3 protein Q00526 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" phosphorylation Ser106 PLNSVSPsPLMLLHP 26202215 t lperfetto "CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3" SIGNOR-273188 VRK2 protein Q86Y07 UNIPROT TKT protein P29401 UNIPROT "up-regulates activity" phosphorylation Thr287 SKKKILAtPPQEDAP 9606 BTO:0001950 37653031 t miannu "Mechanistically, VRK2 promoted Thr287 phosphorylation of TKT and then recruited FBXL6 to promote TKT ubiquitination and activation. " SIGNOR-277842 MAPK3 protein P27361 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser279 SSPTAPLsPMSPPGY 9606 9535909 t lperfetto "These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication." SIGNOR-249466 GSK3A protein P49840 UNIPROT STAT2 protein P52630 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser393 LTPEKGQsQGLIWDF 9606 BTO:0002181 31843895 t miannu "GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation." SIGNOR-276762 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser126 PILVDTAsPSPMETS 9606 BTO:0000567 11242082 t lperfetto "Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation." SIGNOR-105707 FLT3 protein P36888 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates activity" phosphorylation Tyr88 KGSLPEFyYRPPRPP 10090 BTO:0001516 28522571 t lperfetto "FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27 Kip1 in acute myeloid leukemia|P27Kip1 (p27) can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88." SIGNOR-269208 RAC1 protein P63000 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR "up-regulates activity" binding 10090 BTO:0000142 8107774 t gcesareni "A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways." SIGNOR-248256 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser688 RLFVENDsPSDGGTP 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104687 TERF2 protein Q15554 UNIPROT ATM protein Q13315 UNIPROT "down-regulates activity" binding SIGNOR-C306 18680434 t lperfetto "It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex" SIGNOR-263323 ORF6 protein Q19QW5 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" 9534 17596301 f lperfetto "Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane." SIGNOR-260271 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1280 QVILAKAsQEHHLSE 9606 BTO:0002181 11114888 t llicata "Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication." SIGNOR-250582 "MLL2 complex" complex SIGNOR-C88 SIGNOR H3-4 protein Q16695 UNIPROT "down-regulates activity" methylation Lys5 kQTARKST 9606 24680668 t miannu "Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation." SIGNOR-268800 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9390557 t lperfetto "Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation." SIGNOR-53576 SMAD7 protein O15105 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates binding 9606 16571110 t gcesareni "Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs" SIGNOR-145389 STUB1 protein Q9UNE7 UNIPROT CTBP2 protein P56545 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23410750 t miannu "Our data showed that CHIP depletion resulted in up-regulation of the steady-state level of CtBP2 ( Fig. 1 B) and that CHIP ubiquitinated CtBP2 for proteasomal degradation ( Fig. 3 A)." SIGNOR-278722 FBXL3 protein Q9UKT7 UNIPROT CRY2 protein Q49AN0 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 17463251 t miannu " We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex. This regulation by SCF(Fbxl3) is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. HEK293T cells were transfected with Cry2, Skp1, Cul1, and Roc1 in the absence or presence of either FLAG-tagged Fbxl3 or a FLAG-tagged Fbxl3(ΔF-box) mutant. Fbxl3, but not an inactive Fbxl3(ΔF-box) mutant (4), induced the ubiquitination of Cry2 (Fig. 2D), which supports the notion that the effect of Fbxl3 on Cry2 is direct." SIGNOR-271648 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto "Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins" SIGNOR-244148 HTR1E protein P28566 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256705 TGFb proteinfamily SIGNOR-PF5 SIGNOR Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f "inferred from 70% family members" lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-Œ±, TGF-Œ≤, tumor necrosis factor (TNF)-Œ±, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-270216 hsa-miR-493-5p mirna URS0000077AED_9606 RNAcentral RHOC protein P08134 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001345 22057916 t "MiR-493 is a new tumor suppressor microRNA in bladder cancer and inhibits cell motility through down-regulation of RhoC and FZD4." SIGNOR-277956 MRPL39 protein Q9NYK5 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262358 PTPN6 protein P29350 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates activity" dephosphorylation Tyr116 EILALQIyCRNESRG 9606 BTO:0002181 32779804 t miannu "We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446." SIGNOR-277527 antigen smallmolecule CHEBI:59132 ChEBI BCR-Ml complex SIGNOR-C434 SIGNOR "up-regulates activity" binding 9606 BTO:0000776 32323266 t scontino "The recognition of antigen by the BCR initiates BCR signaling cascade." SIGNOR-268203 AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT "up-regulates activity" 9606 16293724 f lperfetto "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway." SIGNOR-244225 PRKCA protein P17252 UNIPROT CORO1B protein Q9BR76 UNIPROT down-regulates phosphorylation Ser2 sFRKVVRQ 9606 16027158 t lperfetto "We have identified serine 2 (ser-2) on coronin 1b as the major residue phosphorylated by pkc in vivo.In this work, we show that coronin 1b interacts in vivo with the arp2/3 complex and that this interaction is inhibited by pkc phosphorylation." SIGNOR-138733 FYN protein P06241 UNIPROT NMT1 protein P30419 UNIPROT unknown phosphorylation Tyr180 YTLLNENyVEDDDNM -1 11594778 t "Human NMT was found to be phosphorylated by non-receptor tyrosine kinase family members of Lyn, Fyn and Lck. Tyr100 is the principle phosphorylation site on hNMT for Lyn and Fyn. The significance of a phosphorylation-dependent interaction between NMT and a tyrosine kinase is not known at present." SIGNOR-251179 GSK3B protein P49841 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser159 NNTSTDGsLPSTPPP 10090 BTO:0003328 16543145 t "MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1." SIGNOR-251242 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" SIGNOR-235782 TGM2 protein P21980 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 16407273 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells." SIGNOR-143642 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR "up-regulates activity" "chemical activation" 9606 18790874 t brain lperfetto "Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS)." SIGNOR-263787 DHX30 protein Q7L2E3 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu "DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU." SIGNOR-261228 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto "THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones." SIGNOR-268658 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000891 10929711 t amattioni "Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity." SIGNOR-80209 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT "down-regulates activity" phosphorylation Ser126 NPEAESSsKEGELDA -1 23901111 t miannu "Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. " SIGNOR-276123 doxorubicin chemical CHEBI:28748 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 19377506 t "An important reason why Top2 has held the interest of researchers studying cancer was the discovery that active anti-cancer drugs, notably etoposide and doxorubicin target Top2" SIGNOR-261911 NR3C1 protein P04150 UNIPROT DUSP1 protein P28562 UNIPROT "up-regulates quantity" 10090 BTO:0000944 11742987 t gcesareni "Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity." SIGNOR-253546 EIF3D protein O15371 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266397 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 t lperfetto "We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735.These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by mapks may regulate the proteolytic function of membrane secretases." SIGNOR-89614 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270414 PPP1R3B protein Q86XI6 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates binding 9606 BTO:0000759 36551183 t miannu "In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)" SIGNOR-271736 PTPN1 protein P18031 UNIPROT GAB1 protein Q13480 UNIPROT "down-regulates activity" dephosphorylation 9606 23521888 t lperfetto "Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well.|The results indicate that PTP1B completely dephosphorylated Gab1 and the mutant protein failed to dephosphorylate Gab1 (Figure\u00a0 xref C)." SIGNOR-276965 AKT1 protein P31749 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates activity" phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto "The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate" SIGNOR-252559 GRIK1 protein P39086 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI "up-regulates quantity" relocalization 9606 BTO:0002609 12393813 t lperfetto "Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine" SIGNOR-268272 ITGAM protein P11215 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 23994464 t apalma "Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1." SIGNOR-255041 3b protein P59633 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" 9606 21561061 f Luana "An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP" SIGNOR-260761 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT "up-regulates activity" phosphorylation Tyr60 KTASSLSyDIHYWIG 9606 BTO:0000567 15342783 t lperfetto "These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton" SIGNOR-247437 Ub:E2 complex SIGNOR-C497 SIGNOR ZSWIM2 protein Q8NEG5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270950 ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT "up-regulates activity" phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 t "C-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. he functional significance of c-Abl-dependent phosphorylation of Rad52 is underscored by our findings that cells that express the phosphorylation-resistant Rad52 mutant, in which tyrosine 104 is replaced by phenylalanine, exhibit compromised nuclear foci formation in response to IR." SIGNOR-251435 SCF-FBW7 complex SIGNOR-C135 SIGNOR GFI1 protein Q99684 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000498 31289136 t miannu "GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation." SIGNOR-277467 CLK2 protein P49760 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "down-regulates activity" phosphorylation 9606 20074525 t miannu "Clk2 could also repress PGC-1alpha activation of Foxo1 on the IRS response element , as well as repress the Pepck promoter .|Clk2 phosphorylates and represses PGC-1\u03b1." SIGNOR-278228 HTR1A protein P08908 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256836 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Thermogenesis phenotype SIGNOR-PH192 SIGNOR up-regulates 9606 24692351 f scontino "TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight." SIGNOR-267491 PROS1 protein P07225 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 7867073 t gcesareni "We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function." SIGNOR-34483 ACTL6A protein O96019 UNIPROT "Neural progenitor-specific SWI/SNF" complex SIGNOR-C477 SIGNOR "form complex" binding 9606 25195934 t miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270620 TP53 protein P04637 UNIPROT FNTB protein P49356 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26469958 f lperfetto "In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs." SIGNOR-242353 "Tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate" chemical CID:46907787 PUBCHEM BRD2 protein P25440 UNIPROT "down-regulates activity" "chemical inhibition" 9606 30080437 t "Simone Vumbaca" "Through the integrative analyses of ChIP-seq and CAGE data, we elucidate the involvement of BRD2 in gene regulation upon BET inhibition by JQ1 in H23 cells." SIGNOR-261124 OGT protein O15294 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR "down-regulates activity" glycosylation 9606 BTO:0000007 22923583 t lperfetto "O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway| O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) to serine or threonine residues" SIGNOR-267586 HIRA protein P54198 UNIPROT "HIRA complex 1" complex SIGNOR-C461 SIGNOR "form complex" binding 9606 30285846 t miannu "H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex." SIGNOR-269434 IKBKB protein O14920 UNIPROT TARDBP protein Q13148 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr8 MSEYIRVtEDENDEP 9606 BTO:0002181 38197897 t miannu "IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK." SIGNOR-277861 PRKDC protein P78527 UNIPROT YBX1 protein P67809 UNIPROT "up-regulates activity" phosphorylation Thr89 EDVFVHQtAIKKNNP 9606 BTO:0000007 36475703 t miannu "The DNA-PK subunits and YB-1 phosphorylated at T89 were found colocalized suggesting their in vivo interaction.DNA-PK directly phosphorylates YB-1 and, this way, modulates YB-1 function. Point mutation of YB-1 at this residue abrogated the translocation of YB-1 into the nucleus." SIGNOR-277611 ZSWIM2 protein Q8NEG5 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 16522193 f miannu "MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin. " SIGNOR-271556 CDK9 protein P50750 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "form complex" binding -1 34955012 t lperfetto "Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb). " SIGNOR-267740 AKT1 protein P31749 UNIPROT CBY1 protein Q9Y3M2 UNIPROT "up-regulates activity" phosphorylation Ser20 TPPRKSAsLSNLHSL 9606 18573912 t miannu "These observations argue that Chibby is a bona fide Akt substrate and that Akt kinase phosphorylates Chibby at the serine 20 residue." SIGNOR-279002 ROCK1 protein Q13464 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni "Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements" SIGNOR-198840 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" 9606 19951971 t lperfetto "PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain." SIGNOR-249628 CDK5 protein Q00535 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" phosphorylation Ser203 DLEFSSGsPGKETNE 9606 17440046 t llicata "Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue" SIGNOR-154401 PRKCA protein P17252 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 t lperfetto "These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels." SIGNOR-249083 FBXW10 protein Q5XX13 UNIPROT GAPDH protein P04406 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000578 37450367 t miannu "Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation. " SIGNOR-277841 MMP9 protein P14780 UNIPROT A2M protein P01023 UNIPROT "down-regulates quantity by destabilization" cleavage Gly702 YEMHGPEgLRVGFYE -1 9344465 t lperfetto "The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the ""bait"" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261781 NEUROG3 protein Q9Y4Z2 UNIPROT NHLH1 protein Q02575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19028584 f miannu "Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. Ngn3 overexpression increased the NSCL1-expressing domain corresponding to young ganglion cells" SIGNOR-254634 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 8622669 t lperfetto "Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways." SIGNOR-40356 PRKG1 protein Q13976 UNIPROT TRPC6 protein Q9Y210 UNIPROT "down-regulates activity" phosphorylation Ser322 KNDYKKLsMQCKDFV -1 19961855 t miannu "PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q). " SIGNOR-276271 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser281 SGTPSSAsPALSRRG 10090 17213202 t lperfetto "Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo." SIGNOR-234465 PLK1 protein P53350 UNIPROT NCAPH2 protein Q6IBW4 UNIPROT "up-regulates activity" phosphorylation Ser288 ESRSPQQsAALPRRY 9606 28717250 t miannu "Plk1 phosphorylation of CAP-H2 at Ser288 is required for the accumulation of CAP-H2 and accurate chromosomal condensation during prophase." SIGNOR-278419 PTCHD1 protein Q96NR3 UNIPROT VPS35 protein Q96QK1 UNIPROT "up-regulates quantity" binding 10090 BTO:0000142 29118110 t miannu "Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus" SIGNOR-266653 CDK1 protein P06493 UNIPROT VHL protein P40337 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser80 QVIFCNRsPRVVLPV 9606 BTO:0000815 36813923 t miannu " Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1. PIN1 then binds to phosphorylated pVHL and facilitates the recruitment of the E3 ligase WSB1, therefore targeting pVHL for ubiquitination and degradation. " SIGNOR-277836 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT "up-regulates activity" phosphorylation Ser748 DSEGFEDsFEEEEEE 9606 BTO:0000599 23287549 t lperfetto "Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62." SIGNOR-265272 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204696 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 10454565 t "Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro" SIGNOR-248479 CXCL8 protein P10145 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu "Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection" SIGNOR-261030 SRC protein P12931 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates activity" phosphorylation 9606 19665017 t miannu "Hence, c-Src-dependent phosphorylation of MPP2 could be part of a negative feedback loop within the circuitry that modulates c-Src activity by MPP2." SIGNOR-279117 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT "up-regulates activity" phosphorylation Tyr405 PTSLRAHyDTPRSLC 10090 20603078 t miannu "Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes." SIGNOR-273846 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161626 TP53 protein P04637 UNIPROT CCNG1 protein P51959 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 9688532 t lperfetto "Individual promoter and intron p53-binding motifs from the rat Cyclin G1 promoter region support transcriptional activation by p53 but do not show co-operative activation." SIGNOR-268961 KATNB1 protein Q9BVA0 UNIPROT KATNA1 protein O75449 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 10751153 t miannu "In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer" SIGNOR-267173 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates binding 9606 17429065 t lpetrilli "Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin." SIGNOR-154316 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2G protein Q13555 UNIPROT up-regulates "chemical activation" 9606 22944199 t lperfetto "Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell)." SIGNOR-198816 KEAP1 protein Q14145 UNIPROT CUL3 protein Q13618 UNIPROT "up-regulates activity" binding 9534 BTO:0001538 15983046 t miannu "Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome.  The N-terminal BTB domain and central linker region of Keap1 bind Cul3, whereas the C-terminal Kelch domain of Keap1 binds Nrf2 via residues located within loops that extend out from the bottom of the Kelch domain" SIGNOR-268925 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser73 SAVRLRSsVPGVRLL -1 11895474 t miannu "In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK. " SIGNOR-250243 DCAF7 protein P61962 UNIPROT DYRK1A protein Q13627 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 14593110 t Giorgia "Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions." SIGNOR-260630 CORT protein O00230 UNIPROT SSTR4 protein P31391 UNIPROT up-regulates binding 9606 BTO:0000938 11011067 t gcesareni "Cortistatin is known to bind all five cloned somatostatin receptors and share many pharmacological and functional properties with somatostatin including the depression of neuronal activity." SIGNOR-82493 POU5F1 protein Q01860 UNIPROT HLX protein Q14774 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254936 GNB/GNG complex SIGNOR-C202 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates 23994464 t apalma "Similar to PLCβ activation, PI3K-activation by neutrophil GPCRs also occurs primarily through Gβγ subunits, through the unique PI3Kγ isoform which is directly activated by Gβγ dimers" SIGNOR-255010 STAT6 protein P42226 UNIPROT KDM6B protein O15054 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19567879 f lperfetto "We demonstrate that IL-4dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter." SIGNOR-249539 SP1 protein P08047 UNIPROT CADM1 protein Q9BY67 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 18794147 f lperfetto "Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation." SIGNOR-268958 PI4K2B protein Q8TCG2 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 10101268 t miannu "The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position." SIGNOR-269100 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9507002 t gcesareni "Our present study established that n-shc and sck are expressed in a region-specific manner in the brain and that n-shc is a higher affinity adapter molecule than sck for trka and trkb receptors" SIGNOR-55864 PHF8 protein Q9UPP1 UNIPROT TOPBP1 protein Q92547 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 33511404 t miannu "TopBP1 Interacts with PHF8 through residue R1314 of TopBP1. Importantly, PHF8 regulates TopBP1 protein level by preventing its ubiquitination and degradation mediated by the E3 ligase UBR5." SIGNOR-273657 ARHGAP19 protein Q14CB8 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260471 NDUFA4 protein O00483 UNIPROT "Cytochrome c oxidase-Mitochondrial respiratory chain complex IV" complex SIGNOR-C280 SIGNOR "form complex" binding 30030361 t lperfetto "Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits" SIGNOR-267752 LAT protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 23150273 t "Phosphorylated tyrosines 171, 191, and 226 [in LAT] bind to the SH2 domains of the Grb2 family of adaptor proteins and must be present for optimal signalling" SIGNOR-251520 PRKCD protein Q05655 UNIPROT PTPRA protein P18433 UNIPROT "up-regulates activity" phosphorylation Ser213 PLLARSPsTNRKYPP 9606 11676480 t lperfetto "In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232." SIGNOR-249114 RNF146 protein Q9NTX7 UNIPROT RNF146 protein Q9NTX7 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 21799911 t "We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation." SIGNOR-260006 F2R protein P25116 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257353 SNX9 protein Q9Y5X1 UNIPROT DNM2 protein P50570 UNIPROT up-regulates binding 9606 BTO:0000567 15703209 t miannu "Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes." SIGNOR-133976 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1651 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248818 SFN protein P31947 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates activity" relocalization 9606 BTO:0005079 27073720 t "Verteporfin increases the level of 14-3-3σ, which promotes the translocation of YAP from nucleus to cytoplasm." SIGNOR-278130 Ub:E2 complex SIGNOR-C497 SIGNOR RLIM protein Q9NVW2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271054 KLC1 protein Q07866 UNIPROT TOR1A protein O14656 UNIPROT "up-regulates activity" binding 10116 14970196 t Monia "We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wildtype torsinA and kinesin-I form a complex in vivo. These studies suggest that wild-type torsinA undergoes anterograde transport along microtubules mediated by kinesin and may act as a molecular chaperone regulating kinesin activity and/or cargo binding." SIGNOR-261172 ATM protein Q13315 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT down-regulates phosphorylation Ser19 GTSKCPPsQRVPALT 9606 18536714 t llicata "Disruption of the hipk2-siah-1 complex is mediated by the atm/atr pathway and involves atm/atr-dependent phosphorylation of siah-1 at ser 19." SIGNOR-177945 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR WIPI2 protein Q9Y4P8 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 30898011 t miannu "Here we show that WIPI2/ATG18B (WD repeat domain, phosphoinositide interacting 2), an autophagy-related (ATG) protein that plays a critical role in autophagosome biogenesis, is a direct substrate of CUL4-RING ubiquitin ligases (CRL4s)" SIGNOR-272302 MAP2K1 protein Q02750 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser304 LSSYGMDsRPPMAIF -1 8226933 t "MEK1 and MEK2 can also be activated by autophosphorylation. Tyrosine 304 may be a candidate for the autophosphorylation site in MEK1." SIGNOR-251415 3-methyladenine chemical CHEBI:38635 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205639 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser341 GTMSRPAsVDGSPVS -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251294 hsa-miR-29a-5p mirna URS0000076995_9606 RNAcentral ATP1B1 protein P05026 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001248 22330642 t parnian "The progestin downregulated miRNA miR-29a targets the ATP1B1 3’UTR" SIGNOR-280434 "CAK complex" complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-269324 D-thyroxine smallmolecule CHEBI:30659 ChEBI THRB protein P10828 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0003736 6777394 t miannu "The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response." SIGNOR-258401 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251618 HDAC3 protein O15379 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 23213415 t gcesareni "We show here that smad7 can form a complex with endogenous histone deacetylase proteins hdac-1 and hdac-3 in nih 3t3 mouse fibroblast cells" SIGNOR-199967 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates 9606 18481201 f lperfetto "Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation." SIGNOR-244877 SP1 protein P08047 UNIPROT PCYT1A protein P49585 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 10744779 t Luana "Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter" SIGNOR-266231 SP1 protein P08047 UNIPROT THBD protein P07204 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22406829 f miannu "In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells." SIGNOR-255216 PLAG1 protein Q6DJT9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11888928 f miannu "Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis" SIGNOR-115772 PRKG1 protein Q13976 UNIPROT ENAH protein Q8N8S7 UNIPROT "down-regulates activity" phosphorylation 9606 15066263 t miannu " Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts. PKG may preferentially phosphorylate sites of Ena/VASP proteins that reduce or inactivate these proteins. Inactivated Ena/VASP proteins dissociate from actin filaments, allowing capping proteins to bind and block monomer addition to plus ends, resulting in filament retraction." SIGNOR-268288 RARG protein P13631 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16659 CSNK2A2 protein P19784 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" phosphorylation Ser421 IACEEEFsDSEEEGE 9606 BTO:0000661 11602581 t llicata "Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1." SIGNOR-250999 GNA12 protein Q03113 UNIPROT hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000599 25965999 f parnian "Our data indicates that Gα12 overexpressed in liver cancer mostly greatly dysregulates the expression of miR-122." SIGNOR-280438 GNA12 protein Q03113 UNIPROT MET protein P08581 UNIPROT "up-regulates activity" 9606 BTO:0000599 25965999 f parnian "All of these results indicate that increased levels of Gα12 causes the induction of c-Met by deregulating miR-122." SIGNOR-280439 NRG2 protein O14511 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-122056 HLA-G protein P17693 UNIPROT LILRB1 protein Q8NHL6 UNIPROT up-regulates binding 9606 15718280 t gcesareni "Hla-g binds a limited repertoire of peptides and interacts with the inhibitory leukocyte ig-like receptors lir-1 and lir-2" SIGNOR-134180 DZIP3 protein Q86Y13 UNIPROT H2AC21 protein Q8IUE6 UNIPROT "up-regulates activity" monoubiquitination Lys119 IQAVLLPkKTESHKP 9606 BTO:0000007 18206970 t miannu " 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation." SIGNOR-271758 KDM5A protein P29375 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264301 PPP3CB protein P16298 UNIPROT FLNA protein P21333 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t "Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation." SIGNOR-248362 CUL3 protein Q13618 UNIPROT CUL3-RBX1-KEAP1 complex SIGNOR-C562 SIGNOR "form complex" binding 9606 24138990 t miannu "KEAP1/CUL3/RBX1 E3-ligase protein complex exert different functions under physiological and oxidative conditions." SIGNOR-279842 CHD8 protein Q9HCK8 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 19255092 t miannu "We also show that CHD8 associates with the elongating form of RNAPII, which is phosphorylated in its carboxy-terminal domain (CTD). Furthermore, CHD8-depleted cells are hypersensitive to drugs that inhibit RNAPII phosphorylation at serine 2, suggesting that CHD8 is required for an early step of the RNAPII transcription cycle." SIGNOR-268806 hsa-miR-148a-3p mirna URS00003BBF48_9606 RNAcentral ADAM17 protein P78536 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001109 33356812 t Tiberia "Transfection of HCT116 with miR-148a inhibited ADAM17 expression and luciferase activity. MiR-148a directly suppresses ADAM17 in colonocytes and is downregulated in colon cancer." SIGNOR-279886 hsa-mir-152-3p mirna URS00003AFD9B_9606 RNAcentral ADAM17 protein P78536 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001109 33356812 t Tiberia "Transfection of HCT116 with miR-152-3p inhibited ADAM17 expression and luciferase activity.MiR-152 directly suppresses ADAM17 in colonocytes and is downregulated in colon cancer." SIGNOR-279887 hsa-miR-338-3p mirna URS00000254A6_9606 RNAcentral ADAM17 protein P78536 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002181 26617808 t Tiberia "MiR-338-3p is significantly reduced in gastric cancer and inhibits cell proliferation, migration and invasion through downregulation of ADAM17, therefore, miR-338-3p may represent a potential therapeutic target for gastric cancer intervention." SIGNOR-279888 hsa-mir-708-3p mirna URS000049EEDF_9606 RNAcentral ADAM17 protein P78536 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001590 29869625 t Tiberia "MiR-708-3p directly regulates its target gene, a disintegrin and metalloproteinase 17 (ADAM17), through a binding site in the 3' untranslated region. MiR-708-3p blocked the expression of ADAM17" SIGNOR-279889 hsa-mir-224-5p  mirna URS0000D55DFB_9606 RNAcentral ADAM17 protein P78536 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0005855 31207072 t Tiberia "Luciferase and Western blot assays revealed that ADAM17 protein was a downstream target of miR-224. MiR-224 inhibits the growth and invasion of OSCC cells by regulating the expression of ADAM17." SIGNOR-279890 "muramyl dipeptide" smallmolecule CHEBI:59414 ChEBI TLR2 protein O60603 UNIPROT "up-regulates activity" binding 9606 BTO:0004297 38510686 t Tiberia "The bacterial cell wall MDP (PGN) is a well-established Toll-like receptor 2 (TLR2) ligand, as demonstrated by the fact that TLR2-deficient mice display defective proinflammatory cytokine responses against PGN." SIGNOR-280447 KCNJ11 protein Q14654 UNIPROT "KATP channel" complex SIGNOR-C274 SIGNOR "form complex" binding 9606 28842488 t lperfetto "ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits." SIGNOR-262055 SLC18A2 protein Q05940 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 30465801 t miannu "Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles." SIGNOR-269197 SMARCC2 protein Q8TAQ2 UNIPROT "Muscle cell-specific SWI/SNF ARID1B variant" complex SIGNOR-C482 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270708 hsamir7085p mirna URS000019D79B_9606 RNAcentral IKBKG protein Q9Y6K9 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004602 25623956 t Tiberia "Transfection of endothelial cells with pre-miR-708 reduced IKK-γ protein levels compared to control groups." SIGNOR-279894 hsa-mir-98-5p mirna URS00004E0808_9606 RNAcentral CHUK protein O15111 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004602 25623956 t Tiberia "Transfection of endothelial cells with pre-miR-98 reduced CHUK levels, compared to control groups." SIGNOR-279895 CUL3-RBX1-KEAP1 complex SIGNOR-C562 SIGNOR NFE2L2 protein Q16236 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0003081 39534872 t miannu "NFE2L2 is primarily regulated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, which, under normal conditions, promotes the ubiquitination and proteasomal degradation of NFE2L2, keeping its cellular levels low." SIGNOR-279844 "bafilomycin A1" chemical CHEBI:22689 ChEBI ATP6V1A protein P38606 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9572882 t "Simone Vumbaca" "The macrolide antibiotic bafilomycin A1 is a very potent and specific inhibitor of V-ATPases." SIGNOR-261084 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120116 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr725 AGGGSATyMDQAPSP 9606 11751923 t llicata "Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor." SIGNOR-113393 "Vincristine sulfate" chemical CHEBI:79401 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000142 30599272 t miannu "Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity." SIGNOR-259254 "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR JUN protein P05412 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 14739464 t miannu "We report that human DET1 (hDET1) promotes ubiquitination and degradation of the proto-oncogenic transcription factor c-Jun by assembling a multisubunit ubiquitin ligase containing DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A), Regulator of Cullins-1 (ROC1), and constitutively photomorphogenic-1.  Ablation of any subunit by RNA interference stabilized c-Jun and increased c-Jun-activated transcription." SIGNOR-271500 CDK1 protein P06493 UNIPROT CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser116 PQKLLGCsPALKRSH 9606 SIGNOR-C17 12411508 t lperfetto "Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover." SIGNOR-95256 ATM protein Q13315 UNIPROT PAN2 protein Q504Q3 UNIPROT "up-regulates activity" phosphorylation Ser1003 TKSTIKPsQMSVARI 9606 BTO:0000007 33097710 t miannu "Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52. " SIGNOR-273508 NOTCH1 protein P46531 UNIPROT HEY1 protein Q9Y5J3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11486044 t lperfetto "These data establish that HERP2 is a novel primary target gene of Notch that, together with HES, may effect diverse biological activities of Notch" SIGNOR-235397 hsa-miR-106a-5p mirna URS00003FE4D4_9606 RNAcentral STAT3 protein P40763 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0006483 36157880 t Tiberia "Interestingly, MiR-106a has been reported to be a downregulated miRNA that suppresses Th17 differentiation and reduces the severity of autoimmune inflammatory response by targeting ROR γ t and STAT3" SIGNOR-279911 FBXO33 protein Q7Z6M2 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 10090 BTO:0000165 18354498 t miannu "Mediation of eIF3-f polyubiquitination by the SCFMAFbx. The association of MAFbx with the essential Skp1, Roc 1 and Cul1 proteins, specific components of an E3 ubiquitin–protein ligase (SCFMAFbx), was previously described. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome." SIGNOR-271769 RAB9A protein P51151 UNIPROT RABEPK protein Q7Z6M1 UNIPROT "up-regulates activity" 9230071 t lperfetto "P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking." SIGNOR-253088 MAP2K1 protein Q02750 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 f gcesareni "Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation." SIGNOR-178636 LONP1 protein P36776 UNIPROT STAR protein P49675 UNIPROT "down-regulates quantity by destabilization" cleavage 10116 BTO:0000542 17579211 t lperfetto "Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by Lon protease: the unexpected effect of proteasome inhibitors" SIGNOR-265726 pipamperone chemical CHEBI:78549 ChEBI HTR2A protein P28223 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000331 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258572 STAT6 protein P42226 UNIPROT ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 f apalma "Cytokines like IL-4 or IL-13 lead to STAT6 phosphorylation with consecutive arginase expression and varying further aspects of M2 polarization (mannose receptor, Ym1, Fizz1)" SIGNOR-255557 hsa-miR-31-5p mirna URS00005416E3_9606 RNAcentral RASA1 protein P20936 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000552 29605672 t Tiberia "The luciferase reporter assay showed that miR-31 mimics significantly repressed the luciferase activity of the constructs containing Rasa1 3'UTR elements." SIGNOR-279926 CDK1 protein P06493 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr221 KDEILPTtPISEQKG 9606 21871177 t gcesareni "These results suggest that the phosphorylation of rps3 by cdk1 occurs at thr221 during g2/m phase and, moreover, that this event is important for nuclear accumulation of rps3." SIGNOR-176131 hsa-miR-31-5p mirna URS00005416E3_9606 RNAcentral SPRED2 protein Q7Z698 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000552 29605672 t Tiberia "Luciferase reporter assay showed that miR-31 mimics significantly repressed the luciferase activity of constructs containing Spred2 3'UTR elements." SIGNOR-279927 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral LRP6 protein O75581 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0003264 23811937 t Tiberia "To understand the role of LRP6 in miR-126-mediated Wnt/β-catenin signaling pathway, we examined the downstream gene expression after CVB3 infection. We confirmed that miR-126 mimetic suppressed LRP6 expression" SIGNOR-279928 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral RHOU protein Q7L0Q8 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0003264 23811937 t Tiberia "To understand the role of and RHOU in miR-126-mediated Wnt/β-catenin signaling pathway, we examined the downstream gene expression after CVB3 infection. We first confirmed that miR-126 mimetic suppressed RHOU expression, while miR-126 inhibitor increased WRCH1 expression." SIGNOR-279929 REEP5 protein Q00765 UNIPROT CXCR1 protein P25024 UNIPROT "up-regulates activity" binding 9606 27966653 t miannu "In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses." SIGNOR-261366 DSCAML1 protein Q8TD84 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000938 30745319 f miannu "Nuclear DSCAM and DSCAML1 impair neurite outgrowth. this demonstrates that enhanced nuclear translocation of the DSCAM and DSCAML1 ICDs profoundly impairs neurite outgrowth and development of primary cortical neurons" SIGNOR-264275 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 t lperfetto "In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity" SIGNOR-171243 NCAPH2 protein Q6IBW4 UNIPROT "Condensin II" complex SIGNOR-C342 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263910 POT1 protein Q9NUX5 UNIPROT RPA3 protein P35244 UNIPROT "down-regulates activity" binding SIGNOR-C306 18680434 t lperfetto "The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA" SIGNOR-263326 LUBAC complex SIGNOR-C527 SIGNOR RIPK2 protein O43353 UNIPROT "up-regulates activity" polyubiquitination Lys61 PLLDSERkDVLREAE 9606 BTO:0005096 33935757 t Tiberia "RIPK2 is subjected to N-terminal methionine (Met1)-linked polyubiquitination by LUBAC after the interaction between RIPK2 and XIAP. Thus, K63-linked polyubiquitination and recruitment of LUBAC are indispensable steps for NF-κB activation by RIPK2." SIGNOR-280451 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" phosphorylation Tyr568 EEINGNNyVYIDPTQ 9606 BTO:0001271 12824176 t lperfetto "Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated" SIGNOR-102633 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser146 RPSQRHGsKYLATAS -1 2413024 t lperfetto "MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities." SIGNOR-248870 RAP1GDS1 protein P52306 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171415 PRKAA2 protein P54646 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser505 GSVKRVTsGPSLGSL 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 20231899 t gcesareni "Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp." SIGNOR-164293 P4HA1 protein P13674 UNIPROT HIF1A protein Q16665 UNIPROT "up-regulates activity" 31239153 f miannu "P4HA1 regulates HIF1a activity in pancreatic cancer. P4HA1 can also increase HIF1a protein level in PDAC cells indicative of a positive feedback loop between P4HA1 and HIF1a." SIGNOR-279875 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t gcesareni "Here we show that in vitro, atm phosphorylates the ser-gln/thr-gln (sq/tq) cluster domain (scd) on chk2, which contains seven sq/tq motifs, and thr68 is the major in vitro phosphorylation site by atm. Atm predominantly phosphorylates chk2 at thr68, promoting homodimerization and activation via intramolecular trans-autophosphorylation at thr383/387." SIGNOR-81438 N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "up-regulates quantity" "precursor of" 9606 17194761 t miannu "N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain." SIGNOR-267525 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser639 YMPMSPKsVSAPQQI 10116 BTO:0000452 11287630 t lperfetto "Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten" SIGNOR-106590 CPSF7 protein Q8N684 UNIPROT "CFI complex" complex SIGNOR-C388 SIGNOR "form complex" binding 9606 BTO:0000567 8626397 t lperfetto "We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity." SIGNOR-266124 CASP7 protein P55210 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto "In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329." SIGNOR-261751 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT "up-regulates activity" phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000567 18079698 t miannu "We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14." SIGNOR-276090 CCKBR protein P32239 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256908 STK39 protein Q9UEW8 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0000988 21317537 t lperfetto "WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression," SIGNOR-264643 MAPK14 protein Q16539 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser396 TFDSLPSsPSSATPH -1 12171600 t miannu "Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%." SIGNOR-249707 RSPO2 protein Q6UXX9 UNIPROT LGR5 protein O75473 UNIPROT up-regulates binding 9606 21693646 t "Furin domain" gcesareni "Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation" SIGNOR-174532 CRK protein P46108 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 8524328 t gcesareni "These results indicate that crk binds to c-cbl in a tyrosine phosphorylation-dependent manner." SIGNOR-39241 INSR protein P06213 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 7512963 t llicata "Insulin stimulates the phosphorylation of tyr538 and the catalytic activity of ptp1c, a protein tyrosine phosphatase with src homology-2 domains. these results suggest that ptp1c is a target protein for the insulin receptor tyrosine kinase" SIGNOR-26870 PRKN protein O60260 UNIPROT MFN1 protein Q8IWA4 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000793 20871098 t miannu "Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2.  Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy." SIGNOR-272779 NatC complex SIGNOR-C417 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 f miannu "About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity." SIGNOR-267236 AKT proteinfamily SIGNOR-PF24 SIGNOR CFLAR protein O15519 UNIPROT "down-regulates quantity" phosphorylation Ser273 LLRDTFTsLGYEVQK 9606 19339247 t gcesareni "TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling." SIGNOR-245304 ARRB2 protein P32121 UNIPROT SLC9A5 protein Q14940 UNIPROT "down-regulates activity" relocalization 21296876 t lperfetto "Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs)" SIGNOR-275506 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000150 19573809 f lperfetto "However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth" SIGNOR-252634 DLG4 protein P78352 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 19075115 f miannu "Postsynaptic density 95 (PSD-95) is an important regulator of synaptic structure and plasticity." SIGNOR-264053 HBA1 protein P69905 UNIPROT AHSP protein Q9NZD4 UNIPROT "down-regulates activity" 9606 2545495 f Regulation miannu "EDRF is rapidly inactivated by hemoglobin and superoxide." SIGNOR-251751 NR3C1 protein P04150 UNIPROT TRIM63 protein Q969Q1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18612045 f areggio "Consistent with these findings, DEX-induced upregulation of MuRF1 is significantly attenuated in mice expressing a homodimerization-deficient GR despite no effect on the degree of muscle loss in these mice vs. their wild-type counterparts. Finally, chromatin immunoprecipitation analysis reveals that both GR and FOXO1 bind to the endogenous MuRF1 promoter in C(2)C(12) myotubes, and IGF-I inhibition of DEX-induced MuRF1 expression correlates with the loss of FOXO1 binding." SIGNOR-254992 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161553 epitope chemical CHEBI:53000 ChEBI "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR "form complex" binding 9606 33374673 t scontino "The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR)." SIGNOR-269479 Cadherins proteinfamily SIGNOR-PF71 SIGNOR CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265812 DYRK1A protein Q13627 UNIPROT SRSF2 protein Q01130 UNIPROT "down-regulates activity" phosphorylation 9606 21470964 t miannu "Dyrk1A inhibits SC35\u2032s activity to promote tau exon 10 inclusion.|Dyrk1A interacts with and phosphorylates SC35 and inhibits its activity to promote tau exon 10 inclusion." SIGNOR-278307 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM43 protein Q96BQ3 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271208 FAM162A protein Q96A26 UNIPROT VDAC1 protein P21796 UNIPROT "up-regulates activity" binding 9606 BTO:0001061 15082785 t Giulio "HGTD-P was coprecipitated with VDAC but not with ANT or cyclophilin D (Fig. 7A, left upper panel).|However, it is not clear at present whether HGTD-P participates directly in channel formation in association with VDAC or modulates its channel-forming activity." SIGNOR-260293 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr18 AIEWPGAyPKLMEID 9606 15952790 t llicata "We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts." SIGNOR-138142 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser318 SRTNSNAsTVSGRLS 9606 20110348 t lperfetto "Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export" SIGNOR-163672 AXIN2 protein Q9Y2T1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 BTO:0000149 11940574 f gcesareni "Although wnts act to stabilize _-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3_, and axin1 or its homolog axin2/axil/conductin promotes _-catenin phosphorylation and subsequent proteasomal degradation." SIGNOR-116480 CSF1 protein P09603 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 t gcesareni "A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (gcsf) and a ligand binding region of gcsf receptor (gcsf-r), has been determined to 2.8 a resolution" SIGNOR-144737 F2R protein P25116 UNIPROT LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 BTO:0000007 22972936 f milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-192048 CAMK2A protein Q9UQM7 UNIPROT ITGB1BP1 protein O14713 UNIPROT "up-regulates activity" phosphorylation Thr38 GGLSRSStVASLDTD 9813144 t llicata "The point mutation T38D localized within the optimal CaMKII recognition motif of ICAP-1alpha results in a strong defect in cell spreading which cannot be overcome by the inhibition of the endogenous CaMKII. This fact strongly suggests that the phosphorylation of Threonine 38 by CaMKII modulates the alpha5beta1 integrin function. Conversely, the mutation T38A produces an analog of ICAP-1alpha that cannot be phosphorylated and that stimulates cell spreading on fibronectin to a similar extent when CaMKII is inhibited." SIGNOR-250632 SKA3 protein Q8IX90 UNIPROT "SKA complex" complex SIGNOR-C364 SIGNOR "form complex" binding -1 22483620 t lperfetto "We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3." SIGNOR-265196 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Thr86 YTLSRAQtVVVEYTH 9606 12496252 t lperfetto "In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation" SIGNOR-96759 BMP4 protein P12644 UNIPROT BMP4 protein P12644 UNIPROT up-regulates binding 9606 11178121 t lperfetto "Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is anabsolute requirement for the biological action and interaction with receptors" SIGNOR-236169 solifenacin chemical CHEBI:135530 ChEBI CHRM1 protein P11229 UNIPROT "down-regulates activity" "chemical inhibition" -1 21524581 t Luana "The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference" SIGNOR-258312 PTEN protein P60484 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 22482061 t lperfetto "Antisense- or shRNA mediated downregulation of PTEN induced SRC Tyr416 phosphorylation, SRC activation, and ultimately elevated TZMB resistance, whereas induction of PTEN phosphatase activity directly dephosphorylated SRC Tyr416 residue and so abolished SRC activity .|These observations indicate that the loss of PTEN phosphatase activity induces SRC activation and so implicates SRC in shaping de novo TZMB resistance in PTEN deficient cells ." SIGNOR-277009 "IL17R complex" complex SIGNOR-C260 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 10090 BTO:0000944 8777726 f lperfetto "3T3 cells were preincubated with an IL-17Rspecific antiserum and then assayed for NF-KB activation by HVS13. Preincubation with the IL-1 7R antiserum dramatically decreased the NF-KB activity induced by HVSl3 as compared with cells preincubated with an irrelevant rat antiserum (Figure 5C). This result indicated that the engagement of the IL-17R by its ligands induced NF-KB activity." SIGNOR-261338 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1A protein P48039 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257545 PATJ protein Q8NI35 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR "form complex" binding 9606 24366813 t lperfetto "To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a)," SIGNOR-203488 IL21R protein Q9HBE5 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000776 12093291 t gcesareni "Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5" SIGNOR-90266 MAPK10 protein P53779 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 24610780 t lperfetto "Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. is regulated by jnk3 via phosphorylation of app at thr668" SIGNOR-204671 SRMS protein Q9H3Y6 UNIPROT MAP2K4 protein P45985 UNIPROT "down-regulates activity" phosphorylation Tyr269 RDAGCRPyMAPERID 9606 BTO:0002181 37020040 t miannu "SRMS directly phosphorylates MKK4 and inhibits MKK4-JNK-c-Jun activation upon platinum treatment. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation." SIGNOR-277903 EGR1 protein P18146 UNIPROT FAP protein Q12884 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 20515787 f "Down-regulation of EGR1 resulted in a significant reduction in endogenous FAP mRNA expression. These findings identify the basal transcriptional requirements of FAP gene expression and show EGR1 is an important regulator of FAP expression." SIGNOR-254248 IL1RL1 protein Q01638 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16286016 t miannu "As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation. " SIGNOR-277705 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr136 AEDAKAIyDFTDTVI 9606 22195962 t llicata "Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1" SIGNOR-191719 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR CDH1 protein P12830 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000586 21598020 t miannu "Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14" SIGNOR-265817 "SAGA complex" complex SIGNOR-C465 SIGNOR H3-2 protein Q5TEC6 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269633 PINK1 protein Q9BXM7 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser392 FKTEGPDsD 9606 29033320 t miannu "Our studies thus indicated that mitophagy\npositively regulated hepatic CSCs by suppressing p53, which otherwise would be activated by\nPINK1 to suppress the expression of NANOG and hepatic CSCs.|These results indicated that the phosphorylation of p53 at S392 by\nPINK1 likely took place on mitochondria." SIGNOR-278418 ETF complex SIGNOR-C463 SIGNOR FADH2 smallmolecule CHEBI:17877 ChEBI "up-regulates quantity" "chemical modification" 9606 33450351 t miannu "ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a)." SIGNOR-269455 CCP110 protein O43303 UNIPROT CALM3 protein P0DP25 UNIPROT "up-regulates activity" binding 9606 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-266348 NUP58 protein Q9BVL2 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262077 UBE2J1 protein Q9Y385 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001379 29892818 t "inferred from family member" scontino "ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244." SIGNOR-270242 SKP1 protein P63208 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243760 PRKACA protein P17612 UNIPROT RASGRF1 protein Q13972 UNIPROT up-regulates phosphorylation Ser927 KEKYRRMsLASAGFP 9606 BTO:0000938 10601308 t llicata "Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors." SIGNOR-73202 WNK4 protein Q96J92 UNIPROT WNK4 protein Q96J92 UNIPROT "down-regulates activity" phosphorylation Ser335 KRASFAKsVIGTPEF -1 25542968 t miannu " Elimination of the catalytic activity (D321A or D321K-K186D) or the autophosphorylation site (S335A) in mutant WNK4-L322F abrogated the positive effect on NCC. " SIGNOR-276871 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni "Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required" SIGNOR-38032 HIF1A protein Q16665 UNIPROT KDM5A protein P29375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271565 S1PR1 protein P21453 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257108 GHSR protein Q92847 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257255 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY4 protein P51582 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257564 CSNK2A1 protein P68400 UNIPROT FHOD3 protein Q2V2M9 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 21149568 t tpavlidou "We have identified a novel striated muscle-specific splice variant of the formin fhod3 that introduces a casein kinase 2 (ck2) phosphorylation site. The specific targeting of muscle fhod3 to the myofibrils in cardiomyocytes is abolished in phosphomutants or by the inhibition of ck2. Phosphorylation of muscle fhod3 also prevents its interaction with p62/sequestosome 1 and its recruitment to autophagosomes." SIGNOR-170525 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 10512765 t gcesareni "Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme." SIGNOR-71024 RUNX3 protein Q13761 UNIPROT PEA15 protein Q15121 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255097 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB1 protein Q9Y5G3 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265703 PTPN1 protein P18031 UNIPROT ABL1 protein P00519 UNIPROT down-regulates dephosphorylation 9606 9566916 t gcesareni "These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo." SIGNOR-56815 SREBF1 protein P36956 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 t "inferred from family member" gcesareni "Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk)" SIGNOR-270288 miR-495 mirna URS000075C517_9606 RNAcentral Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 26055960 f miannu "Our results suggest that activating mutation of FLT3 in AML can lead, through the induction of JUN, to an increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently may causes block of myeloid differentiation." SIGNOR-255801 protriptyline chemical CHEBI:8597 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9537821 t miannu "Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter." SIGNOR-258737 CD3E protein P07766 UNIPROT NCK1 protein P16333 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000661 12110186 t "We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck." SIGNOR-259934 TCF25 protein Q9BQ70 UNIPROT "RQC complex" complex SIGNOR-C559 SIGNOR "form complex" binding 28528489 t lperfetto "The ribosome-bound quality control (RQC) complex is a multi-protein complex conserved throughout eukaryotes and composed of the E3 ubiquitin ligase Ltn1/Listerin, the ATPase Cdc48/p97 with its co-factors Ufd1/UFD1L and Npl4/NPLOC4, as well as the factors Rqc1/TCF25 and Rqc2/NEMF (Fig. 1)." SIGNOR-277698 RIPK3 protein Q9Y572 UNIPROT OGDC complex SIGNOR-C397 SIGNOR "up-regulates activity" phosphorylation -1 29358703 t miannu "Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135." SIGNOR-268066 "Myog/SWI/SNF complex" complex SIGNOR-C94 SIGNOR MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 17194702 t miannu "Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle" SIGNOR-151697 BCS1L protein Q9Y276 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto "We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains." SIGNOR-262544 PEA15 protein Q15121 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates 9606 11702783 f gcesareni "Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase." SIGNOR-111499 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser309 DSLSPVAsLPKQIFQ 25855382 t lperfetto "PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant" SIGNOR-275560 TSSK3 protein Q96PN8 UNIPROT TSSK3 protein Q96PN8 UNIPROT "up-regulates activity" phosphorylation Ser166 PKSHRELsQTFCGST -1 16336268 t Manara "We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation." SIGNOR-260785 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14976552 t gcesareni "We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli" SIGNOR-122725 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ARRB1 protein P49407 UNIPROT down-regulates phosphorylation 9606 10347142 t "inferred from 70% family members" gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-270094 CSNK2A1 protein P68400 UNIPROT GBF1 protein Q92538 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser292 VVSPSTDsGLEFSSQ 9606 BTO:0002181 29898406 t miannu "We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation." SIGNOR-277397 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser391 GAATPRTsQFTKYWT 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141002 CSNK2A1 protein P68400 UNIPROT PSMA3 protein P25788 UNIPROT unknown phosphorylation Ser243 AEKYAKEsLKEEDES -1 8619999 t llicata "Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery." SIGNOR-250938 RIMBP3B protein A6NNM3 UNIPROT RIMS1 protein Q86UR5 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264364 ABL1 protein P00519 UNIPROT YTHDC1 protein Q96MU7 UNIPROT down-regulates phosphorylation 9606 15175272 t lperfetto "We show that yt521-b is tyrosine phosphorylated by c-abl in the nucleus.We propose that tyrosine phosphorylation causes sequestration of YT521-B in an insoluble nuclear form, which abolishes the ability of YT521-B to change alternative splice sites." SIGNOR-125167 TFE3 protein P19532 UNIPROT ATP6V1C1 protein P21283 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 24448649 f lperfetto "Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A)." SIGNOR-276811 hsa-miR-382-5p mirna URS000035E174_9606 RNAcentral ROR1 protein Q01973 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000948 26575700 t Parnian "Collectively, these data suggest that miR‑382 may inhibit ROR1 expression by targeting its 3'-UTR.| these findings suggested that miR‑382 inhibited migration and invasion by directly targeting ROR1 in SKOV3 and COV434 cells." SIGNOR-278845 CRYGD protein P07320 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 10521291 f "The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification." SIGNOR-253620 GCK protein P35557 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor." SIGNOR-266448 RLN2 protein P04090 UNIPROT RXFP2 protein Q8WXD0 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 t gcesareni "Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway." SIGNOR-114585 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-251588 ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI "up-regulates quantity" "precursor of" 29928787 t lperfetto "In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells." SIGNOR-275638 PAK1 protein Q13153 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 18775988 t gcesareni "P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339." SIGNOR-180812 H3-4 protein Q16695 UNIPROT "Nucleosome_H3.1t variant" complex SIGNOR-C325 SIGNOR "form complex" binding -1 20498094 t miannu "A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1." SIGNOR-263725 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89150 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Tyr334 MQDNSGTyGKIWEGS 9534 BTO:0000298 11381116 t "The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2)." SIGNOR-251385 EIF2S1 protein P05198 UNIPROT ATF4 protein P18848 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 27629041 t miannu "ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap dependent translation while concomitantly initiates the preferential translation of ISR specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery" SIGNOR-260169 KIT protein P10721 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9534 7509796 t "Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells" SIGNOR-255948 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 t miannu "GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments." SIGNOR-249711 PTPN3 protein P26045 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" dephosphorylation Tyr537 CKNVVPLyDLLLEML 9606 26079946 t miannu "Our recent studies further demonstrated that PTPH1 dephosphorylates estrogen receptor at Y537, increases estrogen receptor stability and nuclear accumulation, and enhances breast cancer sensitivity to anti-estrogens [ ]." SIGNOR-277127 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258006 CUL4A protein Q13619 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "form complex" binding 9606 22649780 t gcesareni "The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors" SIGNOR-234793 NFE2L2 protein Q16236 UNIPROT Ferritin complex SIGNOR-C563 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 39534872 t miannu "NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. In HCC cells, NFE2L2-mediated upregulation of FTH1 enhances the cellular antioxidant defense by increasing the capacity for iron storage, thereby reducing erastin- or sorafenib-induced ferroptosis" SIGNOR-279862 SYN1 protein P17600 UNIPROT ACTB protein P60709 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 15265865 t miannu "Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner." SIGNOR-269184 SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 21628332 f lperfetto "SOCS3 attenuates IL-6-induced STAT3 anti-inflammatory effects, as well as IL-4-induced insulin receptor substrate-2/PI3K-mediated gene expression." SIGNOR-249567 RAD23B protein P54727 UNIPROT RPA2 protein P15927 UNIPROT "up-regulates activity" binding 24086043 t lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275699 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 11724780 t gcesareni "Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk" SIGNOR-112289 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr932 IRRESSVyDISEHRR -1 11024032 t "Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro." SIGNOR-251174 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22703233 f lperfetto "Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products." SIGNOR-249551 CDC25A protein P30304 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" dephosphorylation 9606 16682204 t miannu "Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1  [4,5] ." SIGNOR-277137 FGFR1 protein P11362 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates 9606 12270934 f lperfetto " Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors" SIGNOR-218010 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 BTO:0000142 16401070 t lperfetto "Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence." SIGNOR-143477 SOSTDC1 protein Q6X4U4 UNIPROT WNT1 protein P04628 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242704 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000567 16825193 t lperfetto "The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding" SIGNOR-236645 AKT1 protein P31749 UNIPROT MDM4 protein O15151 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto "We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2." SIGNOR-252517 CDC7 protein O00311 UNIPROT ESCO1 protein Q5FWF5 UNIPROT down-regulates phosphorylation 9606 23314252 t gcesareni "We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1." SIGNOR-200397 MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" phosphorylation Ser474 RTHFPQFsYSASIRE 9606 12181443 f lperfetto "We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek." SIGNOR-91408 TACR1 protein P25103 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257048 CDK7 protein P50613 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser403 PEEFISLsPPHEALD 9606 10428966 t lperfetto "These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain." SIGNOR-69776 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 9606 21084559 t gcesareni "Phosphorylation of yap ser127 and of the corresponding sites in yki and taz generates a protein-binding motif for the 14-3-3 family proteins, which, upon binding by a 14-3-3 protein, leads to their cytoplasmic retention. One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73." SIGNOR-169719 FASN protein P49327 UNIPROT "long-chain fatty acid anion" smallmolecule CHEBI:57560 ChEBI "up-regulates quantity" "chemical modification" 9606 15507492 t "Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬†" SIGNOR-267208 CSNK1A1 protein P48729 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C110 22083140 t gcesareni "In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]" SIGNOR-177233 E2F1 protein Q01094 UNIPROT CTNND2 protein Q9UQB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001033 21106062 f miannu "Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression." SIGNOR-251876 AXL protein P30530 UNIPROT TNS2 protein Q63HR2 UNIPROT "up-regulates quantity" phosphorylation Tyr483 GPLDGSPyAQVQRPP 9606 30419905 t miannu "In this study, however, we demonstrate for the first time that Axl directly binds to and phosphorylates TNS2 at Y483.|Overall these results suggest that Axl positively regulates TNS2 expression." SIGNOR-278471 CDK2 protein P24941 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates phosphorylation Thr847 FRYIPPNtPENFWEV 9606 19202191 t llicata "Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo" SIGNOR-183840 Ub:E2 complex SIGNOR-C497 SIGNOR UNKL protein Q9H9P5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271227 SLC36A4 protein Q6YBV0 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI "up-regulates quantity" relocalization 8355 21097500 t lperfetto "HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM)." SIGNOR-264735 PXN protein P49023 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 18650496 f "VEGF pathway" Gianni "Through the interactions of its multiple protein-protein binding modules, many of which are regulated by phosphorylation, paxillin serves as a platform for the recruitment of numerous regulatory and structural proteins that together control the dynamic changes in cell adhesion, cytoskeletal reorganization and gene expression that are necessary for cell migration and survival." SIGNOR-261944 MAPK1 protein P28482 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation Ser62 LLPTPPLsPSRRSGL 9534 BTO:0004055 8386367 t lperfetto "Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62." SIGNOR-235700 PLK1 protein P53350 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT "up-regulates activity" phosphorylation Ser311 SDALTDDsMSMTDSS 9606 BTO:0001061 26438599 t miannu "Plk1 phosphorylates axin2 at Ser311. " SIGNOR-277180 "Mitochondrial Fe-S Cluster Assembly Complex" complex SIGNOR-C276 SIGNOR "iron-sulfur cluster" smallmolecule CHEBI:30408 ChEBI "up-regulates quantity" "chemical modification" -1 27519411 t lperfetto "As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]¬∑[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry." SIGNOR-262129 NTRK2 protein Q16620 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 12074588 t gcesareni "We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction." SIGNOR-89764 DVL2 protein O14641 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 9606 17529994 t amattioni "Dix domain of dvl2 mediates dynamic polymerization, which is essential for the signaling activity of dvl2." SIGNOR-155224 CSNK2A1 protein P68400 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Ser45 LFRLSEHsSPEEEAS -1 2557337 t llicata "Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase" SIGNOR-250928 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 14633987 t lperfetto "These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction." SIGNOR-119370 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 t lperfetto "Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a." SIGNOR-244685 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 8376365 t gcesareni "Phosphorylation at either ser(16) or ser(63) strongly reduced or abolished the ability of stathmin to bind to and sequester soluble tubulin and its ability to act as a catastrophe factor by directly binding to the microtubules. The known in vivo phosphorylation sites of stathmin are ser-16 and ser-63 for cyclic amp-dependent protein kinase (pka)." SIGNOR-38318 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Ser282 FFAKRKRsAPEKSSG 9606 BTO:0000150 23421998 t lperfetto "Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination" SIGNOR-201042 MTOR protein P42345 UNIPROT EIF4E protein P06730 UNIPROT "down-regulates activity" phosphorylation 9606 35697076 t miannu "Mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates and inhibits eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1)." SIGNOR-278963 SRC protein P12931 UNIPROT CTNND2 protein Q9UQB3 UNIPROT "up-regulates activity" phosphorylation Tyr1154 QEPSRKDyETYQPFQ 9606 24412473 t miannu "Furthermore, according to our data from immunoprecipitation to py20 antibody, c-Src can phosphorylate delta-catenin on Y1073, Y1176, Y1179 and Y1112, with the predominant sites being Y1073, Y1112 and Y1176.|Interestingly, we found that c-Src can increase the stability of delta-catenin in MEF cells." SIGNOR-278326 PTGER1 protein P34995 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257083 PRKACA protein P17612 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser879 LIDRNQKsDKKPDRE 9606 BTO:0000763 22798526 t lperfetto "We showed that pkc_ phosphorylation of p120 at serine (s)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for ve-cadherin and mediated aj disassembly secondary to ve-cadherin internalization" SIGNOR-198288 CSNK2A1 protein P68400 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250831 PRKCB protein P05771 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto "Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication." SIGNOR-249049 CRYAB protein P02511 UNIPROT CRYGD protein P07320 UNIPROT "up-regulates activity" binding -1 20621668 t miannu "Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age." SIGNOR-253621 CSNK2A1 protein P68400 UNIPROT RGS19 protein P49795 UNIPROT unknown phosphorylation Ser24 ADRPPSMsSHDTASP -1 10760275 t llicata "Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles." SIGNOR-250943 CUDC-101 chemical CID:24756910 PUBCHEM HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 20143778 t miannu "By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively." SIGNOR-262265 "B-WICH complex" complex SIGNOR-C447 SIGNOR "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 25883140 t miannu "The chromatin-remodelling complex B-WICH, comprised of William syndrome transcription factor, the ATPase SNF2h and nuclear myosin, specifically activates RNA polymerase III transcription of the 5S rRNA and 7SL genes." SIGNOR-268841 NEK6 protein Q9HC98 UNIPROT FOXJ2 protein Q9P0K8 UNIPROT "up-regulates activity" phosphorylation Thr23 PQLTLRAtIEKLGSA 9606 27899381 t miannu "Additionally, we found that NEK6 phosphorylated FOXJ2 at Thr23 and Ser254 (XREF_FIG, lanes 3 and 5), and NCOA5 at Ser21 and Ser151 (XREF_FIG, lanes 3 and 4)." SIGNOR-278964 DKK1 protein O94907 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 f "Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6." gcesareni "It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass." SIGNOR-195573 AMBRA1 protein Q9C0C7 UNIPROT PPP2CB protein P62714 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 25438055 t "phosphorylation site remapping based on mass spec table" lperfetto "We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene." SIGNOR-272964 SPOP protein O43791 UNIPROT GLYR1 protein Q49A26 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations." SIGNOR-272824 CHEK1 protein O14757 UNIPROT FANCE protein Q9HB96 UNIPROT up-regulates phosphorylation Ser374 LFLGRILsLTSSASR 9606 17296736 t llicata "Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway." SIGNOR-153023 GRK5 protein P34947 UNIPROT GRK5 protein P34947 UNIPROT "up-regulates activity" phosphorylation Ser484 VLDIEQFsTVKGVNL -1 8144599 t "Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5." SIGNOR-251201 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 15829969 t lperfetto "During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 ." SIGNOR-135381 IKBKB protein O14920 UNIPROT COPS5 protein Q92905 UNIPROT "down-regulates activity" phosphorylation Ser201 KPPDEGPsEYQTIPL -1 31950832 t lperfetto "Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro." SIGNOR-275518 NEDD4L protein Q96PU5 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253458 ABL1 protein P00519 UNIPROT GPX1 protein P07203 UNIPROT "up-regulates activity" phosphorylation Tyr98 EILNSLKyVRPGGGF 9606 12893824 t lperfetto "GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress." SIGNOR-104324 MKRN1 protein Q9UHC7 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys291 TEEENLRkKGEPHHE 9606 BTO:0002552 19536131 t miannu "Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53" SIGNOR-271846 miR-27b mirna URS000075B0A5_9606 RNAcentral PPARG protein P37231 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10116 26239616 t Luana "Overexpression of miR-132 significantly reduced the expression levels of MeCP2, at both the mRNA and protein level, whereas downregulation of miR-132 increased the mRNA and protein expression levels of MeCP2" SIGNOR-264608 DDX5 protein P17844 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 17369852 t miannu "Wt p68 co-immunoprecipitates efficiently with hdac1, the k53r p68 does not / sumoylation is important for the interaction of p68 with hdac1 and for transcriptional repression by p68" SIGNOR-153715 PRKG1 protein Q13976 UNIPROT PTS protein Q03393 UNIPROT up-regulates phosphorylation Ser19 AQVSRRIsFSASHRL 9606 BTO:0000142 10531334 t gcesareni "Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps" SIGNOR-71680 perifosine chemical CHEBI:67272 ChEBI AKT1 protein P31749 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001130 14617782 t "Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation" gcesareni "Perifosine is an alkylphospholipid that targets the pleckstrin homology domain of akt and blocks its membrane translocation, hence preventing akt phosphorylation and activation" SIGNOR-252629 YY1 protein P25490 UNIPROT ATP6V1A protein P38606 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 28592880 t Giorgia "We investigated the relationship between transcription factor YY1 and ATP6V1A, and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A. To validate that YY1 transcriptionally regulates ATP6V1A, we discovered that the ATP6V1A core promoter region contains three YY1 binding sites. Moreover, RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression, while YY1 overexpression increased ATP6V1A expression level." SIGNOR-260635 IKK-complex complex SIGNOR-C14 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR down-regulates phosphorylation 9606 10195894 t lperfetto "Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response" SIGNOR-216373 pazopanib chemical CHEBI:71219 ChEBI FLT1 protein P17948 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257734 ERN1 protein O75460 UNIPROT XBP1 protein P17861-2 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 31226023 t miannu "Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity." SIGNOR-260183 SHOC2 protein Q9UQ13 UNIPROT MRAS protein O14807 UNIPROT up-regulates binding 9606 10783161 t gcesareni "Sur-8 interacts with ras and raf and is able to form a ternary complex with the two proteins. Thus, sur-8 may function as a scaffold that enhances ras-map kinase signal transduction by facilitating the interaction between ras and raf." SIGNOR-77082 CEP76 protein Q8TAP6 UNIPROT PLK1 protein P53350 UNIPROT "down-regulates activity" binding 9606 BTO:0001938 27065329 t miannu "Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification." SIGNOR-262731 ESR1 protein P03372 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253470 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9534 BTO:0000298 9482734 t lperfetto "Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin" SIGNOR-227862 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser215 RRSRAASsQRAEEED 9606 22422861 t lperfetto "Chmp4c functioned in the aurora b-dependent abscission checkpoint to prevent both premature resolution of intercellular chromosome bridges and accumulation of dna damage. Chmp4c engaged the chromosomal passenger complex (cpc) via interaction with borealin, which suggested a model whereby chmp4c inhibits abscission upon phosphorylation by aurora b" SIGNOR-196728 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu72 EEAREVFeDSDKTNE -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263673 ROS stimulus SIGNOR-ST2 SIGNOR NLRP3 protein Q96P20 UNIPROT "up-regulates activity" 28531279 f lperfetto "Different mechanisms have been proposed for NLRP3 activation, including potassium efflux, calcium influx, reactive oxygen species (ROS), oxidized mitochondrial DNA, translocation of cardiolipin from the inner mitochondrial membrane, phagosome destabilization, perturbation in cell volume and pore-formation mechanisms driven by the host or bacteria" SIGNOR-256427 MAPK14 protein Q16539 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 22933625 f apalma "The IL-10-mediated shift in macrophage phenotype in injured muscle may be amplified by activation of mitogen-activated protein kinase (MAPK), especially p38 MAPK, through signaling that is antagonized by MAPK phosphatase-1 (MKP-1)." SIGNOR-255447 CASP8 protein Q14790 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates activity" cleavage Asp324 RMQSLQLdCVAVPSS 9606 BTO:0000007;BTO:0000093;BTO:0000567 10521396 t amattioni "These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability." SIGNOR-71265 GRB10 protein Q13322 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 10090 BTO:0001516 23246379 t "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation" SIGNOR-255945 KLHL8 protein Q9P2G9 UNIPROT RAPSN protein Q13702 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0000944 19158078 t miannu "We found that rapsyn was polyubiquitinated by KLHL8-containing E3 ligase, but not by KEAP1-containing E3 ligase, clearly indicating that rapsyn is a direct substrate of KLHL8-containing E3 ligase in mammals. We next examined the effect of KLHL-8 depletion on the ubiquitination of rapsyn by performing RNAi experiments in mammalian cells. We found that knockdown of KLHL8 in 3T3 cells reduced the level of rapsyn ubiquitination (Fig. 5C), again indicating that the maintenance mechanism for rapsyn stability is conserved in mammals.The in vitro ubiquitination of mammalian rapsyn by CUL3-containing E3 ligase and the effect of KLHL8 knockdown on the ubiquitination of rapsyn." SIGNOR-271781 ETV3 protein P41162 UNIPROT DUSP6 protein Q16828 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 22028473 t miannu "ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation." SIGNOR-262780 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1167 ESAPAESsPSKIMSK 9606 8816480 t gcesareni "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1" SIGNOR-43943 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation Tyr1069 EDSFLQRySSDPTGA -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254699 MYC protein P01106 UNIPROT CUL1 protein Q13616 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12835716 t gcesareni "Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2" SIGNOR-102749 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 BTO:0001271 12835716 t lperfetto "Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2" SIGNOR-217172 SERPINC1 protein P01008 UNIPROT F9 protein P00740 UNIPROT "down-regulates activity" cleavage 31030036 t lperfetto "Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1" SIGNOR-264140 UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 21311563 t lperfetto "Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP(3)R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes" SIGNOR-171902 hsa-miR-326 mirna URS00000A939F_9606 RNAcentral SMO protein Q99835 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002035 25173582 t Parnian "These data indicated that miR-326 directly modulated SMO expression by binding to the 3′UTR." SIGNOR-277978 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG -1 11955436 t "β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)" SIGNOR-260015 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr754 KIYSGDYyRQGRIAK 9606 8702477 t gcesareni "By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain." SIGNOR-42922 FGR protein P09769 UNIPROT KCND3 protein Q9UK17 UNIPROT "up-regulates activity" phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 t miannu "These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels." SIGNOR-276394 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT "up-regulates activity" binding 9606 18923185 t miannu "IL-6 and IL-11 are the only members of the family that signal via the induction of a gp130 homodimer after binding their specific -receptors, IL-6R and IL-11R. When IL-6 binds to the homodimerized IL-6Rα/gp130Rβ, it results in a signaling cascade that is initiated by the autophoshorylation and activation of JAK." SIGNOR-255324 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR down-regulates 9606 23620016 f "In the current study, addition of ERK inhibitors suppressed IL-6-induced RORgammat expression and promoted TGF-beta-induced Foxp3 expression." SIGNOR-254686 DAPK1 protein P53355 UNIPROT TPM1 protein P09493 UNIPROT "up-regulates activity" phosphorylation Ser283 HALNDMTsI 9606 BTO:0000007 17895359 t miannu "We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling." SIGNOR-262845 RET protein P07949 UNIPROT DOK5 protein Q9P104 UNIPROT up-regulates binding 9606 11470823 t gcesareni "Dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase" SIGNOR-109516 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser72 KSERYSSsGSPANSF 9606 BTO:0000093 35513296 t miannu "Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings" SIGNOR-277906 BMX protein P51813 UNIPROT RUFY1 protein Q96T51 UNIPROT "up-regulates activity" phosphorylation Tyr389 TKVELETyKQTRQGL 9534 11877430 t miannu "Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes." SIGNOR-262678 FKBP5 protein Q13451 UNIPROT CD274 protein Q9NZQ7 UNIPROT "up-regulates quantity by expression" "catalytic activity" 9606 BTO:0002035 28978117 t Barakat "FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels" SIGNOR-274973 BTRC protein Q9Y297 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9534 BTO:0004055 10514424 t miannu "Interaction with beta-TrCP is also necessary for ubiquitination of IkappaBbeta upon stimulation of cells, and deletion of the F-box in beta-TrCP abolishes its ability to ubiquitinate IkappaBbeta. Therefore, these results indicate that beta-TrCP plays a critical role in the activation of NF-kappaB by assembling the ubiquitin ligase complex for both phosphorylated IkappaBalpha and IkappaBbeta.β-TrCP recognizes IκBα phosphorylated at Ser-32 and Ser-36 through its WD40 domain, whereas the F-box motif recruits additional proteins including Skp1 and Cullin to form the Skp1-cullin-F-box (SCF) ubiquitin ligase complex" SIGNOR-272555 HOXD10 protein P28358 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." SIGNOR-241226 GALR2 protein O43603 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256741 SAE1 protein Q9UBE0 UNIPROT "SAE1/SAE2 complex" complex SIGNOR-C294 SIGNOR "form complex" binding -1 15660128 t lperfetto "E1 enzymes facilitate conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins. Structures of human heterodimeric Sae1/Sae2-Mg.ATP and Sae1/Sae2-SUMO-1-Mg.ATP complexes were determined at 2.2 and 2.75 A resolution, respectively." SIGNOR-263003 GATAD2A protein Q86YP4 UNIPROT "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263846 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser242 NQRKAKRsLAPRFDL 9606 11152499 t tpavlidou "We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity." SIGNOR-85765 AKAP12 protein Q02952 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR "up-regulates activity" relocalization 14657015 t lperfetto "A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor." SIGNOR-271837 IRF7 protein Q92985 UNIPROT IFNA1 protein P01562 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16612387 f gcesareni "Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production." SIGNOR-146119 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT "up-regulates activity" phosphorylation Thr527 PPKAKDPtVS -1 35080342 t miannu "Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9." SIGNOR-277578 SATB1 protein Q01826 UNIPROT AREG protein P15514 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255133 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-249646 NAB2 protein Q15742 UNIPROT GFI1 protein Q99684 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 16923394 f miannu "Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene." SIGNOR-256042 PRKCG protein P05129 UNIPROT PEBP1 protein P30086 UNIPROT "up-regulates activity" phosphorylation Ser153 RGKFKVAsFRKKYEL 10116 BTO:0003036 12551925 t lperfetto "Here we report that one mechanism involves dissociation of Raf kinase inhibitory protein (RKIP) from Raf-1. Classic and atypical but not novel PKC isoforms phosphorylate RKIP at serine 153 (Ser-153). RKIP Ser-153 phosphorylation by PKC either in vitro or in response to 12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor causes release of RKIP from Raf-1, whereas mutant RKIP (S153V or S153E) remains bound. I" SIGNOR-249190 ATR protein Q13535 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser68 EELDTLAsQALSQCP 9606 15451423 t lperfetto "When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro." SIGNOR-129469 DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates 9606 26527132 f lperfetto "Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair." SIGNOR-242616 ANK2 protein Q01484 UNIPROT PPP2R5A protein Q15172 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0003324 19840192 t miannu "Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins." SIGNOR-266729 MTOR protein P42345 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "form complex" binding 9606 25628925 t lperfetto "Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)" SIGNOR-205615 GART protein P22102 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI "down-regulates quantity" "chemical modification" 9606 34283828 t miannu "In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR)." SIGNOR-267299 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates activity" phosphorylation Tyr1363 TFFTDNSy 9606 BTO:0000394 12881528 t lperfetto "Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail." SIGNOR-104092 MC4R protein P32245 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257069 GLI3 protein P10071 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "The basal expression of Gli1, Ptc1, and Hip1 was positively associated with the loss of Gli3 alleles.These findings implicate Gli3 as a repressor of Hh target gene expression." SIGNOR-209638 ATM protein Q13315 UNIPROT SP1 protein P08047 UNIPROT unknown phosphorylation Ser101 DLTATQLsQGANGWQ 9606 18619531 t llicata "Thus, phosphorylation of ser-101 on sp1 is a general response to dna damage, dependent on both atm and atr." SIGNOR-179435 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-180458 RBBP7 protein Q16576 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR "form complex" binding 9606 BTO:0000007 14609955 t miannu "hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays." SIGNOR-268815 CRP protein P02741 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates quantity by destabilization" 17942113 f miannu "C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. we found that CRP decreased the eNOS dimer/monomer ratio further supporting eNOS uncoupling." SIGNOR-252217 RNF7 protein Q9UBF6 UNIPROT DEPTOR protein Q8TB45 UNIPROT "down-regulates activity" ubiquitination 9606 23136067 t miannu "SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes." SIGNOR-271449 GRIA2 protein P42262 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 f Luana "AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by naïve ones." SIGNOR-265796 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1696 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248774 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248735 GNAI3 protein P08754 UNIPROT ADCY5 protein O95622 UNIPROT "down-regulates activity" binding 7108 BTO:0001240 8119955 t "Marta Tosoni" "Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3" SIGNOR-278076 fenoterol chemical CHEBI:149226 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1). " SIGNOR-257869 RNF19B protein Q6ZMZ0 UNIPROT UCKL1 protein Q9NWZ5 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000914 16709802 t miannu "We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and has as one of its substrates, URKL-1, thus defining this cytolytic protein as an E3 ubiquitin ligase." SIGNOR-271590 MDM2 protein Q00987 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" 9606 18292944 f amattioni "Overexpression of hdm2 resulted in a decrease in the level of p21waf1" SIGNOR-160977 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Thr345 GADSDVEtPSNFGKY 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262984 AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 t lperfetto "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." SIGNOR-244361 FBH1 protein Q8NFZ0 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding -1 25585578 t miannu "The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64." SIGNOR-272452 PIM1 protein P11309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18593906 t gcesareni "We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro." SIGNOR-179296 MAP2K2 protein P36507 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 t gcesareni "The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform." SIGNOR-179393 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser146 FYKRRGAsDLSSEEG -1 8954982 t llicata "Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149." SIGNOR-251034 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49 protein P0CI25 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271152 "Non-erythrocytic spectrin" complex SIGNOR-C385 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 f lperfetto "Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell" SIGNOR-266029 NF1 protein P21359 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 7549116 f miannu "Our results pointed to a key role that NF1 might play in the functioning of the AFP promoter. Indeed, overexpression of NF1 induced a specific decrease in the activity of the AFP promoter. Competition between NF1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter would be critical for modulating its activity." SIGNOR-254636 MAPK8 protein P45983 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 15538382 t lperfetto "Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment." SIGNOR-252964 SRC protein P12931 UNIPROT FLOT1 protein O75955 UNIPROT "up-regulates activity" phosphorylation Tyr149 MGISVVSyTLKDIHD 9606 BTO:0001583 24983503 t done miannu "Taken together, we conclude that mitochondrial c-Src phosphorylates flotillin-1 at Tyr56 and Tyr149, and that these phosphorylations are required for its interaction with CxII and the prevention of ROS production." SIGNOR-273804 JNK proteinfamily SIGNOR-PF15 SIGNOR PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation 9606 18553930 t "inferred from 70% family members" gcesareni "Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells." SIGNOR-269981 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser269 GNLLGRNsFEVRVCA 9606 20959462 t llicata "Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity." SIGNOR-168745 PRKACA protein P17612 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni "We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus." SIGNOR-97550 FBXO3 protein Q9UK99 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0004573 18809579 t miannu "O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. " SIGNOR-271744 LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 t lperfetto "Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling" SIGNOR-252598 C1QBP protein Q07021 UNIPROT C1QA protein P02745 UNIPROT "down-regulates activity" binding SIGNOR-C308 28018340 t lperfetto "Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping." SIGNOR-263402 SLC4A10 protein Q6U841 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "up-regulates quantity" relocalization 9606 26136660 t miannu "Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride" SIGNOR-264919 PRKCB protein P05771 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 8288587 t gcesareni "Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619." SIGNOR-37478 AKT1 protein P31749 UNIPROT SH2B2 protein O14492 UNIPROT "up-regulates activity" phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 t gcesareni "This study identifies APS as a novel physiological substrate for PKB and the first serine phosphorylation site on APS" SIGNOR-252557 PTPRG protein P23470 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1059 DIYKDPDyVRKGDAR -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254708 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249321 lovastatin chemical CHEBI:40303 ChEBI HMGCR protein P04035 UNIPROT "down-regulates activity" "chemical inhibition" -1 6933445 t miannu "Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent." SIGNOR-258403 USF1 protein P22415 UNIPROT B2M protein P61769 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12480693 f miannu "Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation." SIGNOR-254655 ATM protein Q13315 UNIPROT AVEN protein Q9NQS1 UNIPROT "up-regulates activity" phosphorylation Ser308 NILPDQTsQDLKSKE -1 18571408 t miannu "Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site)." SIGNOR-262637 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252746 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT "up-regulates activity" 9606 11090075 t apalma "We show that the ectopic expression of PML-RARα is sufficient to elevate levels of cyclin A1 in U937 myeloid leukemia cells and cyclin A1 is negatively regulated by the RARα pathway." SIGNOR-256373 RPS6KA1 protein Q15418 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 18722121 t lperfetto "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-217553 PTPRG protein P23470 UNIPROT SHC1 protein P29353 UNIPROT "down-regulates activity" dephosphorylation Tyr350 EPPDHQYyNDFPGKE -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254724 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 BTO:0001271 8441409 t lperfetto "Sh1 domain autophosphorylation of p210 bcr/abl is required for transformation but not growth factor independence." SIGNOR-39142 MST1 protein P26927 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates activity" phosphorylation Ser226 LNPQWNEsFTFKLKP 9606 BTO:0002181 26414765 t miannu "Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα. " SIGNOR-277179 "lysophosphatidylserine 14:0(1-)" chemical CHEBI:72402 ChEBI P2RY10 protein O00398 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257558 "Complement C1q" complex SIGNOR-C308 SIGNOR "Complement C1 complex" complex SIGNOR-C309 SIGNOR "form complex" binding -1 29449492 t lperfetto "The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases" SIGNOR-263396 RPL37 protein P61927 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262463 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR "BRCA1-C complex" complex SIGNOR-C299 SIGNOR "form complex" binding 25400280 t lperfetto "The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2" SIGNOR-263221 PRKACA protein P17612 UNIPROT ITPKA protein P23677 UNIPROT "up-regulates activity" phosphorylation Ser121 LQQPRRLsTSSVSST -1 9374536 t miannu "Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328" SIGNOR-249994 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR2 protein P30874 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257582 SETD1B protein Q9UPS6 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" methylation Lys5 kQTARKST 9606 32546566 t miannu "SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks." SIGNOR-265576 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Tyr1006 PATPLLDyALEVEKI 9606 BTO:0000007 32420483 t done miannu " We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells." SIGNOR-274107 AURKB protein Q96GD4 UNIPROT CDCA2 protein Q69YH5 UNIPROT "down-regulates activity" phosphorylation Ser542 KKINRRKsQETKCTK 9606 BTO:0000567 32938714 t done miannu "This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin." SIGNOR-274002 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Thr309 SDGATMKtFCGTPEY 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-248633 1-naphthol chemical CHEBI:10319 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258163 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273051 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR KRT8 protein P05787 UNIPROT unknown phosphorylation 16554440 t "inferred from 70% family members" lperfetto "Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002)." SIGNOR-270135 VKORC1 protein Q9BQB6 UNIPROT "Reduced Vitamin K" smallmolecule CHEBI:8784 ChEBI "up-regulates quantity" "chemical modification" 9606 31226734 t lperfetto "The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form" SIGNOR-265901 F2RL1 protein P55085 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257232 SLC9A8 protein Q9Y2E8 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265607 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR FBXL2 protein Q9UKC9 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272447 CHKA protein P35790 UNIPROT DEPTOR protein Q8TB45 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017875 t miannu "DEPTOR phosphorylation by mTOR in response to growth signals, and in collaboration with casein kinase I (CKI), generates a phosphodegron that binds Œ≤TrCP.|These data suggests that CKI overexpression may overcome a requirement for phosphorylation at the major mTOR sites in DEPTOR for formation of the degron and are consistent with our finding that CKI can phosphorylate S286 and S287 in DEPTOR in vitro in the absence of mTOR." SIGNOR-279604 TICAM2 protein Q86XR7 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 14519765 t lperfetto "Tram binds trif directly and recruits it to tlr4" SIGNOR-118367 WNT9A protein O14904 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-132070 SMARCD2 protein Q92925 UNIPROT "Muscle cell-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C483 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex." SIGNOR-270733 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 t gcesareni "Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway." SIGNOR-90529 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249009 DBP protein Q10586 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 8383844 f "inferred from family member" miannu "Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators" SIGNOR-270225 KLHL12 protein Q53G59 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 22358839 t miannu "By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division." SIGNOR-272011 LAMTOR3 protein Q9UHA4 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates binding 9606 15547943 t gcesareni "We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations." SIGNOR-130924 ITGAV protein P06756 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253205 RLIM protein Q9NVW2 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27684546 t miannu "This suggests that RLIM negatively regulates the transcriptional activity of c-Myc.|We further showed that RLIM can promote polyubiquitination of c-Myc in cells." SIGNOR-278551 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr605 KDLVSCAyQVARGME 9606 12601080 t lperfetto "Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways." SIGNOR-98634 MAPK8 protein P45983 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni "Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset." SIGNOR-164089 HOXA10 protein P31260 UNIPROT MYLK protein Q15746 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002196 15886193 t Luana "Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively" SIGNOR-261643 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 t lperfetto "We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication." SIGNOR-216690 MLNR protein O43193 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256880 MTNR1B protein P49286 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256986 MAPK9 protein P45984 UNIPROT ELK3 protein P41970 UNIPROT "down-regulates activity" phosphorylation 11042694 t miannu "JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export." SIGNOR-250138 BCOR protein Q6W2J9 UNIPROT HOXA7 protein P31268 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 26847029 f irozzo "Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation." SIGNOR-256013 VCB-Cul2 complex SIGNOR-C524 SIGNOR TNFRSF1B protein P20333 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 15899873 t miannu "While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-alpha by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation" SIGNOR-271545 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser51 LRPSTSRsLYASSPG -1 2500966 t miannu "Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure." SIGNOR-250069 KIF5B protein P33176 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 f miannu "The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue." SIGNOR-264068 MARCHF9 protein Q86YJ5 UNIPROT VAMP8 protein Q9BV40 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001522 19457934 t miannu "MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. " SIGNOR-271531 EIF3L protein Q9Y262 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266389 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser952 DSRSHQNsPTELNKD 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104691 calcium(2+) smallmolecule CHEBI:29108 ChEBI CIB2 protein O75838 UNIPROT "up-regulates activity" "chemical activation" 9606 35408910 t miannu "Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions." SIGNOR-269667 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM6B protein O15054 UNIPROT "up-regulates activity" "chemical activation" 29981745 t lperfetto "Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3." SIGNOR-273461 TP53 protein P04637 UNIPROT GADD45A protein P24522 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23576563 f gcesareni "P53 acetylated at k120 subsequently bound to the promoters of its target apoptotic genes, bax and gadd45, to promote their expression and lead to apoptosis." SIGNOR-201679 IGF1R protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni "Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively)" SIGNOR-252690 DOK1 protein Q99704 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257681 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Thr63 LSSAWPGtLRSGMVP 9606 22721717 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-197949 CFB protein P00751 UNIPROT "C3 convertase complex (C3bBb)" complex SIGNOR-C314 SIGNOR "form complex" binding 9606 BTO:0000089 cleavage:Arg259 GPGEQQKrKIVLDPS 26489954 t "complement factor B, b fragment: PRO_0000027547" lperfetto "Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over)" SIGNOR-263486 TRIM17 protein Q9Y577 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0001976 22976837 t miannu "Here, we identified Trim17 as a novel E3 ubiquitin-ligase for Mcl-1. Indeed, Trim17 co-immunoprecipitated with Mcl-1. Trim17 ubiquitinated Mcl-1 in vitro. Overexpression of Trim17 decreased the protein level of Mcl-1 in a phosphorylation- and proteasome-dependent manner. Finally, knock down of Trim17 expression reduced both ubiquitination and degradation of Mcl-1 in neurons." SIGNOR-272032 PAK4 protein O96013 UNIPROT PACSIN1 protein Q9BY11 UNIPROT "up-regulates activity" phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu "We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo." SIGNOR-263023 MAP1LC3C protein Q9BXW4 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates binding 9606 BTO:0000007 19250911 t gcesareni "We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. . downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1." SIGNOR-184258 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation 9606 18694962 t "Translocation from Nuleus to Cytoplasm" gcesareni "Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization." SIGNOR-269996 EEF1A2 protein Q05639 UNIPROT Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269522 CGAS protein Q8N884 UNIPROT 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI "up-regulates quantity" "chemical modification" 23258413 t lperfetto "Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family." SIGNOR-276593 SYK protein P43405 UNIPROT FLT3 protein P36888 UNIPROT "up-regulates activity" phosphorylation Tyr768 HSEDEIEyENQKRLE 9606 24525236 t miannu "Only two mutants, FLT3-KD (V5) Y768A and Y955A, were resistant to SYK-mediated FLT3 phosphorylation, suggesting that SYK directly phosphorylates FLT3 at sites Y768 and Y955 ( ).|SYK Enhances FLT3 WT and Mutant Activation by Phosphorylation of Residues Y768 and Y955." SIGNOR-278431 streptozocin chemical CHEBI:9288 ChEBI SLC2A2 protein P11168 UNIPROT "down-regulates quantity" "chemical inhibition" 10090 9421374 t miannu "In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells." SIGNOR-259314 PCK2 protein Q16822 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "down-regulates quantity" "chemical modification" 9606 24632615 t miannu "Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine." SIGNOR-266556 CEP135 protein Q66GS9 UNIPROT CENPJ protein Q9HC77 UNIPROT "up-regulates activity" binding 9606 23511974 t miannu "In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation." SIGNOR-269677 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0001516 14981546 t "These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation." SIGNOR-261522 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu "Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton" SIGNOR-266597 BDKRB2 protein P30411 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257344 PRKCA protein P17252 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1360 VLRSPSGsQRPSVSD 9606 15121854 t lperfetto "Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures" SIGNOR-124494 STXBP4 protein Q6ZWJ1 UNIPROT STX4 protein Q12846 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 15753124 t miannu "Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4." SIGNOR-262634 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT "down-regulates activity" phosphorylation Ser711 NPAKEPTsVSENEGI -1 11328814 t miannu "Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity" SIGNOR-262977 PRKACA protein P17612 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata "The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl." SIGNOR-17901 Ub:E2 complex SIGNOR-C497 SIGNOR RMND5B protein Q96G75 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271256 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 12172553 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-91388 POLR3K protein Q9Y2Y1 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266135 ERBB2 protein P04626 UNIPROT MBD4 protein O95243 UNIPROT "up-regulates activity" phosphorylation 9606 22964581 t miannu "Importantly, we found that overexpression of HER2 alone is sufficient to induce MED1 phosphorylation at Thr (1032), a key site that is known to be critical for its functions, whereas blockage of HER2 or its downstream MAP kinase diminishes its phosphor ylation levels in these cells." SIGNOR-279408 CLTC protein Q00610 UNIPROT "AP-3/clathrin vescicle" complex SIGNOR-C250 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260670 serotonin smallmolecule CHEBI:28790 ChEBI HTR7 protein P34969 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264289 HIPK3 protein Q9H422 UNIPROT HSF1 protein Q00613 UNIPROT "up-regulates activity" phosphorylation 9606 18793336 t miannu "We show that Yak1 directly phosphorylates Hsf1 in vitro, leading to the increase in DNA binding activity of Hsf1." SIGNOR-279054 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 12223490 t gcesareni "We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage." SIGNOR-92593 MATK protein P42679 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" phosphorylation Tyr508 YTATEGQyQQQP -1 9171348 t miannu "In vitro phosphorylation assays showed that Chk suppressed Lyn activity by phosphorylating its C-terminal negative regulatory tyrosine." SIGNOR-250177 GSK3B protein P49841 UNIPROT TSC2 protein P49815 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0003293 16959574 t lperfetto "Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation." SIGNOR-149380 CLK2 protein P49760 UNIPROT SRSF1 protein Q07955 UNIPROT "up-regulates activity" phosphorylation -1 8617202 t miannu "In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors." SIGNOR-273858 MAPK4 protein P31152 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0001109 30688659 t miannu " Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. " SIGNOR-275450 EGFR protein P00533 UNIPROT PCNA protein P12004 UNIPROT up-regulates phosphorylation Tyr211 QLTFALRyLNFFTKA 9606 BTO:0000150 17115032 t lperfetto "Here, we show that the chromatin-bound pcna protein is phosphorylated on tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of egf receptor (egfr) in the nucleus. Phosphorylation on tyr 211 by egfr stabilizes chromatin-bound pcna protein and associated functions." SIGNOR-150852 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRID1 protein Q9ULK0 UNIPROT "up-regulates activity" "chemical activation" 9606 27586965 t miannu "Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors" SIGNOR-264468 RIMS2 protein Q9UQ26 UNIPROT CACNA1D protein Q01668 UNIPROT "up-regulates activity" binding 9606 BTO:0005822 28642685 t miannu "Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells." SIGNOR-264356 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 22310283 t gcesareni "Thus, our data revealed a novel interplay between pka phosphorylation and tal1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis." SIGNOR-195987 AURKA protein O14965 UNIPROT MBD3 protein O95983 UNIPROT up-regulates phosphorylation Ser24 REEVPRRsGLSAGHR 9606 BTO:0000567 12354758 t llicata "These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3" SIGNOR-93693 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 f miannu "The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice" SIGNOR-256475 NF2 protein P35240 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "up-regulates activity" binding 9606 33058421 t miannu "The Hippo pathway tumor suppressor Merlin/NF2 is known to be regulated by phosphorylation. Here, the E3 ubiquitin ligase NEDD4L is shown to promote Hippo pathway activation via ubiquitination of Merlin." SIGNOR-263663 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR up-regulates 9606 21529719 f milica "In vertebrates, cell density information feeds into the Hpo pathway, which is transmitted, in part, through the Crumbs polarity complex. The Crumbs complex contains Angiomotin (AMOT), a protein that binds YAP/TAZ and SMAD to inhibit their nuclear activity." SIGNOR-230700 "D-ribulose 5-phosphate" smallmolecule CHEBI:17363 ChEBI "D-xylulose 5-phosphate(2-)" smallmolecule CHEBI:57737 ChEBI "up-regulates quantity" "precursor of" 9606 34775382 t miannu "The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux." SIGNOR-267063 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 9606 BTO:0000574 11739188 t lperfetto "Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology" SIGNOR-112649 SLC9A5 protein Q14940 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265604 SP3 protein Q02447 UNIPROT LORICRIN protein P23490 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12200429 f miannu "Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins." SIGNOR-254537 Fibrin complex SIGNOR-C317 SIGNOR Fibrin_clot_formation phenotype SIGNOR-PH153 SIGNOR up-regulates binding 9606 BTO:0000131 18544683 t lperfetto "A fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel.|Fibrin clots were formed as described for turbidity experiments, in which the fibrinogen, calcium, and polyP (when included) were preincubated for 15 minutes before adding thrombin." SIGNOR-263531 MAPK1 protein P28482 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 9606 15486195 t lperfetto "In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel" SIGNOR-129874 WWTR1 protein Q9GZV5 UNIPROT PAX8 protein Q06710 UNIPROT up-regulates binding 9606 BTO:0000763 19010321 t miannu "Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation." SIGNOR-182253 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 t llicata "Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo." SIGNOR-250767 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT "down-regulates activity" phosphorylation Ser54 RVKALPLsPRKRLGD 9606 SIGNOR-C83 10339564 t lperfetto "Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction." SIGNOR-67544 PTPRA protein P18433 UNIPROT PTPRA protein P18433 UNIPROT "down-regulates activity" dephosphorylation Tyr798 YIDAFSDyANFK 9606 7518772 t "Transient overexpression of c-Src together with RPTP alpha in human embryonic kidney 293 cells increased phosphorylation of Tyr789, suggesting that c-Src may phosphorylate RPTP alpha in vivo. RPTP alpha had autodephosphorylation activity in vitro. When expressed in 293 cells the level of Tyr789 phosphorylation was higher in a non-functional mutant of RPTP alpha than in wild type RPTP alpha, indicating that RPTP alpha may have autodephosphorylation activity in vivo as well.|We show that RPTP alpha, but not a mutant of RPTP alpha with a Tyr-->Phe mutation at position 789, bound to GRB2 in vitro." SIGNOR-248439 PINK1 protein Q9BXM7 UNIPROT RHOT1 protein Q8IXI2 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0000007 22078885 t miannu "PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C)." SIGNOR-272728 MAPKAPK2 protein P49137 UNIPROT BAG2 protein O95816 UNIPROT up-regulates phosphorylation Ser20 GRFCRSSsMADRSSR 9606 BTO:0000567 15271996 t lperfetto "We provided definite evidence that mapkapk2 phosphorylates bag2 at ser 20 in vitro and in vivo. These results demonstrate that bag2 is a novel component of the p38 mapk signaling pathways." SIGNOR-126953 PBXIP1 protein Q96AQ6 UNIPROT PBX2 protein P40425 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 24488098 t miannu "This protein that we have termed hematopoietic PBX-interacting protein (HPIP) is mainly localized in the cytosol and in small amounts in the nucleus. The region of PBX that interacts with HPIP includes both the homeodomain and immediate N-terminal flanking sequences. Strikingly, electrophoretic mobility shift assays revealed that HPIP inhibits the ability of PBX-HOX heterodimers to bind to target sequences. " SIGNOR-273667 LYN protein P07948 UNIPROT FCGR2B protein P31994 UNIPROT "up-regulates activity" phosphorylation Tyr292 GAENTITySLLMHPD -1 8756631 t lperfetto "Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn" SIGNOR-249380 LRRK2 protein Q5S007 UNIPROT CADPS2 protein Q86UW7 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 28647363 f gianni "This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells." SIGNOR-268928 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Ser206 ATPPTLSsTVLIVRN 9606 12815053 t lperfetto "M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1" SIGNOR-102494 "SAGA complex" complex SIGNOR-C465 SIGNOR H3-4 protein Q16695 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269630 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys66 QFETSAAkLKRKYWW 9606 BTO:0000007 23353890 t miannu "Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains." SIGNOR-272093 "PIK-75 Hydrochloride" chemical CID:45265864 PUBCHEM PRKDC protein P78527 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206214 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 12747827 t lperfetto "Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e." SIGNOR-236694 SLC12A3 protein P55017 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "up-regulates quantity" phosphorylation 21613606 t lperfetto "Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). " SIGNOR-264633 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates binding 9606 BTO:0001130 16597412 t gcesareni "Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors." SIGNOR-145677 palbociclib chemical CHEBI:85993 ChEBI CCND1 protein P24385 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189693 "L-asparagine zwitterion" smallmolecule CHEBI:58048 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "up-regulates quantity" "precursor of" 9606 24657844 t miannu "Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia." SIGNOR-267536 "Food intake" phenotype SIGNOR-PH152 SIGNOR "vitamin D" smallmolecule CHEBI:27300 ChEBI "up-regulates quantity" 9606 30080183 f lperfetto "Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin. Vitamin D can also be obtained from nutrition." SIGNOR-270565 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR IDH2 protein P48735 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr197 GTFKMVFtPKDGSGV 34929314 t lperfetto "During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome" SIGNOR-267622 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates activity" dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 t "Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)" SIGNOR-248799 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr216 KLDSGGFyITSRTQF 9606 BTO:0000150 12753909 t lperfetto "This study establishes that her2/hrg signaling selectively upregulates tyr phosphorylation of c-src at tyr-215 located within the sh2 domain, increases c-src kinase activity" SIGNOR-236246 PER2 protein O15055 UNIPROT POU2F1 protein P14859 UNIPROT "down-regulates activity" binding 9606 BTO:0001939 23836662 t miannu "This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2." SIGNOR-254148 BIRC2 protein Q13490 UNIPROT PACS2 protein Q86VP3 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 24633224 t miannu "Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay." SIGNOR-272851 MAP3K3 protein Q99759 UNIPROT WDR62 protein O43379 UNIPROT "up-regulates quantity by stabilization" binding 30566428 t lperfetto "Specifically, we demonstrate that MEKK3 interacts with WDR62 to stabilize WDR62 and regulates JNK activity in a synergic way. On the other hand, JNK activity also regulates the phosphorylation of WDR62 at T1053 in a feedback loop which facilities the recruitment of FBW7 degradation of WDR62" SIGNOR-271714 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CHEK1 protein O14757 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 19716789 t miannu " Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint." SIGNOR-271880 CDK9 protein P50750 UNIPROT ACTL6A protein O96019 UNIPROT "up-regulates activity" phosphorylation 9606 21699904 t miannu "Collectively, these results suggest that the cdk9 and Cyclin T complex more efficiently phosphorylates Baf53 in vitro." SIGNOR-279689 tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI "up-regulates quantity" "precursor of" 9606 16429158 t miannu "YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr" SIGNOR-270523 PAK1 protein Q13153 UNIPROT PGAM2 protein P15259 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser118 QVKIWRRsFDIPPPP 9606 24567357 t miannu "The ability of Pak1 to phosphorylate wild-type PGAM2 was increased after exposure of the cells to etoposide (XREF_FIG).|Bar, 20 \u00b5m. (E) Primary mouse embryonic fibroblasts at early passages were treated with 20 \u00b5M etoposide in the presence of 20 \u00b5M MG132, and cell lysates were immunoblotted with antibodies against Pak1 and phospho-Ser118 in phosphoglycerate mutase as indicated. (F) Pak1 kinase phosphorylates PGAM2 at Ser118 in vitro." SIGNOR-280237 NEK2 protein P51955 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 24695856 t lperfetto "Our data support a model in which centrosome disjunction is triggered by the hyperphosphorylation of c-nap1, a major linker component. This occurs in response to a shift in the balance of activities of the nek2?_Pp1 bi-stable switch. C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro." SIGNOR-204833 MRPL48 protein Q96GC5 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262348 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT "up-regulates activity" phosphorylation Tyr299 HKLGGGQyGEVYVGV -1 34144039 t miannu " PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2." SIGNOR-277301 WDFY3 protein Q8IZQ1 UNIPROT GABARAP protein O95166 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 24668264 t miannu "Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy." SIGNOR-266796 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 11909979 t gcesareni "Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1." SIGNOR-116252 KCND3 protein Q9UK17 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 10090 24762397 t miannu "Kv4.3 belongs to voltage activated (Kv) K+ channel, mammalian Shal-related family. It is encoded by KCND3 gene and expressed in heart, brain and smooth muscle. Transient outward K+ current (I(to)) plays a crucial role in the early phase of cardiac action potential repolarization. Kv4.3 K(+) channel is an important component of I(to). The function and expression of Kv4.3 K(+) channel decrease in variety of heart diseases, especially in heart hypertrophy/heart failure." SIGNOR-265657 MYC protein P01106 UNIPROT HNRNPA2B1 protein P22626 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20010808 t "We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2," SIGNOR-268691 PRKG1 protein Q13976 UNIPROT RYR1 protein P21817 UNIPROT unknown phosphorylation Ser2843 KKKTRKIsQSAQTYD -1 8380342 t lperfetto "Automated Edman sequence analysis of the major phosphopeptide obtained from PK-A and PK-G phosphorylation and one phosphopeptide obtained from PK-CaM phosphorylation yielded the sequence KISQTAQTYDPR (residues 2841€“2852) with serine 2843 as phosphorylation site" SIGNOR-248918 F2RL2 protein O00254 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257146 ACOT8 protein O14734 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI "down-regulates quantity" "chemical modification" 33148467 t lperfetto "The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA)." SIGNOR-271810 LYN protein P07948 UNIPROT YY1 protein P25490 UNIPROT "down-regulates activity" phosphorylation Tyr383 IHTGDRPyVCPFDGC 9606 BTO:0002181 26198631 t miannu "In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B)." SIGNOR-276928 CCNA1 protein P78396 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 15829981 f lperfetto "Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth." SIGNOR-249637 TRIM59 protein Q8IWR1 UNIPROT MACROH2A1 protein O75367 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 31488827 t miannu "Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. " SIGNOR-272931 TAB3 protein Q8N5C8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 14670075 t lperfetto "We have identified a new binding partner of the tgfbeta (transforming growth factor-beta)-activated protein kinase (tak1), termed tab.two distinct tak1 complexes are present in cells. One comprises tak1 complexed with tab1 and tab2, and the other tak1 complexed with tab1 and tab3 (tak1-binding protein-3). Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1." SIGNOR-120325 JAG1 protein P78504 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 18660822 t "Binding Calcium-dependent" gcesareni "Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch." SIGNOR-179625 GSK3B protein P49841 UNIPROT MARK2 protein Q7KZI7 UNIPROT "down-regulates activity" phosphorylation Ser212 KLDTFCGsPPYAAPE -1 18424437 t miannu "MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase." SIGNOR-276163 BUB1B protein O60566 UNIPROT CDC20 protein Q12834 UNIPROT "up-regulates activity" phosphorylation 9606 11030144 t miannu "Furthermore, BUBR1 phosphorylates p55CDC in vitro, and the phosphorylation of p55CDC by BUBR1 appears to be correlated with spindle checkpoint activation." SIGNOR-279507 SRC protein P12931 UNIPROT WWOX protein Q9NZC7 UNIPROT up-regulates phosphorylation Tyr33 TTKDGWVyYANHTEE 9606 15070730 t llicata "The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73." SIGNOR-123819 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258819 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT "down-regulates activity" phosphorylation Ser293 PAPARPRsPSQTRKG 9606 15262992 t lperfetto "Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2." SIGNOR-126859 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr310 LPNQEENyVTPIGDG BTO:0000007 12540842 t lperfetto "To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2." SIGNOR-249372 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24877152 f "Conversely, a reduced amount of IGF-1R diminished the levels of P-AKT, allowing dissociation and nuclear translocation of Smad3 and enhancement of the TGFŒ≤1 signaling pathway and fibrosis" SIGNOR-254375 phenformin chemical CHEBI:8064 ChEBI KCNJ8 protein Q15842 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000783 BTO:0001260 20188727 t lperfetto "Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1)." SIGNOR-262030 MAPKAPK2 protein P49137 UNIPROT LPCAT2 protein Q7L5N7 UNIPROT "up-regulates activity" phosphorylation Ser34 PMVPRQAsFFPPPVP 10090 BTO:0002601 20663880 t miannu "Mass spectrometry and mutagenesis analyses identified Ser34 of LPCAT2 as the phosphorylation site to enhance the catalytic activities. The experiments using inhibitors and siRNA against MAPK cascades demonstrated that LPCAT2 phosphorylation through LPS-TLR4 signaling may directly depend on MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2)." SIGNOR-263077 DUSP1 protein P28562 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates activity" dephosphorylation Ser118 AELVRTDsPNFLCSV 9606 27031422 t miannu "In a separate study, MKP-1 was shown to induce osteogenesis by dephosphorylating Ser125 on Runx2 isoform type II (37).|MKP-1 increases RUNX2 activity and downregulates MAPK, cyclin D1 in differentiated osteoblasts inducing growth arrest and mineralization." SIGNOR-277143 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR ERO1A protein Q96HE7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 27855403 t miannu "Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex" SIGNOR-272332 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells" SIGNOR-248348 "Angiotensin 1-7" protein P01019-PRO_0000420660 UNIPROT MAS1 protein P04201 UNIPROT "up-regulates activity" binding 9606 23488800 t miannu "Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7)." SIGNOR-260229 miR-155 mirna URS000062749E_9606 RNAcentral GFI1 protein Q99684 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255762 "A5/b1 integrin" complex SIGNOR-C163 SIGNOR DLL1 protein O00548 UNIPROT "up-regulates quantity by expression" 10090 25786978 f lperfetto "First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs." SIGNOR-253286 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131829 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-81129 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t "Does not bind to the ERBB1, ERBB2 and ERBB3 receptors" gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-26280 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRB2 protein P07550 UNIPROT up-regulates "chemical activation" 9606 22863277 t gcesareni "In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function." SIGNOR-198501 DDIT3 protein P35638 UNIPROT PPP1R15A protein O75807 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31226023 t miannu "ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress." SIGNOR-260173 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTPRR protein Q15256 UNIPROT "up-regulates activity" phosphorylation 11493009 t "inferred from 70% family members" lperfetto "Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL." SIGNOR-270147 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "precursor of" 9606 30193097 t miannu "√Ǭ†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).√Ǭ†" SIGNOR-266586 "sphingosine 1-phosphate(1-)" smallmolecule CHEBI:60119 ChEBI S1PR5 protein Q9H228 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257580 PLK3 protein Q9H4B4 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 18062778 t llicata "The direct phosphorylation of thr(1342) of topoisomerase iialpha by plk3 was demonstrated with an in vitro kinase assay, and overexpression of plk3 induced the phosphorylation of thr(1342) in cellular topoisomerase iialpha. it is possible that plk3 regulates the activity of topoisomerase iia by phosphorylation in a cell-cycle dependent manner. Another possibility is that plk3 regulates the activity of topoisomerase iia when the checkpoint is activated." SIGNOR-159596 CDK2 protein P24941 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 t lperfetto "Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown)." SIGNOR-87101 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis." SIGNOR-164408 entinostat chemical CHEBI:132082 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257904 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity" acetylation 9606 20851880 t gcesareni "These results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300" SIGNOR-167966 SLC2A1 protein P11166 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266038 FLT3 protein P36888 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" 10090 14981546 f "Immunoblot analysis indicated an increased level of Foxo3a phosphorylation on residue Thr32, as shown by the appearance of additional slower-migrating phospho-species immediately after induction of FLT3-ITD4 expression" SIGNOR-261523 DRD4 protein P21917 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256846 PRKCA protein P17252 UNIPROT ATP1A1 protein P05023 UNIPROT "down-regulates activity" phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 t miannu "Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit." SIGNOR-262941 CXCL8 protein P10145 UNIPROT CXCR1 protein P25024 UNIPROT up-regulates binding 9606 11350788 t gcesareni "Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades." SIGNOR-107920 ZMYND8 protein Q9ULU4 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 27477906 t lperfetto "Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported" SIGNOR-262040 PAK3 protein O75914 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser744 GLKVGVSsRINEWLT 9606 BTO:0000887;BTO:0001260 20858431 t gcesareni "We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin." SIGNOR-167980 SLC6A4 protein P31645 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000227 16789923 t miannu "The function of the serotonin transporter (SERT) is to take up and release serotonin (5-hydroxytyptamine (5-HT)) from cells and this function of SERT in the central nervous system (CNS) is well-documented; SERT is the target of selective serotonin reuptake inhibitors used in the treatment of CNS disorders, such as depression." SIGNOR-263953 INS protein P01308 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 10090 12530968 f lperfetto "The forkhead transcription factor foxo1 is regulated by insulin via akt-dependent phosphorylation and nuclear exclusion." SIGNOR-97392 CKM protein P06732 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI "up-regulates quantity" "chemical modification" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265788 TFDP1 protein Q14186 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253859 PIM1 protein P11309 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou "Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene." SIGNOR-179304 RAB38 protein P57729 UNIPROT "AP-3 complex" complex SIGNOR-C247 SIGNOR "up-regulates activity" relocalization 9606 23247405 t lperfetto "Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes." SIGNOR-260699 TGFB1 protein P01137 UNIPROT ACTA2 protein P62736 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000452 11988769 t miannu "A TGF-β1 response element that has a sequence different to that known for Smad binding has been identified in the α- SM actin promoter and seems to be essential for expression of α-SM actin in both SM cells 72 and myofibroblasts73 . How TGF-β1 activates expression of α-SM actin through this TGF-β1 control element is, as yet, unknown" SIGNOR-277681 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys673 KFDVEVLkQLLKLLP 9606 BTO:0000007 28448495 t miannu "SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J)." SIGNOR-272804 PRKAA1 protein Q13131 UNIPROT USP10 protein Q14694 UNIPROT "up-regulates activity" phosphorylation Ser76 DTLPRTPsYSISSTL 9606 BTO:0001109 26876938 t miannu "Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10. " SIGNOR-277207 PPP3CC protein P48454 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t "CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII)." SIGNOR-248508 EIF2S1 protein P05198 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR "form complex" binding 9606 32955564 t lperfetto "In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3." SIGNOR-269114 HDAC1 protein Q13547 UNIPROT KLK3 protein P07288 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 11994312 f "To define a mechanism for repression of AR function, we demonstrate that AR activity is specifically down-regulated by the histone deacetylase activity of HDAC1. Furthermore, using both mammalian two-hybrid and immunoprecipitation experiments, we show that AR and HDAC1 interact, suggestive of a direct role for down-regulation of AR activity by HDAC1. In chromatin immunoprecipitation assays, we provide evidence that AR, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, suggesting that acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity." SIGNOR-253666 PRKACA protein P17612 UNIPROT GRIK2 protein Q13002 UNIPROT "up-regulates activity" phosphorylation Ser715 FMSSRRQsVLVKSNE 9606 BTO:0000007 8094892 t miannu "GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response." SIGNOR-250315 TSHR protein P16473 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 25878058 t scontino "The primary signal transduction pathway for TSH receptor is activation of adenylate cyclase via a Gαs G protein-coupled receptor." SIGNOR-267136 EAPP protein Q56P03 UNIPROT MAOB protein P27338 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20980443 f miannu "we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), that down-regulate MAO B via MAO B core promoter, which contains Sp1 sites." SIGNOR-253867 PRKN protein O60260 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 11590439 t miannu "Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1." SIGNOR-278550 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 10660596 t gcesareni "The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling." SIGNOR-74860 MAP2K1 protein Q02750 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 12270934 t "inferred from 70% of family members" lbriganti "Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis." SIGNOR-269909 PRKD1 protein Q15139 UNIPROT NOS1 protein P29475 UNIPROT "up-regulates activity" phosphorylation Ser1417 TNRLRSEsIAFIEES 9606 24740233 t miannu "In addition, we demonstrate that protein kinase D1 activates nNOS by phosphorylating the activatory residue Ser1412, leading to increased \u00b7NO production, hence establishing a novel role of PKD in the regulation of \u00b7NO synthesis.|PKD1 phosphorylates nNOS at activatory Ser 1412 in vitro and in live cells." SIGNOR-278426 NCAPH protein Q15003 UNIPROT "Condensin I" complex SIGNOR-C341 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263906 IRX3 protein P78415 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003324 21825130 t Luana "Irx3 directly represses Cx43 transcription " SIGNOR-266044 MAPK14 protein Q16539 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" phosphorylation Thr56 FSSQPGHtPHPAASR 9606 16714293 t gcesareni "Bcl-2 phosphorylation by p38 mapkin this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, ser(87) and thr(56) as the bcl-2 residues phosphorylated by p38 mapk and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of bcl-2 protein." SIGNOR-146786 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI "up-regulates quantity" "precursor of" 9606 27487822 t miannu "In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions." SIGNOR-266266 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser195 RRSDSLLsFRLDLDL 10090 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262766 SMARCA1 protein P28370 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR "form complex" binding 9606 BTO:0000007 14609955 t miannu "hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays." SIGNOR-268818 PTK2 protein Q05397 UNIPROT ACTN1 protein P12814 UNIPROT "down-regulates activity" phosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0004055 11369769 t lperfetto "The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (fak).Tyrosine phosphorylation reduced the amount of alpha-actinin that cosedimented with actin filaments." SIGNOR-108329 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr362 SPPAEDVyDVPPPAP 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246409 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT "up-regulates activity" binding 10090 10712517 t ggiuliani "Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand." SIGNOR-255781 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 12324477 t lperfetto "Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated T cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. cd40 binds its ligand cd40l." SIGNOR-93432 PRPF4 protein O43172 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270622 MAPK3 protein P27361 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Ser623 ALDFQPSsPSPHRKP 9606 15356145 t lperfetto "Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623." SIGNOR-128731 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 1303753 t gcesareni "Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product." SIGNOR-16235 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0003725 11439327 t miannu "We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line." SIGNOR-272577 SMURF1 protein Q9HCE7 UNIPROT ANXA6 protein P08133 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272681 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 31160049 t miannu "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-277655 PSMA5 protein P28066 UNIPROT XBP1 protein P17861 UNIPROT "down-regulates quantity by destabilization" binding -1 19941857 t 1 miannu "We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination." SIGNOR-239213 TNFRSF21 protein O75509 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 32454942 f miannu "Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress." SIGNOR-263830 IFNG protein P01579 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001760 11009425 f gcesareni "In contrast, in differentiated myotubes, tnf plus interferon-gamma (ifn-gamma) signaling was required for nf-kappab-dependent down-regulation of myod and dysfunction of skeletal myofibers." SIGNOR-82467 BHLHE40 protein O14503 UNIPROT PER2 protein O15055 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 14672706 f lperfetto "Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression" SIGNOR-253717 CAMKK1 protein Q8N5S9 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10833263 t llicata "Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway." SIGNOR-252609 FGF2 protein P09038 UNIPROT HBB protein P68871 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251795 CHUK protein O15111 UNIPROT BCL3 protein P20749 UNIPROT "up-regulates activity" phosphorylation Ser454 PSPAPGGs -1 28689659 t miannu "Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. " SIGNOR-277363 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis." SIGNOR-164483 NFIB protein O00712 UNIPROT ETV5 protein P41161 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268880 MAPK8 protein P45983 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0002923 23255093 t lperfetto "Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3," SIGNOR-235704 PIM2 protein Q9P1W9 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr454 RAPIIAVtRNPQTAR 9606 24142698 t miannu "Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis" SIGNOR-267472 TRIM68 protein Q6AZZ1 UNIPROT TFG protein Q92734 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 24999993 t miannu "Our results suggest that TRIM68 degrades TFG at a point of pathway convergence in which downstream events lead to the activation of both NF-kappaB and IRF3.|TRIM68 polyubiquitinates TFG leading to its degradation via its RING domain which also plays an important role in TRIM68 negative inhibition on IFN-beta production." SIGNOR-278737 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT "up-regulates activity" phosphorylation Ser83 QHDDGRVsYPLCFIF -1 9030586 t miannu "Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82." SIGNOR-249983 TET1 protein Q8NFU7 UNIPROT SLIT2 protein O94813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27708339 t irozzo "Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9." SIGNOR-259093 CAMK2D protein Q13557 UNIPROT CAMK2D protein Q13557 UNIPROT up-regulates phosphorylation 9606 19725819 t areggio "Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels." SIGNOR-255954 beta-carboline chemical CHEBI:109895 ChEBI "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t brain lperfetto "The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005)." SIGNOR-263805 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Thr594 LHGKKNStVDCNGVV 9606 22514276 t miannu "A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues." SIGNOR-197067 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CLIP1 protein P30622 UNIPROT "up-regulates activity" phosphorylation Thr287 KIGFPSTtPAKAKAN 19687009 t lperfetto "Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression." SIGNOR-275471 SHANK3 protein Q9BYB0 UNIPROT GRIA3 protein P42263 UNIPROT "up-regulates quantity" binding 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264603 PTPN6 protein P29350 UNIPROT SYK protein P43405 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 10458769 t miannu "We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene." SIGNOR-70234 MAPK3 protein P27361 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 t gcesareni "Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis." SIGNOR-134841 PSEN1 protein P49768 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 2195779 t gcesareni "Importantly, our data show that binding of ps1 to cadherin mediates the effects of ps1 on the phosphorylation, ubiquitination, and destabilization of beta-catenin. Thus, cadherins mediate both the association of ps1 and beta-catenin and the effects of ps1 on the cellular levels of beta-catenin" SIGNOR-22837 KCNE3 protein Q9Y6H6 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 11506885 t miannu "Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height" SIGNOR-265589 AKT proteinfamily SIGNOR-PF24 SIGNOR VIM protein P08670 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser39 TTSTRTYsLGSALRP 9606 20856200 t llicata "The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis." SIGNOR-167971 GSK3B protein P49841 UNIPROT CABYR protein O75952 UNIPROT unknown phosphorylation Thr151 PATPKTTtPPSSPPP -1 15752768 t "GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated." SIGNOR-251224 DUSP5 protein Q16690 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 15713638 t fstefani "Here we demonstrate that dusp5, an inducible nuclear phosphatase, interacts specifically with erk2 via a kinase interaction motif (kim) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of dusp5 in vivo, as it inactivates erk2 but not jun n-terminal protein kinase or p38 map kinase." SIGNOR-134049 PTPRO protein Q16827 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation 9606 20564182 t miannu "Both Lyn and ZAP70 were dephosphorylated by wild-type PTPROt, but not by its catalytic site mutant.|Lyn kinase and ZAP70 are substrates of PTPROt in B-cells: Lyn inactivation by PTPROt sensitizes leukemia cells to VEGF-R inhibitor pazopanib." SIGNOR-277144 CDK6 protein Q00534 UNIPROT CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR "form complex" binding 8114739 t lperfetto "Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells." SIGNOR-273028 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163768 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 20086174 t "inferred from 70% of family members" lperfetto "We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2." SIGNOR-269944 RUNX1 protein Q01196 UNIPROT BAALC protein Q8WXS3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22493267 f miannu "We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis." SIGNOR-255077 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258010 dehydroepiandrosterone chemical CHEBI:28689 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 9489820 t "systemic lupus erythematosus" gcesareni SIGNOR-251707 FBXW7 protein Q969H0 UNIPROT MED13L protein Q71F56 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 SIGNOR-C135 23322298 t miannu "The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association." SIGNOR-266688 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Ser664 QSAFAGFsFVNPKFE 10090 BTO:0000944 11959144 t "PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex" SIGNOR-248596 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120224 EEF1A2 protein Q05639 UNIPROT Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269527 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARA protein P10276 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 19058965 t Luana "Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. " SIGNOR-258138 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1166 QKGSHQIsLDNPDYQ 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250624 FBXL18 protein Q96ME1 UNIPROT ERCC3 protein P19447 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 30762924 t miannu "These results led us to propose a model that spironolactone may trigger the phosphorylation of XPB at Ser90 by CDK7, which promotes the recognition and polyubiquitination of XPB by SCFFBXL18 for proteasomal degradation." SIGNOR-277434 ECM stimulus SIGNOR-ST20 SIGNOR "Av/b6 integrin" complex SIGNOR-C179 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259039 FAS protein P25445 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 19305384 t lperfetto "Fas/FasL, TRAIL/DR4, TRAIL/DR5 and TNF-alpha/TNFR1 are ligand/receptor pairs of the tumor necrosis factor/nerve growth factor family, which are able to induce apoptosis by trimerization of the receptor by its corresponding ligand." SIGNOR-217809 SMURF1 protein Q9HCE7 UNIPROT RABEP2 protein Q9H5N1 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272690 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAP2K1 protein Q02750 UNIPROT "down-regulates activity" phosphorylation Thr386 IGLNQPStPTHAAGV 9606 BTO:0000007 10567369 t lperfetto "An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2" SIGNOR-244561 TNKS2 protein Q9H2K2 UNIPROT RNF146 protein Q9NTX7 UNIPROT "up-regulates activity" 9606 BTO:0000007 21478859 f lperfetto "Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation." SIGNOR-263337 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodo-L-thyronine smallmolecule CHEBI:11684 ChEBI "up-regulates quantity" "small molecule catalysis" 20978344 t "inferred from family member" "The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4)" SIGNOR-270305 PYCARD protein Q9ULZ3 UNIPROT "Pyrin inflammasome" complex SIGNOR-C226 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256414 "Ionizing radiation" stimulus SIGNOR-ST16 SIGNOR ELE1-RET "fusion protein" SIGNOR-FP10 SIGNOR up-regulates 9606 23128507 f miannu "In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents" SIGNOR-251984 SRC protein P12931 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Tyr773 DTANNPLyKEATSTF 9606 BTO:0003904 11723131 t lperfetto "The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength." SIGNOR-247202 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000150 19573809 f lperfetto "However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth" SIGNOR-252704 ASB2 protein Q96Q27 UNIPROT FLNA protein P21333 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 18799729 t miannu "ASB2 is the specificity subunit of an E3 ubiquitin ligase complex and is proposed to exert its effects by regulating the turnover of specific proteins; however, no ASB2 substrates had been identified. Here, we report that ASB2 targets the actin-binding proteins filamin A and B for proteasomal degradation. " SIGNOR-271740 "PAX7/MLL1 complex" complex SIGNOR-C90 SIGNOR MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 f miannu "Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5." SIGNOR-198638 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." SIGNOR-254374 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser249 LSPIDMEsQERIKAE 9606 1846781 t lperfetto "Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity." SIGNOR-21780 DCAF7 protein P61962 UNIPROT DYRK1B protein Q9Y463 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 14593110 t miannu "Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions." SIGNOR-260631 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT "up-regulates activity" phosphorylation Ser2 sDHGDVSL 9534 BTO:0000298 11483516 t llicata "BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads." SIGNOR-250596 SESN2 protein P58004 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR "down-regulates activity" binding 10090 BTO:0002572 25457612 t "We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2" SIGNOR-253560 ATF2 protein P15336 UNIPROT SIRT4 protein Q9Y6E7 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0002572 33861966 t miannu "Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2)." SIGNOR-267831 NEDD4L protein Q96PU5 UNIPROT SPHK2 protein Q9NRA0 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 34305532 t miannu "In this study, we found that NEDD4L interacted with SphK2 to ubiquitinate SphK2 protein.|NEDD4L Mediates the Degradation of SphK2 Protein Through the Ubiquitin-Proteasomal Pathway." SIGNOR-278660 Ub:E2 complex SIGNOR-C497 SIGNOR WDR59 protein Q6PJI9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271115 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." SIGNOR-244827 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 15766588 t gcesareni "Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22." SIGNOR-134524 MAPK10 protein P53779 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t "Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons" gcesareni "Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191" SIGNOR-124005 SMARCB1 protein Q12824 UNIPROT "Muscle cell-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C483 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex." SIGNOR-270737 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR "glutamic acid" smallmolecule CHEBI:18237 ChEBI "down-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270381 GRIK4 protein Q16099 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264945 CDK1 protein P06493 UNIPROT RECQL4 protein O94761 UNIPROT "up-regulates activity" phosphorylation Ser251 EVSIRVGsPQPSSSG 9606 BTO:0002181 29229926 t miannu " During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs." SIGNOR-277375 GLS protein O94925 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "down-regulates quantity" "chemical modification" 9606 22049910 t miannu "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-260000 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Ser76 ISNKDQHsISYTLSR -1 19264966 t miannu "The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites." SIGNOR-276134 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation 22848740 t "When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form." SIGNOR-255755 TRAF2 protein Q12933 UNIPROT UBE2N protein P61088 UNIPROT "up-regulates activity" binding 9606 BTO:0000459 18635759 t lperfetto "Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades." SIGNOR-179479 "BMS 794833" chemical CID:44155856 PUBCHEM KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190419 NXPH1 protein P58417 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 t gcesareni "Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1" SIGNOR-62775 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser660 FSAERRNsILTETLH -1 1377674 t miannu "CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795." SIGNOR-250349 CNKSR2 protein Q8WXI2 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 14597674 t gcesareni "We show cnk2 interacts with raf. cnk2 interacts with the gef domain of rlf and with both the regulatory and catalytic domains of raf. The raf interaction was also mapped to the carboxyl-terminal half of cnk2. Overexpression of cnk2 results in inhibition of the mapk signaling pathway." SIGNOR-119039 MAFA protein Q8NHW3 UNIPROT SLC2A2 protein P11168 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17149590 f miannu "the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA." SIGNOR-254565 calcium(2+) smallmolecule CHEBI:29108 ChEBI KCNMA1 protein Q12791 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 31152168 t miannu "The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway)" SIGNOR-269192 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1721 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248823 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr1021 PNEGDNDyIIPLPDP -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248417 OGG1 protein O15527 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275715 GH1 protein P01241 UNIPROT GHR protein P10912 UNIPROT "up-regulates activity" binding 9606 7862673 t miannu "Although growth hormone (GH) receptors (GHRs) in many species bind human (h) GH as well as their own GH, the hGHR only binds primate GH." SIGNOR-255451 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21881539 f lperfetto "Concomitant attenuation of NR1D1 downregulation (-2.4-fold compared with -4.1-fold in placebo; P=0.04), a transcriptional repressor of ARNTL, supported the view that ramipril might modulate glucose homeostasis pathways involving the NR1D1 ARNTL axis." SIGNOR-253719 Enolase proteinfamily SIGNOR-PF74 SIGNOR 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI "down-regulates quantity" "chemical modification" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266531 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT "down-regulates activity" phosphorylation Ser21 AFIAARGsFDGSSSQ -1 1527025 t "The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase." SIGNOR-251186 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" phosphorylation Thr155 DSTPPPGtRVRAMAI -1 12628923 t llicata "CK2 phosphoryl ates Thr155, which targets p53 to degradation by the Ub system." SIGNOR-250968 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI ADCY10 protein Q96PN6 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 31827278 t miannu "In these cells, trafficking of V-ATPase to the plasma membrane has been shown to be mediated by activation of bicarbonate-dependent soluble adenylate cyclase (sAC), which increases cAMP levels, thereby activating protein kinase A (PKA)" SIGNOR-277762 SRC protein P12931 UNIPROT LMNA protein P02545 UNIPROT "up-regulates activity" phosphorylation Tyr45 LNDRLAVyIDRVRSL 9606 34385357 t miannu "In this study, we found that the constitutively active Src Y527F mutant caused the disassembly of lamin A/C. We demonstrate that Src directly phosphorylates lamin A mainly at Tyr45 both in vitro and in intact cells." SIGNOR-279288 ADRA2B protein P18089 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256857 FCRL3 protein Q96P31 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" binding -1 12051764 t miannu "Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2." SIGNOR-274011 GSK3B protein P49841 UNIPROT NIFK protein Q9BYG3 UNIPROT "up-regulates activity" phosphorylation Thr234 TVDSQGPtPVCTPTF -1 16244663 t miannu "The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1." SIGNOR-262698 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" phosphorylation Ser49 HKAELQGsDEDEHVR -1 9461343 t llicata "Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. " SIGNOR-251017 UBE4B protein O95155 UNIPROT ATXN3 protein P54252 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 14749733 t miannu "Mammalian E4B (UFD2a), a ubiquitin chain assembly factor (E4), copurified with the polyubiquitylation activity for ataxin-3. E4B interacted with, and thereby mediated polyubiquitylation of, ataxin-3.  Collectively, these data suggest that E4B promotes the degradation of ataxin-3, and that this effect surmounts the stabilization of ataxin-3 conferred by expansion of the polyglutamine tract." SIGNOR-271502 MARCHF1 protein Q8TCQ1 UNIPROT INSR protein P06213 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27577745 t miannu "MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation." SIGNOR-278819 TBX22 protein Q9Y458 UNIPROT MSX2 protein P35548 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9031 BTO:0005956 20033915 t miannu "the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22." SIGNOR-265567 CSNK2A1 protein P68400 UNIPROT MECOM protein Q03112 UNIPROT "up-regulates activity" phosphorylation Ser1037 IGNSNHGsQSPRNVE 23858473 t "phosphorylation site remapping based on Fig 5" lperfetto "We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation." SIGNOR-273427 PPAT protein Q06203 UNIPROT "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI "down-regulates quantity" "chemical modification" 9606 9914248 t miannu "Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine." SIGNOR-267293 PRKCD protein Q05655 UNIPROT TUT1 protein Q9H6E5 UNIPROT "up-regulates activity" phosphorylation 9606 22244330 t miannu "PKCdelta associates with and directly phosphorylates Star-PAP." SIGNOR-279385 AMPK complex SIGNOR-C15 SIGNOR WDR45 protein Q9Y484 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001938 28561066 t miannu "WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes." SIGNOR-268480 PTPN11 protein Q06124 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t "Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling." SIGNOR-252094 IFNA1 protein P01562 UNIPROT "ISGF3 complex" complex SIGNOR-C124 SIGNOR "up-regulates quantity by stabilization" 9606 22171011 f 2 miannu "IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9." SIGNOR-240610 methotrexate chemical CHEBI:44185 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0004254 23581023 t miannu "Methotrexate, a structural analogue of folic acid, is one of the most frequently used chemotherapeutics, especially in haematological malignancies, various solid tumours and also inflammatory disorders. Methotrexate interferes with folate metabolism, mainly by inhibition of dihydrofolate reductase, resulting in the suppression of purine and pyrimidine precursor synthesis." SIGNOR-258481 MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000222 21902831 t lperfetto "TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner." SIGNOR-236093 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0002181 SIGNOR-C3 10942774 t lperfetto "PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1." SIGNOR-226714 PCSK2 protein P16519 UNIPROT "Neurophysin 1" protein P01178-PRO_0000020496 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0001073 11690596 t miannu "Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension." SIGNOR-270337 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120220 "HIF-1 complex" complex SIGNOR-C418 SIGNOR BNIP3 protein Q12983 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27692180 t miannu "HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID." SIGNOR-267454 6 protein P0DTC6 UNIPROT KPNA2 protein P52292 UNIPROT "down-regulates activity" binding 9606 32979938 t miannu "The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F)." SIGNOR-262513 ORF6 protein Q19QW5 UNIPROT KPNA2 protein P52292 UNIPROT "down-regulates activity" relocalization 9534 17596301 t lperfetto "Taken together, these data support a direct interaction between KPNA2 and ORF6 in the context of virus infection.|SARS-CoV, but not SARSdeltaORF6, retains KPNA2 at the ER/Golgi membrane." SIGNOR-260272 HOPX protein Q9BPY8 UNIPROT LORICRIN protein P23490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 21256618 f miannu "In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation." SIGNOR-254464 HOXB8 protein P17481 UNIPROT ACTA2 protein P62736 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002196 15886193 t Luana "Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively" SIGNOR-261641 PRKCD protein Q05655 UNIPROT CHAT protein P28329 UNIPROT "up-regulates quantity" phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000930 15381704 t lperfetto "Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity." SIGNOR-249272 DAB2IP protein Q5VWQ8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" binding 9606 27858941 t miannu "DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit." SIGNOR-254751 GBE1 protein Q04446 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI "up-regulates quantity" "chemical modification" 9606 26199317 t miannu "Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating Œ±-1,6-glucosidic branches from Œ±-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains" SIGNOR-267942 RFFL protein Q8WZ73 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 18450452 t miannu "We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation." SIGNOR-271482 ZNF692 protein Q9BU19 UNIPROT PCK1 protein P35558 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17097062 f gcesareni "In this study, we demonstrate that a newly identified transcription factor, arebp, is a novel target of ampk. Arebps function is to repress transcription of the pepck gene upon phosphorylation by ampk." SIGNOR-150556 AMPD1 protein P23109 UNIPROT water smallmolecule CHEBI:15377 ChEBI "down-regulates quantity" "chemical modification" 9606 26321268 t miannu "AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia." SIGNOR-280481 ORC5 protein O43913 UNIPROT ORC complex SIGNOR-C419 SIGNOR "form complex" binding 9606 32808929 t lperfetto "The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA" SIGNOR-267563 "D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:61527 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "precursor of" 9606 21310273 t miannu "GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans" SIGNOR-267813 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT "up-regulates activity" phosphorylation Ser732 EAINEAIsVKQEVTD 9606 BTO:0002181 34216621 t miannu " Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction. " SIGNOR-277323 TGIF1 protein Q15583 UNIPROT WWP1 protein Q9H0M0 UNIPROT up-regulates binding 9606 15359284 t gcesareni "We demonstrate that tiul1 degrades not only the activated type i receptor in association with smad7 but also smad2 in association with tgif.the steady-state levels of tgif are not affected by tiul1, but the interaction of tiul1 with tgif allows this ubiquitin ligase to target smad2 for degradation." SIGNOR-128854 TWIST1 protein Q15672 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 21931630 f miannu "Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2." SIGNOR-255593 PMPCB protein O75439 UNIPROT PINK1 protein Q9BXM7 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0000007 22354088 t miannu "Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy." SIGNOR-261363 EEF1A1 protein P68104 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269513 ATM protein Q13315 UNIPROT AATF protein Q9NY61 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser189 EGDDAEDsQGESEED 9606 BTO:0001109 17157788 t lperfetto "The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. |DNA damage stabilizes Che-1 protein|In addition, substitution of Che-1 Ser187 with an alanine (Che-1S187A) prevented Che-1 phosphorylation by ATM (Figure 2F), supporting this residue as an ATM-target site." SIGNOR-264415 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser113 SPAPPAIsPIIKNAI 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262765 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT "up-regulates activity" phosphorylation Tyr193 EDEESEDyQNSASIH 10090 BTO:0001930 14722116 t miannu "Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases." SIGNOR-273575 GDNF protein P39905 UNIPROT ID3 protein Q02535 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252181 CDK5 protein Q00535 UNIPROT DNM1 protein Q05193 UNIPROT "up-regulates activity" phosphorylation Ser774 SVPAGRRsPTSSPTP -1 12855954 t llicata "Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE. " SIGNOR-250661 TWIST1 protein Q15672 UNIPROT MYB protein P10242 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255529 CNR2 protein P34972 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256700 MIPOL1 protein Q8TD10 UNIPROT RHOB protein P62745 UNIPROT "up-regulates activity" binding 9606 31609475 t miannu "MIPOL1 protein interacts with tumor suppressor RhoB and enhances its cellular activity" SIGNOR-261134 CALM1 protein P0DP23 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t gcesareni "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-114101 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249394 ARHGAP15 protein Q53QZ3 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260470 COL1A1 protein P02452 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "up-regulates activity" binding 35267698 t lperfetto "Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]." SIGNOR-272346 GRM6 protein O15303 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 20055706 t miannu "MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits." SIGNOR-264084 MAPDA protein Q6DHV7 UNIPROT N(6)-methyl-AMP(2-) smallmolecule CHEBI:144842 ChEBI "down-regulates quantity" "chemical modification" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. " SIGNOR-280495 FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000848 9006895 t gcesareni "Sek-1 binds directly and specifically to the actin-binding protein abp-280. As a consequence, active sek-1 is capable of phosphorylating and activating in vitro added bacterial recombinant sapk." SIGNOR-45887 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP2K4 protein P45985 UNIPROT down-regulates phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0000007 11707464 t lperfetto "Akt phosphorylated sek1 on serine 78." SIGNOR-244285 DAB2 protein P98082 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "up-regulates activity" binding 9606 27858941 t miannu "In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation." SIGNOR-254744 P2RY10 protein O00398 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256726 APC2 protein O95996 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 9601641 t acerquone "Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells." SIGNOR-57673 TGFA protein P01135 UNIPROT NKD2 protein Q969F2 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 18757723 t miannu "Here, we show that Naked2 is a short-lived protein with a half-life of 60 min caused by its rapid ubiquitin-mediated proteasomal degradation. Overexpression of TGF-alpha stabilizes Naked2 protein in an EGF receptor (EGFR)-independent manner; a physical interaction between the cytoplasmic tail of TGF-alpha and Naked2 is necessary and sufficient for this protection. We have identified a RING finger protein, AO7/RNF25, as a ubiquitin ligase for Naked2, and we have shown that overexpression of TGF-alpha reduces binding of AO7 to Naked2." SIGNOR-271739 THR proteinfamily SIGNOR-PF84 SIGNOR RARA protein P10276 UNIPROT up-regulates binding 9606 15650024 t "inferred from family member" gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-270313 tolbutamide chemical CHEBI:27999 ChEBI CFTR protein P13569 UNIPROT "down-regulates activity" "chemical inhibition" 10090 1281220 t miannu "The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively." SIGNOR-258345 MAPDA protein Q6DHV7 UNIPROT water smallmolecule CHEBI:15377 ChEBI "down-regulates quantity" "chemical modification" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. " SIGNOR-280496 MAPDA protein Q6DHV7 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" "chemical modification" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. " SIGNOR-280497 N(6)-methyl-AMP(2-) smallmolecule CHEBI:144842 ChEBI methylammonium smallmolecule CHEBI:59338 ChEBI "up-regulates quantity" "precursor of" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. " SIGNOR-280500 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PKM protein P14618 UNIPROT "down-regulates activity" phosphorylation Ser37 MCRLDIDsPPITARN 9606 28607489 t miannu "We show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity, which was not further affected by pre-incubation with cyclin D3-CDK6 (Extended Data Fig. 3a, b)." SIGNOR-276454 PFDN6 protein O15212 UNIPROT "URI1 prefoldin co-chaperone" complex SIGNOR-C514 SIGNOR "form complex" binding 9606 30484151 t miannu "In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR95" SIGNOR-270918 TNF protein P01375 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates activity" 9606 9204951 f miannu "The de novo synthesis of 6-BH4 depends on the induction of GTP-CH-1, e.g., by tumor necrosis factor-alpha (TNF alpha)." SIGNOR-252210 FBXO21 protein O94952 UNIPROT EID1 protein Q9Y6B2 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 26085330 t miannu "SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO)" SIGNOR-272429 MAPK1 protein P28482 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 18694962 t "Translocation from Nuleus to Cytoplasm" gcesareni "Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization." SIGNOR-179959 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 11483655 t lperfetto "We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases" SIGNOR-247176 NFY complex SIGNOR-C1 SIGNOR ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18025157 f "We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein." SIGNOR-255746 DHRS9 protein Q9BPW9 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "down-regulates quantity" "chemical modification" 9606 21621639 t lperfetto "Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10" SIGNOR-265116 PPBP protein P02775 UNIPROT OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258412 PPARGC1A protein Q9UBK2 UNIPROT COX4I1 protein P13073 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000443 23021218 f lperfetto "PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b)." SIGNOR-253098 "dasatinib (anhydrous)" chemical CHEBI:49375 ChEBI ABL1 protein P00519 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258063 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT "down-regulates activity" dephosphorylation Ser1137 KRLRPEDsFMSVYPM 9606 BTO:0000567 15737063 t lperfetto "Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase" SIGNOR-275534 DTX1 protein Q86Y01 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16554461 f gcesareni "Notch1-induced erbb2 expression in cerebellar astroglia occurs via dtx1" SIGNOR-145319 MAPDA protein Q6DHV7 UNIPROT water smallmolecule CHEBI:15377 ChEBI "down-regulates quantity" "chemical modification" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. " SIGNOR-280502 MAPDA protein Q6DHV7 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" "chemical modification" 9606 29884623 t miannu "We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. " SIGNOR-280503 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24024136 t irozzo "In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs)." SIGNOR-256276 EPHB1 protein P54762 UNIPROT CASKIN1 protein Q8WXD9 UNIPROT "up-regulates activity" phosphorylation Tyr336 TGNDRVGyFPSSLGE 9534 23181695 t miannu "EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation." SIGNOR-262861 FBXO25 protein Q8TCJ0 UNIPROT ELK1 protein P19419 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23940030 t miannu "The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1 protein. FBXO25 is one of the 69 known human F-box proteins that serve as specificity factors for a family of ubiquitin ligases composed of SKP1, Rbx1, Cullin1, and F-box protein (SCF1) that are involved in targeting proteins for degradation across the ubiquitin proteasome system. FBXO25 interacted with and mediated the ubiquitination and proteasomal degradation of ELK-1 in HEK293T cells." SIGNOR-272127 KLF1 protein Q13351 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0000725 28026072 f irozzo "Activation of KLF1 at day 10 of the differentiation process when hematopoietic progenitor cells were present, enhanced erythroid commitment and differentiation." SIGNOR-256086 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser768 DEAYVMAsVDNPHVC 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250625 PIN1 protein Q13526 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates quantity by destabilization" binding 9606 16699525 t lperfetto "Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication." SIGNOR-252256 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193630 PTPRG protein P23470 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" dephosphorylation Tyr694 LAKAVDGyVKPQIKQ -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254730 COMMD5 protein Q9GZQ3 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" 9606 30021164 f miannu "We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling.We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling. However, the dynamics of Rho GTPase activities are highly complex and tightly regulated in order to achieve their specific subcellular localization (Marjoram et al., 2014); thus, the mechanism by which COMMD5 directly or indirectly regulates the activity of RhoA needs to be investigated further." SIGNOR-261690 EPHA3 protein P29320 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 BTO:0000938 9632142 t gcesareni "We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation." SIGNOR-58139 GSK690693 chemical CHEBI:90677 ChEBI AKT1 protein P31749 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258118 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT "down-regulates activity" phosphorylation Ser423 QMVNGAHsASTLDEA 9606 19393267 t lperfetto "Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1." SIGNOR-185580 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser399 DNITLPPsQPSPTGG 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249667 DLX5 protein P56178 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 19497851 t gcesareni "Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian cells" SIGNOR-241914 N protein P59595 UNIPROT FOSB protein P53539 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 14623261 t Luana "The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well" SIGNOR-260728 CBL protein P22681 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 20332299 t lperfetto "Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface." SIGNOR-30794 PTGS2 protein P35354 UNIPROT "prostaglandin D2" smallmolecule CHEBI:15555 ChEBI up-regulates "chemical modification" 9606 11751058 t gcesareni "Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2" SIGNOR-113282 AMPK complex SIGNOR-C15 SIGNOR KPNA2 protein P52292 UNIPROT up-regulates phosphorylation Ser105 QAARKLLsREKQPPI 9606 15342649 t lperfetto "Ampk phosphorylated importin alpha1 on ser(105). Accordingly, expression of importin alpha1 proteins bearing k22r or s105a mutations failed to mediate the nuclear import of hur in intact cells. Our results point to importin alpha1 as a critical downstream target of ampk and key mediator of ampk-triggered hur nuclear import." SIGNOR-216449 PRKACA protein P17612 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262750 PCSK7 protein Q16549 UNIPROT RELA protein Q04206 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 f lperfetto "Treatment with sb203580 significantly reduced this cooperation, consistent with the idea that p38 indirectly stimulates the transactivating activity of p65 through a mechanism involving cbp." SIGNOR-235734 NEK1 protein Q96PY6 UNIPROT ME1 protein P48163 UNIPROT "down-regulates activity" phosphorylation Ser336 KKIWLVDsKGLIVKG 31735643 t lperfetto "PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation." SIGNOR-275570 "C5 convertase complex" complex SIGNOR-C312 SIGNOR C5 protein P01031 UNIPROT "up-regulates activity" cleavage Arg677 KEILRPRrTLQKKIE 31331124 t lperfetto "Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b" SIGNOR-263452 WWTR1 protein Q9GZV5 UNIPROT TTF1 protein Q15361 UNIPROT up-regulates binding 9606 BTO:0000763 19010321 t miannu "Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation." SIGNOR-182296 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" phosphorylation Thr187 CDIQTHMtNNKGSAA -1 20538596 t lperfetto "Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation." SIGNOR-227540 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f irozzo "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins." SIGNOR-255851 Ub:E2 complex SIGNOR-C497 SIGNOR RNF223 protein E7ERA6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271259 sabcomeline chemical CHEBI:134846 ChEBI CHRM2 protein P08172 UNIPROT "up-regulates activity" "chemical activation" 10116 9399977 t miannu "SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes" SIGNOR-258674 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser756 HSCLEQAs 9606 10195894 t "Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response." SIGNOR-251284 DYRK3 protein O43781 UNIPROT AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 23415227 t miannu "Thus, DYRK3 directly phosphorylates PRAS40 at Thr246, a phosphorylation site responsible for regulation of PRAS40, resulting in decreased binding of PRAS40 to mTORC1, allowing activation of mTORC1 signaling in unstressed cells and reactivation of mTORC1 during stress recovery.Finally, we studied the dynamics of how DYRK3 couples SG partitioning with mTORC1 regulation." SIGNOR-279167 SRC protein P12931 UNIPROT RASA1 protein P20936 UNIPROT down-regulates phosphorylation 9606 11389730 t lperfetto "The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity" SIGNOR-86008 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249362 HOXA9 protein P31269 UNIPROT MYCN protein P04198 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5." SIGNOR-254213 SLBP protein Q14493 UNIPROT H2AC11 protein P0C0S8 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265403 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 25624485 t "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity." gcesareni "Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts" SIGNOR-141647 RNF8 protein O76064 UNIPROT ACD protein Q96AP0 UNIPROT "up-regulates quantity by stabilization" polyubiquitination Lys147 QDLDVQKkLYDCLEE 9606 22101936 t miannu "The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres." SIGNOR-272722 PRKACA protein P17612 UNIPROT PTPRR protein Q15256 UNIPROT "down-regulates activity" phosphorylation Ser339 GLQERRGsNVSLTLD 9534 10601328 t miannu "The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue. treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.‚ " SIGNOR-250038 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 19153083 t gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-183480 PLK1 protein P53350 UNIPROT KIF4A protein O95239 UNIPROT "down-regulates activity" phosphorylation 9606 28817632 t miannu "Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome." SIGNOR-280069 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 39534872 t miannu "NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Heme oxygenase 1 (HMOX1, also known as HO-1), an NFE2L2-dependent inducible enzyme, plays a crucial role in the degradation of heme, a pro-oxidant, into three biologically active products: biliverdin, free iron, and carbon monoxide" SIGNOR-279861 NFE2L2 protein Q16236 UNIPROT MT1G protein P13640 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 39534872 t miannu "NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. The expression of MT1G during ferroptosis is regulated by the NFE2L2 signaling pathway. In the context of cancer, particularly HCC, the upregulation of MT1G has been linked to resistance against sorafenib, a kinase inhibitor commonly used in cancer therapy" SIGNOR-279866 NFE2L2 protein Q16236 UNIPROT GSS protein P48637 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 39534872 t miannu "NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy" SIGNOR-279870 AR protein P10275 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24493753 t miannu "In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression." SIGNOR-253466 ANAPC7 protein Q9UJX3 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252007 F2RL1 protein P55085 UNIPROT RARG protein P13631 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254858 PTPRJ protein Q12913 UNIPROT LAT protein O43561 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11259588 t flangone "We propose that cd148 negatively regulates tcr signaling by interfering with the phosphorylation and function of plcgamma1 and lat" SIGNOR-105787 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-252995 AKT2 protein P31751 UNIPROT PCBP1 protein Q15365 UNIPROT "down-regulates activity" phosphorylation Ser43 VKRIREEsGARINIS 10090 BTO:0004183 20154680 t miannu "We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs." SIGNOR-262625 BTG2 protein P78543 UNIPROT HOXB9 protein P17482 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10617598 t miannu "The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation." SIGNOR-220987 ZBP1 protein Q9H171 UNIPROT RIPK3 protein Q9Y572 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 32200799 t gianni "ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis." SIGNOR-266430 SP1 protein P08047 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11013220 f irozzo "In this system, the basal transcription level from the p15Ink4B promoter was increased with increasing levels of Sp1, and Sp1 was required for transcriptional induction by Smads. Finally, inactivation of the Sp1 binding sites in the p15Ink4B promoter decreased the basal transcription level and TGF-β responsiveness." SIGNOR-256289 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 17251915 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp" SIGNOR-152814 "CID 132010322" chemical CID:132010322 PUBCHEM BRD4 protein O60885 UNIPROT "down-regulates activity" "chemical inhibition" 9606 31969702 t Monia "ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4" SIGNOR-261102 SNAI2 protein O43623 UNIPROT CXCR4 protein P61073 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 22074556 f miannu "We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells." SIGNOR-255171 FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14592841 f "Thus, induction of C/EBPα and PU.1 expression is inhibited in 32D cells due to the expression of FLT3/ITD" SIGNOR-261529 CSF1 protein P09603 UNIPROT CSF1R protein P07333 UNIPROT "up-regulates activity" binding 9606 BTO:0000876 BTO:0001103 24890514 t apalma "The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34)" SIGNOR-255568 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys636 EITFLDAkKSLNLNI 9606 BTO:0000007 28448495 t miannu "SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J)." SIGNOR-272802 NR2E3 protein Q9Y5X4 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22174013 t Luana "NR2E3 directly regulates expression of ESR1 | Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes." SIGNOR-266207 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIA4 protein P48058 UNIPROT "up-regulates activity" "chemical activation" 9606 30825796 t miannu "In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses" SIGNOR-264611 VAMP2 protein P63027 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR "form complex" binding 9606 30267828 t miannu "The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells." SIGNOR-263966 17beta-estradiol smallmolecule CHEBI:16469 ChEBI MAPK15 protein Q8TD08 UNIPROT up-regulates "chemical activation" 9606 BTO:0000150 11043579 t gcesareni "Estrogen rapidly activates the mitogen-activated protein kinases, erk-1 and erk-2, via an as yet unknown mechanism." SIGNOR-83277 TSPAN7 protein P41732 UNIPROT DRD2 protein P14416 UNIPROT "down-regulates quantity" binding 9606 BTO:0000007 28223337 t miannu "Tetraspanin-7 (TSPAN7) is expressed to variable degrees in different tissues, with the highest level in the brain, and multiple mutations in TSPAN7 have been implicated in intellectual disability. Our results showed that TSPAN7 was associated with DRD2 and reduced its surface expression by enhancing DRD2 internalization.Finally, TSPAN7 negatively affects DRD2-mediated signaling." SIGNOR-265557 HDAC6 protein Q9UBN7 UNIPROT SRSF2 protein Q01130 UNIPROT up-regulates deacetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 t miannu "Our data support a model in which hdac6 has a key role in the maintenance of srsf2 protein level by inhibiting tip60_mediated acetylation and proteasomal degradation." SIGNOR-170590 PCDHA5 protein Q9Y5H7 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-265669 sirolimus chemical CHEBI:9168 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR down-regulates "chemical inhibition" -1 17350953 t lperfetto "Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kDa FK506- and rapamycin-binding protein (FKBP12, or FKBP) and the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR) kinase. The resulting ternary complex has been used to conditionally perturb protein function, and one such method involves perturbation of a protein of interest through its mislocalization." SIGNOR-219385 "Nucleosome_H2A.Z.2 variant" complex SIGNOR-C323 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto "All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage." SIGNOR-273456 L-thyroxine smallmolecule CHEBI:18332 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR "up-regulates activity" "chemical activation" 10116 BTO:0000759 2158622 t "inferred from family member" miannu "We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts." SIGNOR-267808 AMPK complex SIGNOR-C15 SIGNOR PIKFYVE protein Q9Y2I7 UNIPROT "up-regulates activity" phosphorylation Ser307 PARNRSAsITNLSLD -1 23905686 t miannu "AMPK phosphorylated PIKfyve at Ser307 both in vitro and in intact cells. We propose that PIKfyve activity is required for the stimulation of skeletal muscle glucose uptake by contraction/AMPK activation. PIKfyve is a new AMPK substrate whose phosphorylation at Ser307 could promote PIKfyve translocation to endosomes for PtdIns(3,5)P2 synthesis to facilitate GLUT4 (glucose transporter 4) translocation." SIGNOR-263031 AKT1 protein P31749 UNIPROT ALYREF protein Q86V81 UNIPROT up-regulates phosphorylation Thr219 GGGTRRGtRGGARGR 9606 18562279 t llicata "Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export." SIGNOR-252518 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser251 PLSPFPVsPLAGPGS 9606 10330152 t lperfetto "The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a)." SIGNOR-67528 aminoglutethimide chemical CHEBI:2654 ChEBI CYP19A1 protein P11511 UNIPROT "down-regulates activity" "chemical inhibition" -1 19470632 t Luana " A new naturally occurring relatively common alteration of enzyme structure at T201M increases enzyme activity and reduces the inhibitory effect of aminoglutethimide." SIGNOR-257824 DRD1 protein P21728 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256796 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." SIGNOR-256190 VEPH1 protein Q14D04 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 23989952 f "or inhibits the Hippo pathway to activate Yki" lperfetto "A double positive-feedback loop between melt and yki, wherein yki acti- vates melt expression, and melt promotes yki" SIGNOR-202540 CCL4 protein P13236 UNIPROT CCR5 protein P51681 UNIPROT "up-regulates activity" binding 10090 20219869 t areggio "The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. " SIGNOR-255116 FANCB protein Q8NB91 UNIPROT "Fanconi anemia core complex" complex SIGNOR-C300 SIGNOR "form complex" binding 9606 BTO:0000567 17396147 t lperfetto "This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo " SIGNOR-263241 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-252342 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249003 ERCC2 protein P18074 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR "form complex" binding 9606 30860024 t lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits" SIGNOR-269312 CUDC-101 chemical CID:24756910 PUBCHEM EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 20143778 t miannu "By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively." SIGNOR-262254 CBL protein P22681 UNIPROT CFLAR protein O15519 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 phosphorylation:Ser2;Tyr182 sAEVIHQV;VQGAGTSyRNVLQAA 19597496 t "CFLAR has to be phosphorylated on Tyr211 and Ser4 by c-Abl and p38, respectively. This phosphorylation facilitated specific interaction between FLIPS and the ubiquitin E3 ligase c-Cbl" gcesareni "We therefore conclude that c-cbl is a e3 ubiquitin ligase for flips and that the interaction of flips with c-cbl requires phosphorylation of both ser4 and tyr211 of flips.This interaction triggered proteasomal degradation of FLIP(S), which promoted activation of caspase-8 and apoptosis." SIGNOR-186998 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 BTO:0000567 17615152 t lperfetto "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo." SIGNOR-244655 PAK5 protein Q9P286 UNIPROT DDX5 protein P17844 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr69 HPDLARRtAQEVETY 9606 BTO:0000150 34936874 t lperfetto "PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer|The increased expression levels of PAK5 and phospho-DDX5 threonine 69 are associated with metastasis and poor clinical outcomes of patients. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5 to stabilize DDX5. Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing." SIGNOR-275658 MAPKAPK2 protein P49137 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2" SIGNOR-166640 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Ser409 LRLDPTLsVDDLANS 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 t lperfetto "Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function." SIGNOR-246743 CDH11 protein P55287 UNIPROT CTNNB1 protein P35222 UNIPROT unknown binding 9606 BTO:0000150 10029089 t miannu "Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin" SIGNOR-64862 USP5 protein P45974 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0002181 26912724 t miannu " Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1." SIGNOR-277210 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR7 protein P34969 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257526 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257941 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser268 SSNASSVsTRLSPLR 9606 BTO:0001109 28945225 t miannu "Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268. " SIGNOR-277326 regorafenib chemical CHEBI:68647 ChEBI FRK protein P42685 UNIPROT "down-regulates activity" "chemical inhibition" 9606 24756792 t miannu "In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically." SIGNOR-259207 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257934 SRC protein P12931 UNIPROT TGFA protein P01135 UNIPROT "up-regulates activity" 9606 17251915 f lperfetto "Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network." SIGNOR-236534 HMGB1 protein P09429 UNIPROT IL2RA protein P01589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 7862168 f 2 miannu "The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells." SIGNOR-240113 INHBA protein P08476 UNIPROT ACVR2A protein P27037 UNIPROT "up-regulates activity" binding 9606 1646080 t gcesareni "A protein of 494 amino acids comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. 125I-activin A binds to transfected COS cells with an affinity of 180 pM and can be competed by activin A, activin B, and inhibin A, but not by transforming growth factor beta 1." SIGNOR-235138 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto "Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl." SIGNOR-78020 CDK8 protein P49336 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15546612 f gcesareni "Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells." SIGNOR-130637 CDH10 protein Q9Y6N8 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265850 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 17615152 t "inferred from 70% family members" gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-270023 EIF3_complex complex SIGNOR-C401 SIGNOR "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "down-regulates activity" 9606 15703437 f lperfetto "EIF3 and, to some extent, eIF1A have been implicated in preventing reassociation of free 40S and 60S subunits and in dissociation of empty 80S ribosomes" SIGNOR-269149 ENPP1 protein P22413 UNIPROT Bone_mineralization phenotype SIGNOR-PH69 SIGNOR up-regulates 9606 19049325 f miannu "PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate." SIGNOR-252195 SOCS3 protein O14543 UNIPROT SIGLEC7 protein Q9Y286 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0001516 17138568 t miannu "SOCS proteins can act as E3 ligases by forming a complex with Elongin B/C and Cul5/Rbx1/2.SOCS3 targets Siglec 7 for degradation" SIGNOR-272642 PTK2 protein Q05397 UNIPROT ATP2B4 protein P23634-6 UNIPROT "up-regulates activity" phosphorylation Tyr1176 LDGEVTPyANTNNNA 9606 12540962 t miannu "Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif." SIGNOR-263194 SPRY4 protein Q9C004 UNIPROT TIMP1 protein P01033 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002058 20501643 f miannu "When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21." SIGNOR-253038 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr218 GDGSDHPyYNSIPSK -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273913 PRKN protein O60260 UNIPROT DDIT4 protein Q9NX09 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 25101677 t miannu "In conclusion, our work in cellular and animal models and in human samples strongly indicates that RTP801 is a substrate of parkin and that RTP801 elevation due to parkin loss of function in both AR-JP and sporadic Parkinson's disease may contribute to neurodegeneration.|We showed that parkin poly-ubiquitinates RTP801, both in vitro and in vivo." SIGNOR-278560 CALM2 protein P0DP24 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266327 SGK1 protein O00141 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation 9606 30382187 t miannu "Notably, A\u03b2-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1\u2013368)." SIGNOR-279281 WEE2 protein P0C1S8 UNIPROT CDK1 protein P06493 UNIPROT "down-regulates activity" phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 11029659 t miannu "Recombinant Wee1B effectively phosphorylated cyclin B-associated Cdk1 on tyrosine-15, resulting in an inactivation of the kinase activity of Cdk1." SIGNOR-279134 KDM1A protein O60341 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 15620353 t miannu "Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription." SIGNOR-264508 6 protein P59634 UNIPROT NUP98 protein P52948 UNIPROT "down-regulates activity" binding 9606 32353860 t miannu "Orf6 of SARS-CoV antagonizes host interferon signaling by perturbing nuclear transport, and the NUP98-RAE1 interaction with Orf6 may perform the same function for SARS-CoV-2." SIGNOR-260976 MDM2 protein Q00987 UNIPROT GRK2 protein P25098 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 33806062 t miannu "Our findings show that the signals enabling activity of the GRK2/MST2/Nek2A axis for separation also switches on Mdm2 degradation of GRK2 to ensure accurate centrosome dynamics and proper mitotic spindle functionality.|Our results show now that EGF-induced phosphorylation of GRK2 on S670 is a key event in initiating centrosome separation and also a relevant clue for limiting centrosome separation, as this event simultaneously triggers the Mdm2-dependent ubiquitination and degradation of GRK2 ( xref )." SIGNOR-278629 INO80D protein Q53TQ3 UNIPROT "INO80 complex" complex SIGNOR-C498 SIGNOR "form complex" binding 9606 25016522 t miannu "Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication." SIGNOR-270843 DYRK1A protein Q13627 UNIPROT PLK2 protein Q9NYY3 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser358 VPDFHLSsPAKNFFK 9606 BTO:0000007 37387444 t miannu " In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability. " SIGNOR-277791 SALL4 protein Q9UJQ4 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19440552 f miannu "Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex." SIGNOR-255126 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "down-regulates activity" phosphorylation Thr346 TGENAGQtPMNINPQ 26375055 t lperfetto "We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity" SIGNOR-276525 SYN3 protein O14994 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 f miannu "Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet." SIGNOR-264107 FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15109499 f miannu "The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression." SIGNOR-252069 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR KIT protein P10721 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29236325 f irozzo "We report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT." SIGNOR-255699 SRC protein P12931 UNIPROT DNM1 protein Q05193 UNIPROT "up-regulates activity" phosphorylation Tyr231 LLPLRRGyIGVVNRS 9606 BTO:0000007 9880482 t lperfetto "Src-mediated tyrosine phosphorylation of dynamin is required for beta2-adrenergic receptor internalization and mitogen-activated protein kinase signalingHere we demonstrate that activation of beta2-adrenergic receptors (beta2-ARs) leads to c-Src-mediated tyrosine phosphorylation of dynamin, which is required for receptor internalization. Two tyrosine residues, Tyr231 and Tyr597, are identified as the major phosphorylation sites" SIGNOR-247124 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser396 FTWKRLRsHSRQYVS 9606 15328002 t gcesareni "Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes." SIGNOR-128411 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273164 SKI protein P12755 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates binding 9606 12419246 t gcesareni "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad6" SIGNOR-95468 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys62 CAVPIAQkSEPHSLS 9606 BTO:0002552 31732561 t lperfetto "AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination." SIGNOR-267673 PHF1 protein O43189 UNIPROT HOXA10 protein P31260 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20565746 t miannu "These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression." SIGNOR-260071 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192774 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser512 PPKSGDRsGYSSPGS 9606 BTO:0000590 9771888 t lperfetto "Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly." SIGNOR-249353 CEBPD protein P49716 UNIPROT MSTN protein O14793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24011072 f miannu "To identify whether p-Stat3 acts through C/EBPŒ¥ to stimulate myostatin, we knocked down C/EBPŒ¥ using siRNA. In this case, the IL-6-induced increase in myostatin expression was blocked when C/EBPŒ¥was suppressed even though p-Stat3 was increased" SIGNOR-255332 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Ser106 DNQLTIKsPSKRELA 9606 10339564 t lperfetto "Based on these results, we propose that phosphorylation of hscdc6 by cdks regulates dna replication of at least two steps: first, by promoting initiation of dna replication and, second, through nuclear exclusion preventing dna rereplication. hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)" SIGNOR-217272 RPL27A protein P46776 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262473 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM13 protein O60858 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271145 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-163274 CyclinC/CDK19 complex SIGNOR-C544 SIGNOR NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273163 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." SIGNOR-236487 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser573 ENSNSCRsSTTTCPE 9606 BTO:0000007 16862148 t lperfetto "ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2)." SIGNOR-249302 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163776 OPHN1 protein O60890 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 BTO:0000938 12932438 f miannu "These results based on the immunodetection of the endogenous protein clearly show that OPHN1 colocalizes with F-actin in both neuronal and glial cells and suggest that OPHN-1 interacts with actin." SIGNOR-268400 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr36 LPPGDYStTPGGTLF 9606 BTO:0000007 SIGNOR-C3 9465032 t lperfetto "Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size." SIGNOR-55697 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251210 GREB1 protein Q4ZG55 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 BTO:0000599 31462641 t miannu "GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription" SIGNOR-265884 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates activity" phosphorylation Tyr1265 FPMTPTTyKGSVDNQ 9606 BTO:0000394 12881528 t lperfetto "Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail." SIGNOR-104080 superoxide smallmolecule CHEBI:18421 ChEBI SOD2 protein P04179 UNIPROT "up-regulates activity" "precursor of" 9606 29301787 t lperfetto "Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD)." SIGNOR-272284 FBXW2 protein Q9UKT8 UNIPROT GCM1 protein Q9NP62 UNIPROT "down-regulates quantity" binding 9606 BTO:0000007 15640526 t miannu "FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system" SIGNOR-271524 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser59 GDSCPHGsPQGPLAP 12818176 t miannu "JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity." SIGNOR-250134 CD38 protein P28907 UNIPROT NADP(+) smallmolecule CHEBI:18009 ChEBI "down-regulates quantity" "chemical modification" 9606 18626062 t miannu "The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR." SIGNOR-264247 hsa-miR-124-5p mirna URS00003AA409_9606 RNAcentral SPHK1 protein Q9NYA1 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002392 22450659 t Parnian "The key finding of the present study was that up- regulation of miR-124 could repress SPHK1 expression by directly targeting the 3′-UTR of SPHK1. In addition, we found that over-expressing miR-124 inhibited proliferation and the anchorage independent growth of gastric cancer cells. proliferation and the anchorage-independent grow" SIGNOR-279810 PAMPs stimulus SIGNOR-ST11 SIGNOR ITLN1 protein Q8WWA0 UNIPROT "up-regulates activity" binding 26148048 t "Human intelectin-1 (hIntL-1) does not bind known human glycan epitopes but does interact with multiple glycan epitopes found exclusively on microbes: β-linked D-galactofuranose (β-Galf), D-phosphoglycerol-modified glycans, heptoses, D-glycero-D-talo-oct-2-ulosonic acid (KO) and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO). | This ligand selectivity suggests that hIntL-1 functions in microbial surveillance." SIGNOR-272498 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269386 seliciclib chemical CHEBI:45307 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206571 CTLA4 protein P16410 UNIPROT "T cell exhaustion" phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 26086965 f Barakat "Both PD-1 and CTLA-4 inhibited the activity of Akt, a crucial molecular in regulating glucose metabolism of T cells by elevating glucose transporter 1 expression and glycolysis, suggesting that glucose metabolism may contribute to T-cell exhaustion" SIGNOR-275415 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1081 TGALTEDsIDDTFLP 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250622 GNRHR protein P30968 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257177 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Thr232 GGLPEVAtPESEEAF 9606 BTO:0004971 7816602 t lperfetto "Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions." SIGNOR-235877 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 18794113 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-180902 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 12612081 t "In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin" SIGNOR-248386 PTPN1 protein P18031 UNIPROT NTRK2 protein Q16620 UNIPROT "down-regulates activity" dephosphorylation Tyr707 DVYSTDYyRVGGHTM 9606 26214522 t Luana "Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling" SIGNOR-264553 PRKAA2 protein P54646 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Ser177 AKELDQGsLCTSFVG 9606 SIGNOR-C14 21673972 t lperfetto "These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes" SIGNOR-174401 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT "up-regulates activity" relocalization 9606 23633519 t lperfetto "Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring." SIGNOR-252641 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 t llicata "We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2." SIGNOR-163537 HIPK2 protein Q9H2X6 UNIPROT HDAC3 protein O15379 UNIPROT "down-regulates activity" phosphorylation Ser374 KMLNHAPsVQIHDVP 10090 BTO:0002572 34244427 t miannu "Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation." SIGNOR-277568 CKB protein P12277 UNIPROT ACTB protein P60709 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000099 19333390 t miannu "In summary, data presented here strongly suggest that locally generated ATP is an important regulator for actin-based cytoskeletal dynamics involved in cell extension and motility and that CK-B is a controlling enzyme in the compartmentalization of ATP availability. CK-B co-localizes with cortical actin and facilitates spreading of astrocytes" SIGNOR-265791 DUSP3 protein P51452 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation 9606 28759036 t miannu "Deficiency in VHR/DUSP3, a suppressor of focal adhesion kinase, reveals its role in regulating cell adhesion and migration.|In vitro assays proved that recombinant VHR directly dephosphorylated FAK and paxillin." SIGNOR-277033 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 10660534 t lperfetto "Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function" SIGNOR-74844 RPS6KA4 protein O75676 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 t lperfetto "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) msk 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf-kb isoform p65 and stat 1 and 3." SIGNOR-217373 FYN protein P06241 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr288 YETADGGyMTLNPRA -1 8756631 t lperfetto "To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation." SIGNOR-249336 CEBPD protein P49716 UNIPROT KLF5 protein Q13887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16054042 f fspada "Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter." SIGNOR-210007 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 t miannu "PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated" SIGNOR-250077 EGR1 protein P18146 UNIPROT PCSK2 protein P16519 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9359835 f miannu "we show that the transcription factor EGR-1 interacts with two distinct elements within the proximal human PC2 promoter region. Transfection experiments also demonstrate that EGR-1 is able to enhance PC2 promoter activity." SIGNOR-253896 TFEB protein P19484 UNIPROT BLOC1S2 protein Q6QNY1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 33176151 f lperfetto "Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4)." SIGNOR-276682 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser260 TLSPVNHsLDLQPVT 9606 SIGNOR-C8 11027280 t gcesareni "Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions." SIGNOR-82974 "2-deoxy-D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:62877 ChEBI acetaldehyde smallmolecule CHEBI:15343 ChEBI "up-regulates quantity" "precursor of" 9606 25229427 t miannu "Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase." SIGNOR-268076 PRKAR2A protein P13861 UNIPROT PRKACA protein P17612 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258752 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 BTO:0000763 20861316 t lperfetto "We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity" SIGNOR-167993 CDK5 protein Q00535 UNIPROT SOX6 protein P35712 UNIPROT "down-regulates quantity" phosphorylation 9606 24662752 t miannu "GST-Sox6 was phosphorylated in vitro by Cdk5 and p35 (XREF_FIG).|Inhibition of Cdk5 activity by DN Cdk5 and roscovitine increases the Sox6 expression in primary cortical neurons." SIGNOR-279365 STUB1 protein Q9UNE7 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 14701756 t miannu "We demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process. " SIGNOR-272947 DIP2A protein Q14689 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" acetylation 10090 BTO:0000142 31600191 t miannu "DIP2A binds to cortactin and modulates cortactin acetylation. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin." SIGNOR-266589 fluoxetine chemical CHEBI:5118 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9537821 t miannu "Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter." SIGNOR-258738 Ub:E2 complex SIGNOR-C497 SIGNOR IHO1 protein Q8IYA8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271239 M protein P59596 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" 9606 25271362 f Luana "Taken together, our results demonstrated that expression of M-protein causes activation of both caspases 8 and 9 via the PKB/Akt signalling cascades. " SIGNOR-260202 3a protein P59632 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" 9606 18632968 f Luana "Thus, caspase-9 activation and cytochrome c release in cells expressing the 3a protein indicated that this viral protein also activates the intrinsic pathway of apoptosis." SIGNOR-260213 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR NAMPT protein P43490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19299583 t miannu "Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1. Transduction of Clock/Bmal1 into mouse embryonic fibroblasts appeared to up-regulate Nampt expression ∼1.6-fold (Fig. 3E)." SIGNOR-268021 "D-xylulose 5-phosphate(2-)" smallmolecule CHEBI:57737 ChEBI "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "precursor of" 9606 24929114 t miannu "Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates." SIGNOR-268141 MYOD1 protein P15172 UNIPROT SP1 protein P08047 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 9148896 t lperfetto "These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport." SIGNOR-241765 HRH2 protein P25021 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257049 PPP6C protein O00743 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" dephosphorylation 9606 19198648 t miannu "In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation.|PP6 may dephosphorylate sites in DNA-PKcs to reduce binding with heterodimer Ku proteins, because DNA-PK activation completely depends on Ku-mediated complex formation with DNA." SIGNOR-277164 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 t lperfetto "Recently, Liu et al. [3] identified CyclinE/CDK2 to be the kinase phosphorylating OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) by elegantly combining genetics and biochemistry. Knockout of all five G1 cyclins (D1, D2, D3, E1 and E2) in mESCs (coined Q-KO cells) and consequent inactivation of CDK2/4/ 6 leads to perturbation of the pluripotent state and to the adaption of the trophectoderm cell fate. This was attributed to reduced phosphorylation of OCT4 (as well as SOX2 and NANOG) leading to an increase of protein turnover [3]." SIGNOR-264437 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 t lperfetto "Recent work found that CyclinE/CDK2 can phosphorylate OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) in vitro|Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2." SIGNOR-264436 SIRT5 protein Q9NXA8 UNIPROT HMGCS2 protein P54868 UNIPROT "up-regulates activity" "post translational modification" Lys83 YNNVEAGkYTVGLGQ 9606 BTO:0000007 24315375 t desuccinylation lperfetto "We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5" SIGNOR-267641 PTGFR protein P43088 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257193 PRKCE protein Q02156 UNIPROT PRKCE protein Q02156 UNIPROT down-regulates phosphorylation Ser729 QEEFKGFsYFGEDLM 9606 11964154 t llicata "Protein kinase-inactive mutants of pkcepsilon were not phosphorylated at ser(729) in cells, and phosphorylation of this site leads to dephosphorylation of the activation-loop thr(566)" SIGNOR-117324 GRHL2 protein Q6ISB3 UNIPROT ZEB1 protein P37275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 23814079 f miannu "we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells." SIGNOR-255624 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 9020159 t lperfetto "We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src." SIGNOR-235786 MAPK3 protein P27361 UNIPROT SYN3 protein O14994 UNIPROT up-regulates phosphorylation Ser470 PQGQQPLsPQSGSPQ 9606 14732590 t lperfetto "A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action." SIGNOR-121402 AEBP2 protein Q6ZN18 UNIPROT "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR "form complex" binding 9606 23110252 t lperfetto "The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48)." SIGNOR-241903 APC-c complex SIGNOR-C150 SIGNOR USP37 protein Q86T82 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 21596315 t lperfetto "USP37 is ubiquitinated by APCCDH1 in late mitosis and early G1 phase||Inactive USP37 now becomes a substrate for APCCDH1, undergoing K11-linked polyubiquitination and proteasomal degradation. Elimination of USP37 ensures that it does not antagonize APC/C substrate degradation during mitosis." SIGNOR-265048 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CEBPB protein P17676 UNIPROT "up-regulates activity" phosphorylation Thr235 SSSSPPGtPSPADAK 9606 BTO:0000551 19723873 t gcesareni "Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction." SIGNOR-238303 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 21502402 t "inferred from 70% family members" llicata "Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro" SIGNOR-270122 CHL1 protein O00533 UNIPROT ANK1 protein P16157 UNIPROT "up-regulates quantity" relocalization 10116 BTO:0000227 7961622 t miannu "Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains." SIGNOR-266724 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT "up-regulates activity" phosphorylation Ser93 RVPKDRPsLTVTPKR 9606 BTO:0000567 21658950 t miannu "Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis" SIGNOR-262657 MAPK10 protein P53779 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t "Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons" gcesareni "Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190" SIGNOR-124009 IFNG protein P01579 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 10116 9397972 f "inferred from family member" scontino "From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y." SIGNOR-270238 BIRC3 protein Q13489 UNIPROT BIRC2 protein Q13490 UNIPROT "up-regulates activity" binding 9606 23070005 t amattioni "Ligand-stimulated aggregation of receptor complexes causes recruitment of multiple traf2 trimers, which in turn leads to cIAP1 or cIAP2 dimerization." SIGNOR-199088 carfilzomib chemical CHEBI:65347 ChEBI PSMB1 protein P20618 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000898 17591945 t miannu "Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM." SIGNOR-259307 "(4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester" chemical CHEBI:103931 ChEBI ADRA1A protein P35348 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258463 RBBP6 protein Q7Z6E9 UNIPROT ZBTB38 protein Q8NAP3 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 24726359 t miannu "Thus, RBBP6 induces ZBTB38 protein degradation, and this depends on the activity of the proteasome.We next tested whether RBBP6 might directly ubiquitinate ZBTB38.|We show that ZBTB38 is directly ubiquitinated by RBBP6 in human and mouse cells, in a process that is independent of p53 and MDM2, and leads to proteasomal degradation." SIGNOR-278594 H4C1 protein P62805 UNIPROT "Nucleosome_H3.3 variant" complex SIGNOR-C339 SIGNOR "form complex" binding 9606 15776021 t miannu "Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes." SIGNOR-263877 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT "up-regulates activity" relocalization 9606 21791611 t lperfetto "One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2" SIGNOR-175269 vorinostat chemical CHEBI:45716 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257919 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser287 SVKSPVSsPNNVTLR 9606 BTO:0005043 22798426 t miannu " Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation." SIGNOR-276110 CAD protein P27708 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "down-regulates quantity" "chemical modification" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267418 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 SIGNOR-C15 21205641 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-170867 "AP-2 complex" complex SIGNOR-C245 SIGNOR AAK1 protein Q2M2I8 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 15496985 t Giorgia "We therefore characterised protein ligands using liquid chromatography tandem mass spectrometry (LC‐MS/MS) and confirmed this using Western blotting to recognise both major and minor bands. Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs" SIGNOR-260393 OPTN protein Q96CV9 UNIPROT SNAP25 protein P60880 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259880 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" ubiquitination 9534 11295495 t lperfetto "The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-235305 CDK5 protein Q00535 UNIPROT HTR6 protein P50406 UNIPROT "down-regulates activity" phosphorylation Ser350 ERQASLAsPSLRTSH 10090 BTO:0000942 32047117 t lperfetto "Cdk5 phosphorylates the 5-HT6R on serine 350 (Ser350)|This suggests that the 5-HT6R is unable to interact with GPRIN1 when it is phosphorylated by Cdk5." SIGNOR-264407 SLC24A2 protein Q9UI40 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 30173760 t miannu "K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+)" SIGNOR-264394 MRTFA protein Q969V6 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 21673106 f "miR-143 and miR-145 target KLF4" gcesareni "This result suggests that mrtf-a, but not myocd, is essential for bmp4-dependent induction ofmir-143/145gene transcription. Of the mirnas identified to target klf4, only mir-143 and mir-145 were induced at least 1.5-fold by both bmp4 and tgf- , suggesting that they may be critical for bmp4- and tgf- -mediated reduction of klf4." SIGNOR-174261 bremazocine chemical CHEBI:3171 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258778 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 12551923 t gcesareni "We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain." SIGNOR-97635 PRKCA protein P17252 UNIPROT UNC5A protein Q6ZN44 UNIPROT "down-regulates quantity" phosphorylation Ser352 TSGFQPVsIKPSKAD 10116 BTO:0003036 16554470 t miannu "We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis." SIGNOR-268180 Gbeta proteinfamily SIGNOR-PF4 SIGNOR KRT8 protein P05787 UNIPROT unknown phosphorylation 16554440 t "inferred from 70% family members" lperfetto "Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002)." SIGNOR-270003 UBAP2L protein Q14157 UNIPROT RNF2 protein Q99496 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 25185265 t Sara "UBAP2L associates with BMI1 and RNF2. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex" SIGNOR-261316 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 t "inferred from 70% family members" gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-270214 TP53 protein P04637 UNIPROT AIFM1 protein O95831 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23506862 t miannu "P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway." SIGNOR-267462 MAPK1 protein P28482 UNIPROT SORBS3 protein O60504 UNIPROT unknown phosphorylation Ser530 DGPQLPTsPRLTAAA 9606 15184391 t "The effect has been demonstrated using O60504-2" llicata "Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _." SIGNOR-125221 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t gcesareni "These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis." SIGNOR-252617 UBE3A protein Q05086 UNIPROT PSMC2 protein P35998 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 28559284 t lperfetto "Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits." SIGNOR-265132 MAPKAPK2 protein P49137 UNIPROT HNRNPA0 protein Q13151 UNIPROT "up-regulates activity" phosphorylation Ser84 VELKRAVsREDSARP 10090 BTO:0000801 12456657 t miannu "MAPKAP-K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS-stimulated cells. The simplest explanation for these findings is that the phosphorylation of hnRNP A0 at Ser84 by MAPKAP-K2 enhances binding to the AREs of these mRNAs or allows hnRNP A0 to displace another protein(s) from the AREs." SIGNOR-262951 GDNF protein P39905 UNIPROT Neural_tissue_regeneration phenotype SIGNOR-PH68 SIGNOR up-regulates 10116 15212950 f miannu "The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. In normal development, GDNF promotes survival of sympathetic, parasympathetic, and spinal motorneurons. It even promotes regeneration of spinal motor neurons after spinal cord injury." SIGNOR-252170 FOXO3 protein O43524 UNIPROT FASLG protein P48023 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10102273 f gcesareni "Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene." SIGNOR-66035 QRICH1 protein Q2TAL8 UNIPROT YARS2 protein Q9Y2Z4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269413 CSNK1A1 protein P48729 UNIPROT PHLPP1 protein O60346 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 BTO:0002181 19797085 t miannu "We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity. " SIGNOR-276261 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM4 protein Q14833 UNIPROT "up-regulates activity" "chemical activation" 9606 25042998 t miannu "Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate" SIGNOR-264074 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT "up-regulates activity" phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000567 18079698 t miannu "We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14." SIGNOR-276086 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser421 DNCASVSsPYESAIG 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250126 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 23450633 f gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." SIGNOR-192783 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser45 FHGVAILsPLLNIEK -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265957 ITGB2 protein P05107 UNIPROT "AD/b2 integrin" complex SIGNOR-C172 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253196 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser389 LKEAEEEsSGGEEED 9606 18649047 t gcesareni "We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2." SIGNOR-179542 "Microprocessor complex" complex SIGNOR-C356 SIGNOR mir-10b mirna URS00004CAC40_9606 RNAcentral "up-regulates quantity" "post transcriptional regulation" 34936874 t lperfetto "Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing." SIGNOR-275661 KEL protein P23276 UNIPROT EDN3 protein P14138 UNIPROT "up-regulates activity" cleavage Trp117 YCHLDIIwINTPEQT -1 10438732 t miannu "These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles." SIGNOR-256354 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARRB2 protein P32121 UNIPROT "up-regulates activity" phosphorylation Thr276 FCKVYTItPLLSDNR 10090 BTO:0002572 26324936 t done miannu "ERK1/2-dependent βarr2 phosphorylation on S14 and T276 induces CXCR4 intracellular sequestration." SIGNOR-274019 EP300 protein Q09472 UNIPROT MAML1 protein Q92585 UNIPROT up-regulates acetylation 9606 17300219 t gcesareni "The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. Furthermore, p300 acetylates maml1 and evolutionarily conserved lysine residues in the maml1 n-terminus are direct substrates for p300-mediated acetylation." SIGNOR-153035 JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000801 8977526 t irozzo "JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation." SIGNOR-256001 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR TP53 protein P04637 UNIPROT "up-regulates quantity by expression" 9606 15044535 f gcesareni "These results indicate that nf-kb actions occur upstream of p53 to regulate both p53 levels and activity." SIGNOR-123602 farnesol chemical CHEBI:28600 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258159 AKT3 protein Q9Y243 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue." SIGNOR-186780 PRKACA protein P17612 UNIPROT STK38 protein Q15208 UNIPROT "down-regulates activity" phosphorylation Ser11 TGSTPCSsMSNHTKE -1 22142472 t miannu "GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress." SIGNOR-276390 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 t gcesareni "Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation." SIGNOR-37470 SGK3 protein Q96BR1 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser484 KRRKRMSsGTEECGE 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275767 CARD11 protein Q9BXL7 UNIPROT BCL10 protein O95999 UNIPROT up-regulates binding 9606 12356734 t gcesareni "Card11 cooperates with bcl10 in a card domain-dependent manner.;These results implicate card11 in factor- specific activation of nf-kappab" SIGNOR-93869 hsa-miR-138-5p mirna URS000040780F_9606 RNAcentral ADGRA2 protein Q96PE1 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0005518 24582749 t Parnian "MiR-138-5p reverses gefitinib resistance in non-small cell lung cancer cells via negatively regulating G protein-coupled receptor 124" SIGNOR-277982 XIAP protein P98170 UNIPROT HIF1A protein Q16665 UNIPROT "up-regulates activity" ubiquitination 9606 28666324 t miannu "HIF1alpha is ubiquitinated by XIAP.|Lys 63 -linked ubiquitination of HIF1alpha by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13.|We find that XIAP and Ubc13 dependent Lys 63 -linked polyubiquitination promotes HIF1alpha nuclear retention leading to an increase in the expression of HIF1 responsive genes.|The data indicate that XIAP promotes the formation of the non-degradative Lys63-linked ubiquitin chains onto hypoxia inducible factor1\u03b1, but does not affect the formation of Lys48-linked chains." SIGNOR-278740 MYC protein P01106 UNIPROT CDK6 protein Q00534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "The degradation of c-myc protein decreases the expression of the cell cycle regulators cdk4 and cdk6, which reversibly slows down the cell cycle." SIGNOR-102737 LCK protein P06239 UNIPROT PRDX1 protein Q06830 UNIPROT "down-regulates activity" phosphorylation Tyr194 DVQKSKEyFSKQK -1 20178744 t miannu "Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation." SIGNOR-276277 "26S Proteasome" complex SIGNOR-C307 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates quantity" destabilization 10090 BTO:0003569 9233789 t "Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin." SIGNOR-270947 ATM protein Q13315 UNIPROT ZNF148 protein Q9UQR1 UNIPROT up-regulates phosphorylation Ser202 GEKPFQCsQCDMRFI 9606 17560543 t lperfetto "Here we found that zbp-89 is phosphorylated by atm kinase in vitro and in vivo. Disruption of the atm phosphorylation motif (202)sq within the zinc finger domain of zbp-89 attenuated its ability to enhance p21(waf1) activation by butyrate. Moreover, disruption of the atm phosphorylation site abrogated the ability of zbp-89 to potentiate butyrate induction of endogenous p21(waf1) expression." SIGNOR-155634 oxymetazoline chemical CHEBI:7862 ChEBI HTR1B protein P28222 UNIPROT "up-regulates activity" "chemical activation" 9913 BTO:0000142 9632357 t miannu "Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives." SIGNOR-258928 LYN protein P07948 UNIPROT IL5RA protein Q01344 UNIPROT "up-regulates activity" phosphorylation 9606 29029406 t miannu "Lyn activate and expand IL-5RA intracellular signaling through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex, provoking eosinophils proliferation and exaggerated activation manifested as CEL.|We further delineated that Lyn can induce IL-5RA tyrosine phosphorylation and physically associate with IL-5RA in F/P expressing cells." SIGNOR-279059 GSK3B protein P49841 UNIPROT PIAS1 protein O75925 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser17 MVMSLRVsELQVLLG 10090 BTO:0002268 26157031 t miannu "We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting. " SIGNOR-276923 CDK1 protein P06493 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni "These results suggest that both ERK and Cdk1 directly phosphorylate Nup50 at Ser221 in intact cells|Notably, erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin." SIGNOR-188061 PRKCA protein P17252 UNIPROT PIP5K1B protein O14986 UNIPROT down-regulates phosphorylation Ser413 PSKKRCNsIAALKAT 9606 23909401 t lperfetto "Collaboration of ampk and pkc to induce phosphorylation of ser413 on pip5k1b resulting in decreased kinase activity and reduced ptdins(4,5)p2 synthesis in response to oxidative stress and energy restriction. we demonstrate that pkc can directly phosphorylate ser413 in vitro" SIGNOR-194820 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR NUDT1 protein P36639 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0005713 28947420 t miannu "Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. " SIGNOR-272791 MAPK8 protein P45983 UNIPROT CDT1 protein Q9H211 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser391 LRSAAPSsPGSPRPA 9606 BTO:0000567 21930785 t miannu " We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2. " SIGNOR-276361 PIN1 protein Q13526 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" isomerization 9606 BTO:0000599 23720771 t lperfetto "In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events" SIGNOR-265757 AKT proteinfamily SIGNOR-PF24 SIGNOR SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t miannu "We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh." SIGNOR-155229 LSM-20934 chemical CHEBI:109533 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258727 PRKCA protein P17252 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser790 IHRKTTAsTRKVSLA -1 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC." SIGNOR-248851 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15573378 t ggiuliani "The Runx2 WT and deletion constructs (1 √¢‚Ǩ‚Äú495, 1√¢‚Ǩ‚Äú464, and 1√¢‚Ǩ‚Äú432) all physically interact with the BMP2 responsive Smad 1" SIGNOR-255834 WNT7A protein O00755 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-253130 TAF1A protein Q15573 UNIPROT "SAGA complex" complex SIGNOR-C465 SIGNOR "form complex" binding 9606 15970593 t lperfetto "Gene promoters with a TATA box tend to be bound by the SAGA complex which includes TBP, SUPT3H, and GCN5 (Basehoar et al., 2004; Rodríguez-Navarro, 2009). Therefore, it was thought that TATA-containing genes were mainly regulated by the SAGA complex, while TATA-less genes were independently regulated by TFIID (Pugh and Tjian, 1991; Basehoar et al., 2004). However, recent studies in yeast indicate that most genes utilize both TFIID and SAGA, and that the relative contribution of each complex likely depends on the individual context" SIGNOR-269591 CDK2 protein P24941 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates phosphorylation Ser443 FLGQTPAsPARYSPV 9606 19066288 t llicata "We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1" SIGNOR-182765 RPL23 protein P62829 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262477 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT "up-regulates activity" phosphorylation Tyr466 VFLRCINyVFFPSLK -1 8605876 t lperfetto "We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2." SIGNOR-246934 FYN protein P06241 UNIPROT CNN1 protein P51911 UNIPROT "down-regulates activity" phosphorylation Tyr261 SQRGMTVyGLPRQVY 9534 BTO:0000298 15206927 t "We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin" SIGNOR-251158 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 22575959 t gcesareni "Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6" SIGNOR-197414 CRTC3 protein Q6UUV7 UNIPROT BCL3 protein P20749 UNIPROT up-regulates binding 9606 BTO:0001271;BTO:0000776;BTO:0000786 17644518 t miannu "The ankyrin repeat domain of bcl3 interacted with torc3 / we determined that bcl3 inhibited transcription from the htlv-1 ltr in a manner dependent on torc3" SIGNOR-156950 GSK3B protein P49841 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates phosphorylation 9606 12123574 t gcesareni "Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling." SIGNOR-90608 USP7 protein Q93009 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni "Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins." SIGNOR-139450 "Activated PSC" phenotype SIGNOR-PH224 SIGNOR TGFB1 protein P01137 UNIPROT "up-regulates quantity" 9606 BTO:0000988 38540204 t miannu "Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction" SIGNOR-277673 "peptide antigen" smallmolecule CHEBI:166824 ChEBI "Class I MHC:Antigen" complex SIGNOR-C426 SIGNOR "form complex" binding 9606 33374673 t scontino "The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR)." SIGNOR-267773 IKK-complex complex SIGNOR-C14 SIGNOR CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000661 15870263 t gianni "In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits." SIGNOR-266435 ASXL2 protein Q76L83 UNIPROT PPARG protein P37231 UNIPROT "up-regulates activity" binding 9606 21047783 t miannu "ASXL2, which does not bind HP1, promotes differentiation by binding to PPARγ and increasing the level of methylated H3K4, leading to the elevation of PPARγ activity. Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ." SIGNOR-260063 H2BC11 protein P06899 UNIPROT "Nucleosome_H3.1 variant" complex SIGNOR-C324 SIGNOR "form complex" binding -1 21812398 t miannu "The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP." SIGNOR-263720 LRIG1 protein Q96JA1 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates 9606 23723069 f miannu "Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation." SIGNOR-202143 FIP1L1 protein Q6UN15 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates binding 9606 14749727 t miannu "Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna." SIGNOR-121700 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" dephosphorylation Ser109 NKFAAHIsPAQGSPK -1 29945972 t miannu "MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation." SIGNOR-277881 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1222 PAFDNLYyWDQDPPE 9606 15156151 t gcesareni "Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227" SIGNOR-124860 VRK1 protein Q99986 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 17938195 t gcesareni "We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis." SIGNOR-265371 ULK2 protein Q8IYT8 UNIPROT ENO1 protein P06733 UNIPROT "down-regulates activity" phosphorylation Ser282 QLADLYKsFIKDYPV 9606 BTO:0000007 27153534 t done miannu "Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown)." SIGNOR-274037 MDM2 protein Q00987 UNIPROT DYRK2 protein Q92630 UNIPROT "down-regulates quantity by destabilization" ubiquitination 19965871 t lperfetto "Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation.|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus." SIGNOR-275579 ANXA1 protein P04083 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 27426034 f miannu "Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups" SIGNOR-261939 IL11 protein P20809 UNIPROT IL11RA protein Q14626 UNIPROT up-regulates binding 9606 10948192 t gcesareni "Il-11 has been shown to induce gp130-dependent signaling through the formation of a high affinity complex with the il-11 receptor (il-11r) and gp130" SIGNOR-81102 SRP19 protein P09132 UNIPROT SRP68 protein Q9UHB9 UNIPROT "up-regulates activity" binding -1 30649418 t miannu "Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54." SIGNOR-261167 CDK1 protein P06493 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser428 KVAASPKsPTAALNE 9606 16198290 t lperfetto "Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis." SIGNOR-140886 CTSL protein P07711 UNIPROT S protein P59594 UNIPROT "up-regulates activity" cleavage -1 16081529 t miannu "A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection." SIGNOR-260218 AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 t lperfetto "Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation" SIGNOR-71480 ZNRF1 protein Q8ND25 UNIPROT CAV1 protein Q03135 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys39 MADELSEkQVYDAHT 9606 BTO:0000007 28593998 t miannu "The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. ZNRF1 mediates CAV1 polyubiquitination at lysine 39 and promote CAV1 degradation to modulate TLR4-mediated immune response." SIGNOR-272327 LY294002 chemical CHEBI:65329 ChEBI PIK3R1 protein P27986 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 t gcesareni "Here we show that inhibition of pi3-k activity by the pharmacological agent ly294002 affects early processes of myoblast differentiation including the transcriptional activation of myogenin." SIGNOR-79347 Ub:E2 complex SIGNOR-C497 SIGNOR LNX2 protein Q8N448 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271195 MBL2 protein P11226 UNIPROT S protein P59594 UNIPROT "down-regulates activity" binding 9606 BTO:0001370 20573835 t miannu "We have demonstrated that MBL selectively binds to SARS-S pseudotyped virus and can inhibit SARS-CoV infection in susceptible cell lines. Our results identified a single N-linked glycosylation site, N330, on S glycoprotein as the target for the specific interactions between MBL and SARS-CoV and provide evidence that the viral interaction with MBL did not affect its interaction with the ACE2 receptor. Binding to MBL did not affect SARS-S interactions with the ACE2 receptor. Furthermore, MBL-mediated inhibition occurred at a step prior to CTSL-mediated activation of SARS-S fusion. Thus, we suggest that the binding of the MBL may interfere with the induction of conformational changes within the S glycoprotein and thus prevent an early, postreceptor-binding event." SIGNOR-260285 IFITMs proteinfamily SIGNOR-PF49 SIGNOR S protein P59594 UNIPROT "down-regulates activity" 9606 BTO:0000007;BTO:0004126 29263263 f miannu "All three IFITMs significantly inhibited the infection by lentiviral particles pseudotyped with IAV hemagglutinin 1 (H1) and neuraminidase 1 (N1) (IAVpp), Spike protein (S) of HCoV-229E (229Epp), HCoV-NL63 (NL63pp), SARS-CoV (SARSpp), and MERS-CoV (MERSpp) in both HEK293 (Fig. 1B) and Huh7.5 (Fig. 1C) cells." SIGNOR-260230 UBE2I protein P63279 UNIPROT N protein P59595 UNIPROT "up-regulates activity" sumoylation Lys62 TALTQHGkEELRFPR 9606 BTO:0000567 17037517 t lperfetto "In this study, we identified Ubc9 as a host protein that interacts specifically with SARS-CoV N protein. This interaction was verified both in vivo and in vitro. Furthermore, we showed that, in addition to phosphorylation, the N protein was modified by covalent attachment of SUMO to its lysine 62 residue. Evidence provided demonstrated that sumoylation may promote homo-oligomerization of the protein." SIGNOR-260263 GRM3 protein Q14832 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 20055706 t miannu "MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits." SIGNOR-264083 GDNF protein P39905 UNIPROT ID2 protein Q02363 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252180 CYP19A1 protein P11511 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000975 27702664 t lperfetto "The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively" SIGNOR-268670 CUL1 protein Q13616 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001271 SIGNOR-C5 12835716 t lperfetto "Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2" SIGNOR-102725 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY 12893243 t lperfetto "The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time." SIGNOR-249224 TLN1 protein Q9Y490 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 16418530 t lperfetto "In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation." SIGNOR-253358 PP2B proteinfamily SIGNOR-PF18 SIGNOR IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18177723 f "inferred from 70% family members" lperfetto "Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy" SIGNOR-269987 CNTN6 protein Q9UQ52 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 BTO:0000938 15082708 t gcesareni "Here, we establish that nb-3, a member of the f3/contactin family, acts as a novel notch ligand to participate in oligodendrocyte generation. Nb-3 triggers nuclear translocation of the notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via deltex1." SIGNOR-254318 phenobarbital chemical CHEBI:8069 ChEBI NR1I2 protein O75469 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000318 9727070 t miannu "The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C)." SIGNOR-258830 ITGB1 protein P05556 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253186 ZBTB7A protein O95365 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15662416 f miannu "Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding." SIGNOR-225900 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma "ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation" SIGNOR-256216 "Androgen deprivation therapy " stimulus SIGNOR-ST31 SIGNOR androgen smallmolecule CHEBI:50113 ChEBI "down-regulates activity" 9606 BTO:0000584 30312731 t miannu "The androgen receptor (AR), a nuclear receptor that is activated by binding to androgens [1], promotes the development of prostate cancer [2]. Although traditional AR-targeted therapies are initially effective, most tumors progress to hormone-refractory prostate cancer or castration-resistant prostate cancer (CRPC) within a few years [3]. CRPC patients are commonly treated with androgen deprivation therapy (ADT); however, ADT accelerates neuroendocrine (NE) differentiation with an increased anti-apoptotic stimulus that enables tumor resistance to the AR-targeted therapies " SIGNOR-277993 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser359 SALSYLQsPITTSPS 9606 10617468 t lperfetto "Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein." SIGNOR-73621 PRKCA protein P17252 UNIPROT NFATC1 protein O95644 UNIPROT "down-regulates activity" phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 t lperfetto "Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1. | Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines." SIGNOR-249175 PRKACA protein P17612 UNIPROT CACNG2 protein Q9Y698 UNIPROT "down-regulates activity" phosphorylation Thr321 NTANRRTtPV 9534 11805122 t miannu "phosphorylation of stargazin at T321 by PKA inhibits its interaction with PSD-95." SIGNOR-250342 Ub:E2 complex SIGNOR-C497 SIGNOR MYCBP2 protein O75592 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271134 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DRB4 protein P13762 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-254002 PAX5 protein Q02548 UNIPROT TLE4 protein Q04727 UNIPROT "down-regulates activity" binding 9606 BTO:0002291 10811620 t Gianni "Grg4 efficiently represses the transcriptional activity of Pax5 in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were also observed between distantly related members of both the Pax2/5/8 and Groucho protein families" SIGNOR-269083 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser38 QVSSLSEsEESQDSS 9606 20730097 t lperfetto "We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5" SIGNOR-167564 2-[2-Amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl]-5-[(4-bromobenzyl)oxy]phenol smallmolecule CID:135651766 PUBCHEM GIPR protein P48546 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257498 "Av/b3 integrin" complex SIGNOR-C177 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257719 PRKCD protein Q05655 UNIPROT PLSCR1 protein O15162 UNIPROT up-regulates phosphorylation Thr161 CGPSRPFtLRIIDNM 9606 10770950 t lperfetto "Following the induction of apoptosis, however, phosphorylation of serine residues decreased and it increased on threonine, consistent with the predicted pkc phosphorylation site at thr-161. Transfection of cho cells with scramblase and pkc_, but not scramblase or pkc_ alone, increased scramblase activity" SIGNOR-76904 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120156 FZD5 protein Q13467 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 10937998 f fspada "Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)" SIGNOR-80610 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR SMURF1 protein Q9HCE7-2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination LYS357 RDLVQKLkVLRHELS 9606 BTO:0000007 21572392 t miannu "Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation.  FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells." SIGNOR-271912 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Thr495 LLSLFEDtLDPT 9606 12738781 t lperfetto "These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site. " SIGNOR-249208 CBLB protein Q13191 UNIPROT NCK1 protein P16333 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 16503409 t lperfetto "Activated Cbl and Cbl-b interacted with Crk-L, Zap-70, Nck, PLC-gamma" SIGNOR-236054 RAP1GAP protein P47736 UNIPROT RAP1A protein P62834 UNIPROT "down-regulates activity" binding 9606 BTO:0001949 22173489 t "Marta Tosoni" "Overexpression of Rap1GAP significantly inhibited Rap1 activation, ERK and Akt phosphorylation of HUVECs compared with pcDNA transfection controls" SIGNOR-278054 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR WBP2 protein Q969T9 UNIPROT "up-regulates activity" binding 9606 25287865 t miannu "The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2" SIGNOR-277670 ATAD5 protein Q96QE3 UNIPROT BRD4 protein O60885 UNIPROT up-regulates binding 9606 BTO:0000007 31875566 t miannu "ATAD5 Interacts with BRD4 through a Conserved BET Protein-Binding Domain. BRD4-ATAD5 binds to acetyl-histones in nascent chromatin. BRD4 release from chromatin correlates with PCNA unloading. Disruption of the interaction between BRD4 and acetyl-histones or between BRD4 and ATAD5 reduces the PCNA amount on chromatin." SIGNOR-266412 NUMA1 protein Q14980 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates binding 9606 11956313 t "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-256541 HRH4 protein Q9H3N8 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256815 GSK3A protein P49840 UNIPROT STAT2 protein P52630 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr385 ILTSNQKtLTPEKGQ 9606 BTO:0002181 31843895 t miannu "GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation." SIGNOR-276761 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser1001 SKESEHDsDESSDDD 9606 BTO:0000661 10066810 t llicata "Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. " SIGNOR-251032 NME1 protein P15531 UNIPROT FZD1 protein Q9UP38 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001567 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255162 FER protein P16591 UNIPROT FER protein P16591 UNIPROT "up-regulates activity" phosphorylation Tyr714 RQEDGGVySSSGLKQ 9534 10998246 t "P94fer undergoes autophosphorylation in-trans in vivo and that oligomerization mediates this process. the N-terminal sequences of the FER tyrosine kinases direct their different cellular autophosphorylation states, thereby dictating their different cellular functions." SIGNOR-251133 BAZ2B protein Q9UIF8 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" binding 9606 31999386 t "inferred from 70% of family members" miannu "The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation." SIGNOR-269843 MRPL11 protein Q9Y3B7 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262382 NLGN4X protein Q8N0W4 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264165 TRAF3 protein Q13114 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" ubiquitination 9606 26882989 t miannu "Biological investigations demonstrated that TRAF3 activates TAK1 protein kinase activity via a direct binding to TAK1, then the RING finger of TRAF3 ubiquitinates TAK1, leading to TAK1 phosphorylation and activation.|TRAF3 activates TAK1 through ubiquitination." SIGNOR-278787 PRLHR protein P49683 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256973 CSNK2A2 protein P19784 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT "down-regulates activity" phosphorylation Ser575 AGESLDQsMEEEEEE 9606 BTO:0000567 12591939 t llicata "We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified" SIGNOR-250985 CYLD protein Q9NQC7 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates activity" deubiquitination 9606 12917691 t lperfetto "Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract)" SIGNOR-117860 FZD2 protein Q14332 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada "Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)" SIGNOR-80601 ADRA2C protein P18825 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256978 CDC25A protein P30304 UNIPROT FOXO1 protein Q12778 UNIPROT "up-regulates activity" dephosphorylation 9606 21670150 t miannu "In this study, we revealed that Cdc25A enhances Foxo1 stability by dephosphorylating Cdk2, and Foxo1 was shown to directly regulate transcription of the metastatic factor MMP1." SIGNOR-277139 PRKDC protein P78527 UNIPROT MCC protein P23508 UNIPROT "up-regulates activity" phosphorylation Ser118 SELRSELsQSQHEVN 9606 BTO:0001109 21779472 t miannu "MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity." SIGNOR-273530 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1457 HSKSPAYtPQNLDSE 9606 12356758 t lperfetto "Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase" SIGNOR-93993 DDX20 protein Q9UHI6 UNIPROT "SMN complex" complex SIGNOR-C158 SIGNOR "form complex" binding 12065586 t lperfetto "SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry." SIGNOR-253117 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser151 VNFGRSRsAQEPARK 9606 24309468 t lperfetto "Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1." SIGNOR-203460 MET-enkephalin smallmolecule CHEBI:6618 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257551 GNRHR protein P30968 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257331 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 8027085 t gcesareni "Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids." SIGNOR-35874 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "carbamoyl phosphate(2-)" smallmolecule CHEBI:58228 ChEBI "up-regulates quantity" "precursor of" 9606 15096496 t "CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules" SIGNOR-267191 MAPK9 protein P45984 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 t gcesareni "Wstf, a specific component of two chromatin remodeling complexes (swi/snf-type winac and iswi-type wich), was phosphorylated by the stimulation of mapk cascades in vitro and in vivo. Ser-158 residue in the wac (wstf/acf1/cbpq46) domain, located close to the n terminus of wstf, was identified as a major phosphorylation target" SIGNOR-188168 RAF1 protein P04049 UNIPROT XIAP protein P98170 UNIPROT "up-regulates activity" phosphorylation 9606 16964381 t miannu "Interaction and stabilization of X-linked inhibitor of apoptosis by Raf-1 protein kinase.|We also demonstrate that Raf-1 phosphorylates XIAP in vitro and in vivo." SIGNOR-279105 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Ser293 FNTLAFPsMKRKDVV 9606 BTO:0000007 12496252 t lperfetto "In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation" SIGNOR-96735 SOD1 protein P00441 UNIPROT DERL1 protein Q9BUN8 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18519638 t "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)" "Various proteins involved in ERAD have been identified recently (Meusser et al. 2005). Among them, components of the retro-translocation machinery including ATPase p97, its cofactors Ufd1 and Npl4, and the ER membrane proteins Derlin-1 and VIMP are of key importance to ERAD function |Here we show that SOD1(mut) specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD." SIGNOR-262785 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Ser493 CPPECPEsLHDLMCQ 9606 33388549 t miannu "P -Ser9 GSK-3\u03b2 phosphorylates Ser43, Ser51, and Ser493 residues of src, regulating src activity." SIGNOR-278444 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR leucine smallmolecule CHEBI:25017 ChEBI "down-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270413 BTRC protein Q9Y297 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates ubiquitination 9606 BTO:0000785 24469040 t lperfetto "_-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs _-trcp-mediated ezh2 degradation." SIGNOR-204481 KIF5B protein P33176 UNIPROT JAKMIP1 protein Q96N16 UNIPROT "up-regulates activity" relocalization 10090 17532644 t SARA "Marlin-1 is associated with kinesin-I and suggest that the movement of Marlin-1 is mediated by plus end microtubuledependent molecular motors" SIGNOR-260989 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 21993628 t gcesareni "The action of kit kinase inhibitors, especially imatinib, sunitinib, dasatinib and pkc412, on different primary and secondary mutants is discussed." SIGNOR-176760 CDK2 protein P24941 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 17389604 t gcesareni "Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1" SIGNOR-154051 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates activity" phosphorylation Thr119 AGTAGALtPQHVRAH 9606 24101154 t miannu "Specifically, we found that YAP is phosphorylated in vitro and in vivo by the cell cycle kinase CDK1 at T119, S289, and S367 during G2/M phase of the cell cycle." SIGNOR-279361 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270368 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT "up-regulates activity" phosphorylation Thr183 ACTNFMMtPYVVTRY -1 11062067 t "MKK7 phosphorylates SAPK2a p38 exclusively at Tyr-182. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7." SIGNOR-251417 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "precursor of" 9606 8755651 t scontino "Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3" SIGNOR-268127 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr775 QGWVPSNyITPVNSL 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260811 MAPK12 protein P53778 UNIPROT JUNB protein P17275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10330170 f gcesareni "Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements." SIGNOR-67532 APH1A protein Q96BI3 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t "Gamma secretase subunit that leads to PS1/PS2 eterodimer complex stabilisation." gcesareni "By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain." SIGNOR-93262 SRC protein P12931 UNIPROT ANXA1 protein P04083 UNIPROT unknown phosphorylation Thr216 AGERRKGtDVNVFNT 9606 24103589 t lperfetto "Location of sites in human lipocortin i that are phosphorylated by protein tyrosine kinases and protein kinases a and cthe primary site of phosphorylation by protein kinase c was also near the amino terminus at ser-27. The major site of phosphorylation by adenosine cyclic 3',5'-phosphate dependent protein kinase was on the carboxy-terminal half of the molecule at thr-216" SIGNOR-202800 RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "up-regulates activity" binding 10090 BTO:0000452 10795740 t gcesareni "We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation" SIGNOR-245026 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 21902831 t lperfetto "Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis." SIGNOR-216860 NLGN2 protein Q8NFZ4 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264166 POLR2H protein P52434 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266172 CBL protein P22681 UNIPROT PDGFRA protein P16234 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 10347229 t lperfetto "Cbl overexpression in nih3t3 cells enhanced the ubiquitination and degradation of the platelet-derived growth factor receptor-alpha (pdgfralpha)" SIGNOR-68024 GAL protein P22466 UNIPROT GALR2 protein O43603 UNIPROT up-regulates binding 9606 10601261 t gcesareni "Galanin showed high affinity for the galr1 (ic(50) = 0.097 nm) and galr2 receptors (ic(50) = 0.48 nm)." SIGNOR-73125 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89182 DYRK1A protein Q13627 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" phosphorylation 9606 22110360 t miannu "Moreover, Dyrk1A appears to directly phosphorylate the C-terminal domain of ASK1.|The current finding that Dyrk1A enhances the activities of ASK1 and JNK1, it could act as a pro-apoptotic player." SIGNOR-279366 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser283 PERSQEEsPPGSTKR 9606 34363019 t miannu "DYRK2 depletion by siRNA substantially increased CDC25A protein levels (Fig.\u00a01C) and led to an extension of its half-life (Supplementary Fig.\u00a01C).|Phosphorylation of CDC25A on S283 by DYRK2 could suggest a role for DYRK2 complementary to the CDK/cyclin complexes\u2019 action during mitotic exit." SIGNOR-279367 KDM5C protein P41229 UNIPROT BDNF protein P23560 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 31691806 f miannu "The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice." SIGNOR-264315 GLUD2 protein P49448 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "down-regulates quantity" "chemical modification" 9913 11254391 t miannu "Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate." SIGNOR-268558 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273070 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr246 STGGTPLtPAARISA 9606 BTO:0000007 16682949 t done miannu "Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1." SIGNOR-274086 CCR2 protein P41597 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 20219869 t areggio "The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2." SIGNOR-255117 TFEB protein P19484 UNIPROT NDUFA8 protein P51970 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 33176151 f lperfetto "Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4)." SIGNOR-276702 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "precursor of" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266538 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18519666 t "inferred from 70% family members" lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-270191 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t "MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction." SIGNOR-175833 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249349 "Translation release factor ERF1-ERF3" complex SIGNOR-C494 SIGNOR "protein polypeptide chain" smallmolecule CHEBI:16541 ChEBI "up-regulates quantity" "chemical modification" 9606 29735640 t miannu "Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide. " SIGNOR-270818 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral SNAI1 protein O95863 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003792 26675258 t Parnian "The overexpression of miR-30a restored E-cadherin levels, and inhibited the expression of both vimentin and Snail." SIGNOR-278000 LUBAC complex SIGNOR-C527 SIGNOR GLYR1 protein Q49A26 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys495 NILQGNFkPDFYLKY 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations." SIGNOR-272838 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI "2'-deoxycytosine 5'-monophosphate(2-)" smallmolecule CHEBI:57566 ChEBI "up-regulates quantity" "precursor of" 20637175 t lperfetto "Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis" SIGNOR-275810 UBE2C protein O00762 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 19632176 f miannu "The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint." SIGNOR-251544 TBK1 protein Q9UHD2 UNIPROT TNIP1 protein Q15025 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser122 KPPSSGTsSEFEVVT 36574265 t lperfetto "TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1" SIGNOR-275733 LEF1 protein Q9UJU2 UNIPROT CLDN2 protein P57739 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0003569 14751232 f lperfetto "Activity of the claudin-2 promoter was elevated in mouse mammary epithelial C57 cells expressing Wnt-1. LEF-1, a nuclear effector of the Wnt signaling pathway which is involved in the regulation of cell differentiation and polarization, was found to bind directly to the claudin-2 promoter as revealed by electrophoretic mobility shift assays. Expression of LEF-1 and beta-catenin both enhanced claudin-2 promoter activity." SIGNOR-254120 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 10090 BTO:0002572 22863277 f "inferred from 70% of family members" milica "Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2." SIGNOR-269868 PHF10 protein Q8WUB8 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270598 TGFB1 protein P01137 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by expression" 9606 17283133 f gcesareni "In normal primary endometrial epithelial cells (eecs), tgfbeta directly induced a dose-dependent increase in p27 protein levels and its nuclear localization" SIGNOR-152945 IKBKB protein O14920 UNIPROT TMIGD2 protein Q96BF3 UNIPROT "up-regulates activity" phosphorylation Ser220 GKDQRGQsIYSTSFP 9606 BTO:0000007 32978258 t miannu "Manipulating the IκB kinase β activity coupled with in vivo and in vitro kinase assays demonstrated that IκB kinase β is a key serine/threonine kinase activated by autophagy stimuli and that it catalyzes phosphorylation of IGPR-1 at Ser220 The subsequent activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase, which leads to phosphorylation of the major pro-autophagy proteins ULK1 and Beclin-1 (BECN1), increased LC3-II levels, and accumulation of LC3 punctum. " SIGNOR-273642 RPS6KA3 protein P51812 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" phosphorylation Thr1109 DRKIIATtLSKLKLE 9606 BTO:0002181 23608533 t miannu "We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding." SIGNOR-276463 TNF protein P01375 UNIPROT NOTCH4 protein Q99466 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004914 14586405 f "We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues." SIGNOR-253607 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTTG1 protein O95997 UNIPROT up-regulates phosphorylation 9606 10906323 t "inferred from 70% family members" gcesareni "Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function." SIGNOR-270155 O-phosphoethanolamine smallmolecule CHEBI:17553 ChEBI GABARAP protein O95166 UNIPROT up-regulates "chemical activation" 9606 16303767 t gcesareni "Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme)" SIGNOR-142011 MYC protein P01106 UNIPROT PRPS2 protein P11908 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18677108 t miannu "Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation." SIGNOR-267376 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR TNK1 protein Q13470 UNIPROT "down-regulates activity" binding 9606 BTO:0000018 34504101 t miannu "We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.Phosphorylation of TNK1 at S502 within the proline rich domain is required for TNK1 binding to 14-3-3.MARKs mediate phosphorylation at S502 and 14-3-3 binding to TNK1, which restrains the movement of TNK1 into heavy membrane-associated clusters." SIGNOR-273869 ABL1 protein P00519 UNIPROT BTK protein Q06187 UNIPROT "down-regulates activity" phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 12445832 t Manara "In this report we describe for the first time that ABL1 and Btk physically interact and that ABL1 can phosphorylate tyrosine 223 in the SH3 domain of Btk. | This is presumably due to the negative regulatory effectof Btk SH3 domain phosphorylation caused by ABL1,which would result in a decreased catalytic activity ofBtk resulting in impaired autophosphorylation." SIGNOR-260801 belinostat chemical CHEBI:61076 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257957 MAPK1 protein P28482 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9534 BTO:0004055 16705159 t "16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling." lperfetto "We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner" SIGNOR-236331 LPAR proteinfamily SIGNOR-PF2 SIGNOR PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser189 YRPKPSSsPVIFAGG 10090 BTO:0000665 17475908 t miannu "All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells." SIGNOR-262669 DIABLO protein Q9NR28 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 17546047 t gcesareni "Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release." SIGNOR-155364 RFC4 protein P35249 UNIPROT "RF-C complex" complex SIGNOR-C375 SIGNOR "form complex" binding 12930972 t lperfetto "RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned" SIGNOR-265508 SOSTDC1 protein Q6X4U4 UNIPROT BMP4 protein P12644 UNIPROT "down-regulates activity" 10090 18032587 f lperfetto "SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7" SIGNOR-242749 SIRT5 protein Q9NXA8 UNIPROT CPS1 protein P31327 UNIPROT "up-regulates activity" "post translational modification" 9606 BTO:0000567 24703693 t deglutarylation lperfetto "Glutarylation suppresses CPS1 activity, which is targeted by SIRT5 for removal|SIRT5 can catalyze the enzymatic removal of lysine glutarylation" SIGNOR-267643 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto "Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes." SIGNOR-252321 CDK5 protein Q00535 UNIPROT CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser313 RCRTLSGsPRPKNFK 9534 11733001 t miannu "P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed." SIGNOR-112418 SRC protein P12931 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 BTO:0000150;BTO:0000567 9500442 t tpavlidou "Although the molecular mechanisms underlying ligand-independent activation of era are not completely understood, phosphorylation of a serine residue in af1 has been implicated in the response to epidermal growth factor. Era is also a target for tyrosine phosphorylation, anda single tyrosine residue located immediately adjacent to af2 has been identified as a substrate for src-family tyrosine kinases." SIGNOR-55857 SYP protein P08247 UNIPROT VAMP2 protein P63027 UNIPROT "up-regulates quantity" binding 9606 26903854 t miannu "Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs." SIGNOR-264117 CSNK2A3 protein Q8NEV1 UNIPROT F8 protein P00451 UNIPROT "down-regulates activity" phosphorylation Ser1656 GRTERLCsQNPPVLK -1 8427963 t lperfetto "Our findings suggest that phosphorylation of factors Va and VIIIa by a platelet casein kinase II-like kinase may downregulate the activity of the two cofactors.| Recombinant human factor VIII also showed incorporation of radioactivity in the presence of purified casein kinase II at the acidic NH2-terminal portion of factor VIII light chain (residues 1648 through 1689). Based on all the considerations reported above Se1657 is the most likely candidate within this region capable of incorporation of radioactivity" SIGNOR-263649 HRAS protein P01112 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 t lperfetto "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-175183 GRB2 protein P62993 UNIPROT KIT protein P10721 UNIPROT down-regulates 9606 BTO:0001271 17904548 f miannu "Grb2 mediates c-kit degradation through recruitment of cbl to c-kit, leading to ubiquitination of c-kit followed by internalization and degradation" SIGNOR-157956 AREG protein P15514 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation 9606 7679104 t gcesareni "Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor" SIGNOR-31199 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" dephosphorylation Thr387 TMKRRDEtMQPAKPS 9606 20513427 t "PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis." SIGNOR-248329 PTPN1 protein P18031 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE 9534 BTO:0004055 16291744 t "The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK |The dephosphorylation at Tyr-397 in FAK triggered by wild-type alpha-actinin and PTP 1B caused a significant increase in cell migration." SIGNOR-248431 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258897 AURKC protein Q9UQB9 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-98361 TCF4 protein P15884 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18852287 t "Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription." SIGNOR-253324 bortezomib chemical CHEBI:52717 ChEBI PSMD2 protein Q13200 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000898 21504411 t miannu "Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma." SIGNOR-259313 FAM83D protein Q9H4H8 UNIPROT CSNK1A1 protein P48729 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273749 MAPK8IP2 protein Q13387 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 10490659 t "These data demonstrated that JIP2 increases JNK activation by the MLK signaling pathway" gcesareni "These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins." SIGNOR-70866 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr494 TGTDKLMtGVISPER 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141030 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT "up-regulates quantity" binding 25296192 t miannu "In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16." SIGNOR-266300 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser726 KKKEKVEs -1 8810272 t lperfetto "Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC." SIGNOR-248953 NOX5 protein Q96PH1 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" "chemical modification" 9606 17237347 t lperfetto "Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS)." SIGNOR-264725 BTK protein Q06187 UNIPROT DDX41 protein Q9UJV9 UNIPROT "up-regulates activity" phosphorylation Tyr414 DVIQEVEyVKEEAKM 10090 BTO:0002572 25704810 t miannu "The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site." SIGNOR-266404 MYC protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000785 20551174 f lperfetto "In tissue culture, ectopic expression of Myc suppresses the cell cycle arrest that occurs in response to several anti-mitogenic signals such as transforming growth factor β (TGFβ), since Myc represses expression of the cyclin-dependent kinase inhibitors (CKIs) p15ink4b, p21cip1, and p57kip2 via interaction with Miz1" SIGNOR-267575 PRKACA protein P17612 UNIPROT RARA protein P10276 UNIPROT "down-regulates activity" phosphorylation Ser219 NSSEQRVsLDIDLWD 9606 20215566 t miannu " Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity. " SIGNOR-276281 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates phosphorylation Ser196 RSLEVWGsQEALEEA 9606 16540648 t miannu "Atr was the major kinase responsible for the cellular phosphorylation of xpa following uv irradiation / we propose that the phosphorylation of xpa by atr checkpoint may positively regulate ner activity and thus may facilitate the cells to recover from ner-related dna damages." SIGNOR-145190 OXGR1 protein Q96P68 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257310 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 16403219 t lperfetto "All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death." SIGNOR-259421 ARHGAP31 protein Q2M1Z3 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260489 MMP23B protein O75900 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272367 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "up-regulates activity" binding 9534 BTO:0004055 12023018 t miannu "We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity." SIGNOR-272611 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr826 SRKVGPGyLGSGGSR 9534 BTO:0004055 8621380 t lperfetto "Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map " SIGNOR-248942 PREX2 protein Q70Z35 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 24367090 t irozzo "Here, we report that P-REX2 interacts with PTEN via two interfaces. In summary, P-REX2 docks to the PDZ-BD of PTEN through its C-terminal domain, reads the phosphorylation state of the PTEN tail via the DH domain, and inhibits PTEN activity by unleashing the PH domain" SIGNOR-259189 COL1A1 protein P02452 UNIPROT DDR2 protein Q16832 UNIPROT "up-regulates activity" binding 9606 BTO:0001282 17318226 t lperfetto "The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75. " SIGNOR-272342 KAT6A protein Q92794 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 SIGNOR-C54 11965546 t miannu "Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation." SIGNOR-117332 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 BTO:0000007 21059642 t "The effect has been demonstrated using Q01196-8" lperfetto "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." SIGNOR-216916 CDC42 protein P60953 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" binding 10090 BTO:0000142 8107774 t gcesareni "A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways." SIGNOR-248243 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT "down-regulates quantity by destabilization" cleavage Glu637 QKLVFFAeDVGSNKG -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261768 PPM1D protein O15297 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 15870257 t gcesareni "Ppm1d dephosphorylates chk1 phospho-ser 345" SIGNOR-135972 MAPK1 protein P28482 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 t gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription." SIGNOR-169001 PBRM1 protein Q86U86 UNIPROT CRABP2 protein P29373 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15601824 f miannu "We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues." SIGNOR-131552 TMPRSS2 protein O15393 UNIPROT S protein P59594 UNIPROT "up-regulates activity" cleavage 9606 32142651 t miannu "Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming." SIGNOR-260217 CASP6 protein P55212 UNIPROT N protein P59595 UNIPROT "up-regulates activity" cleavage Asp403 LPAADMDdFSRQLQN 9534 BTO:0001444 18155731 t Luana "Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403" SIGNOR-260212 GDF5 protein P43026 UNIPROT Cartilage_development phenotype SIGNOR-PH75 SIGNOR up-regulates 9606 21976273 f miannu "Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation." SIGNOR-252418 CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser273 PGQGGSTsAFEQLQR 9534 11733001 t miannu "P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed." SIGNOR-273183 arecoline chemical CHEBI:2814 ChEBI CHRM3 protein P20309 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258640 UBE4B protein O95155 UNIPROT FEZ1 protein Q99689 UNIPROT "up-regulates activity" polyubiquitination 10116 BTO:0001009 15466860 t K27 miannu " E4B mediated the polyubiquitylation of FEZ1 but did not affect its intracellular stability, suggesting that such modification of FEZ1 is not a signal for its proteolysis. Polyubiquitylation of FEZ1 by E4B required Lys(27) of ubiquitin. Expression of a dominant-negative mutant of E4B in rat pheochromocytoma PC12 cells resulted in inhibition of neurite extension induced either by nerve growth factor or by coexpression of FEZ1 and constitutively active PKCzeta. These findings indicate that E4B serves as a ubiquitin ligase for FEZ1 and thereby regulates its function but not its degradation. The polyubiquitin chain attached by E4B to FEZ1 might therefore facilitate the interaction of FEZ1 with an unidentified target that functions in neuritogenesis." SIGNOR-271510 CSNK1E protein P49674 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates activity" phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 t lperfetto "Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846" SIGNOR-274047 INCENP protein Q9NQS7 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates binding 9606 12925766 t gcesareni "Using recombinant proteins, we found that aurora b kinase activity was stimulated by incenp and that the c-terminal region of incenp was sufficient for activation." SIGNOR-86218 Hypoxia stimulus SIGNOR-ST25 SIGNOR EGLN1 protein Q9GZT9 UNIPROT down-regulates 9606 32755251 f lperfetto "Under hypoxic conditions, PHD2 activity is limited, and therefore HIF-1α protein is stabilized, leading to an increase in the transcription of erythropoietin as well as hundreds of target genes that coordinate diverse processes" SIGNOR-261995 AMBRA1 protein Q9C0C7 UNIPROT HUWE1 protein Q7Z6Z7 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 phosphorylation:Ser1043 CRPEALNsGVEYYWD 30217973 t lperfetto "AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome" SIGNOR-272962 MAPK3 protein P27361 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-203290 COL15A1 protein P39059 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium" SIGNOR-254678 CDK2 protein P24941 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation 9606 26960431 t miannu "Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity.|Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry." SIGNOR-279322 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 17977820 t lperfetto "In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I" SIGNOR-209784 MAPK14 protein Q16539 UNIPROT MAPKAPK3 protein Q16644 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 11157753 t lperfetto "These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38." SIGNOR-235451 PRKACA protein P17612 UNIPROT CACNA1H protein O95180 UNIPROT "down-regulates activity" phosphorylation Ser1107 LPDSRRGsSSSGDPP 9606 19131331 t miannu "Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity." SIGNOR-263110 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190203 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 t miannu "PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1." SIGNOR-262868 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR BIRC5 protein O15392 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys91 CAFLSVKkQFEELTL 10090 BTO:0002268 25778398 t miannu "Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation." SIGNOR-272439 ATR protein Q13535 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11865061 t gcesareni "Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation." SIGNOR-115134 CACNA2D3 protein Q8IZS8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9606 31746409 f miannu "The results indicated that the overexpression of CACNA2D3 induced an increase in intracellular Ca2+ and increased the levels of p-p38 MAPK. These data indicated that the p38 MAPK pathway is activated by overexpression of CACNA2D3 and P4 induction." SIGNOR-266857 SGF29 protein Q96ES7 UNIPROT "SAGA complex" complex SIGNOR-C465 SIGNOR "form complex" binding 9606 34811519 t lperfetto "Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module" SIGNOR-269572 TSC1 protein Q92574 UNIPROT TSC complex SIGNOR-C101 SIGNOR "form complex" binding 9606 12172553 t lperfetto "TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR)." SIGNOR-217910 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "up-regulates quantity" "precursor of" 9606 31422819 t miannu "Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate." SIGNOR-266921 SOCS4 protein Q8WXH5 UNIPROT DAB1 protein O75553 UNIPROT "down-regulates quantity by destabilization" binding 9534 BTO:0000298 24210661 t miannu "SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1." SIGNOR-272139 PRKCE protein Q02156 UNIPROT GAD1 protein Q99259 UNIPROT "down-regulates activity" phosphorylation Thr91 RDARFRRtETDFSNL -1 15147202 t lperfetto "We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. Site-directed mutation of T91 to alanine abolished PKA-mediated phosphorylation and inhibition of GAD activity." SIGNOR-249264 SHMT1 protein P34896 UNIPROT 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI "up-regulates quantity" "chemical modification" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269688 RPS6KA1 protein Q15418 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto "In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway" SIGNOR-178586 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263438 LNX2 protein Q8N448 UNIPROT NUMB protein P49757 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 26451611 t miannu "Polyubiquitination of Human Numb by LNX2. The Zn-RING-Zn domain of LNX2 is a dimer and assumes a rigid elongated structure that undergoes autoubiquitination and undergoes N-terminal polyubiquitination. LNX2 can bind numb and induce its ubiquitination and subsequent proteasomal degradation" SIGNOR-272423 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Thr112 EGMQIPStQFDAAHP 9606 12432063 t llicata "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin" SIGNOR-251067 CACNA1D protein Q01668 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795])." SIGNOR-264331 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu60 LERECMEeTCSYEEA -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263669 CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto "In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329." SIGNOR-261749 TNF protein P01375 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253479 SPX protein Q9BT56 UNIPROT GALR2 protein O43603 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24517231 t lperfetto "Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III." SIGNOR-268574 AURKB protein Q96GD4 UNIPROT CDCA2 protein Q69YH5 UNIPROT "down-regulates activity" phosphorylation Ser977 EPGKRRKsFCISTLA 9606 BTO:0000567 32938714 t done miannu "This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin." SIGNOR-274004 SATB1 protein Q01826 UNIPROT IGFBP2 protein P18065 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255129 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9823 BTO:0004007 10523831 t lperfetto "Phosphorylation of the adapter protein shc by growth factor receptors provides association sites for grb2-sos, thereby activating the ras/map kinase pathway." SIGNOR-235615 LCK protein P06239 UNIPROT ITK protein Q08881 UNIPROT up-regulates phosphorylation Tyr512 RFVLDDQyTSSTGTK -1 9312162 t "Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. The major site of Lck phosphorylation on Itk was mapped to the conserved tyrosine (Tyr511) in the activation loop of the Itk kinase domain." SIGNOR-251380 BRAP protein Q7Z569 UNIPROT KSR1 protein Q8IVT5 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 23105109 t miannu "Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15." SIGNOR-272028 VCP protein P55072 UNIPROT "RQC complex" complex SIGNOR-C559 SIGNOR "form complex" binding 28528489 t lperfetto "The ribosome-bound quality control (RQC) complex is a multi-protein complex conserved throughout eukaryotes and composed of the E3 ubiquitin ligase Ltn1/Listerin, the ATPase Cdc48/p97 with its co-factors Ufd1/UFD1L and Npl4/NPLOC4, as well as the factors Rqc1/TCF25 and Rqc2/NEMF (Fig. 1)." SIGNOR-277695 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19114991 t lpetrilli "In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity" SIGNOR-182822 AKT1 protein P31749 UNIPROT HK2 protein P52789 UNIPROT "up-regulates activity" phosphorylation Thr473 QHRARQKtLEHLQLS 9606 BTO:0000192 31435020 t "K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization" SIGNOR-259984 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr312 ISYDIPPtPGNTYQI 9606 15379552 t lperfetto "Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)" SIGNOR-129196 TRAF6 protein Q9Y4K3 UNIPROT MAP3K8 protein P41279 UNIPROT "up-regulates activity" 9606 BTO:0000007 16371247 f "The activation of Cot-MKK1-ERK1/ERK2 signalling pathway by IL-1 is dependent on the activity of the transducer protein TRAF6." SIGNOR-252254 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 7535770 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-28063 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2D protein Q14814 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser110 GEDSLEQsPLLEDKY 10090 BTO:0000944 25733682 t miannu " MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding. " SIGNOR-276888 RET protein P07949 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t lperfetto "The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity" SIGNOR-166514 SIX1 protein Q15475 UNIPROT EZR protein P15311 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 16488997 t "We now show that the gene encoding Ezrin is a direct transcriptional target of Six1." SIGNOR-259374 BMP1 protein P13497 UNIPROT COL7A1 protein Q02388 UNIPROT "up-regulates quantity" cleavage Ala2821 RPLPSYAaDTAGSQL 9606 BTO:0000667 11986329 t miannu " We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA/DTAG within the NC-2 domain. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen." SIGNOR-256338 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT "up-regulates activity" phosphorylation Ser607 NLIDLAGsERCSTAH 9606 BTO:0000565 28630147 t miannu "Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C)." SIGNOR-266417 NEK6 protein Q9HC98 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 20595392 t done miannu "Our data also show that NEK6 interacts with STAT3, an oncogenic transcription factor, and phosphorylates STAT3 on Ser(727), which is important for transcriptional activation. These results demonstrate that NEK6 interacts with and phosphorylates STAT3, an event that could play an important role in oncogenesis. For the maximal activation of STAT3 signaling, phosphorylation of both Tyr705 and Ser727 is required. Phosphorylation of Tyr705 induces dimerization, nuclear translocation, and DNA binding of the STAT3 protein, whereas phosphorylation of Ser727 is important for transcriptional activation." SIGNOR-273901 PTK2 protein Q05397 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 17828307 t miannu "Cell reconstitution showed that FAK catalytic activity is required for alpha5beta1-stimulated Src activation in part through direct FAK phosphorylation of Src at Tyr-418." SIGNOR-278452 BRD4 protein O60885 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "up-regulates activity" binding 9606 16109377 t miannu "Binding of Brd4 to Core P-TEFb Is Essential for Transcription." SIGNOR-266411 VRK2 protein Q86Y07 UNIPROT GAPDH protein P04406 UNIPROT "up-regulates activity" phosphorylation Ser151 LKIISNAsCTTNCLA 9606 BTO:0000578 37450367 t miannu "Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation. " SIGNOR-277840 NUPR1 protein O60356 UNIPROT ATF4 protein P18848 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 19946894 f lperfetto "Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4." SIGNOR-253731 ITGA2B protein P08514 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253197 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131838 BST1 protein Q10588 UNIPROT NAD(+) smallmolecule CHEBI:15846 ChEBI "down-regulates quantity" "chemical modification" 9606 18626062 t miannu "The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR." SIGNOR-264250 MRGPRX2 protein Q96LB1 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257172 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNB1 protein P14635 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189969 POU5F1 protein Q01860 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 f flangone "Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. " SIGNOR-242067 CDR2 protein Q01850 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" binding 20383333 t lperfetto "Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis." SIGNOR-252000 "SWI/SNF ACTL6A-ARID1A-SMARCA2 variant" complex SIGNOR-C470 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 f miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269828 POU5F1 protein Q01860 UNIPROT DLX5 protein P56178 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254935 VHL protein P40337 UNIPROT CARD9 protein Q9H257 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 17936701 t "We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2." SIGNOR-266899 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-250557 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t "We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction" SIGNOR-259921 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 18487050 t Luana "For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. " SIGNOR-257795 SGK1 protein O00141 UNIPROT WNK4 protein Q96J92 UNIPROT "down-regulates activity" phosphorylation Ser1217 PGIMRRNsLSGSSTG 9606 27517916 t miannu "Constitutively active SGK1 S422D phosphorylates WNK4 at Ser-1169 [ xref ] and Ser-1196 [ xref ], relieving the inhibitory effect of WNK4 on NCC\u2019s activity [ xref , xref ].|SGK1 is thought to modulate NCC activity by inhibiting WNK4 , , ]." SIGNOR-278453 ATOH7 protein Q8N100 UNIPROT POU4F2 protein Q12837 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 11172005 t Luana "Thus, these data suggest that the expression of Brn3b can be activated directly by Math5 and that it is also subject to positive feedback regulation by Brn3 proteins." SIGNOR-261567 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser27 ADREAASsPAGEPLR 9606 20027304 t "This phosphorylation increased sirt1 nuclear localization" gcesareni "Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53." SIGNOR-162314 sabcomeline chemical CHEBI:134846 ChEBI CHRM4 protein P08173 UNIPROT "up-regulates activity" "chemical activation" 10116 9399977 t miannu "SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes" SIGNOR-258675 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR PSEN1 protein P49768 UNIPROT "down-regulates activity" phosphorylation Ser353 SHLGPHRsTPESRAA 9606 BTO:0000007 17360711 t gcesareni "We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin." SIGNOR-228018 MAPK1 protein P28482 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 9606 16314496 t fstefani "We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription." SIGNOR-142458 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265777 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000150 10550055 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-72083 VIM protein P08670 UNIPROT LARP6 protein Q9BRS8 UNIPROT "up-regulates activity" binding 9606 21746880 t miannu "Interaction of LARP6 with vimentin.Here, we report that vimentin filaments associate with collagen mRNAs in a 5'SL- and LARP6-dependent manner and stabilize collagen mRNAs. LARP6 interacts with vimentin filaments through its La domain and colocalizes with the filaments in vivo." SIGNOR-277624 NOTCH1 protein P46531 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19165418 f lperfetto "Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1." SIGNOR-183507 CDH19 protein Q9H159 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265858 SP1 protein P08047 UNIPROT TNC protein P24821 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000452 15001984 t Luana "Sp1 and Ets1 are potent transactivators of the TN-C promoter." SIGNOR-261600 "Caspase 9 complex" complex SIGNOR-C229 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 15657060 t lperfetto "Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3." SIGNOR-256448 SUN5 protein Q8TC36 UNIPROT "LINC complex" complex SIGNOR-C303 SIGNOR "form complex" binding 24481844 t lperfetto "LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM." SIGNOR-263289 EPAS1 protein Q99814 UNIPROT CACNA1A protein O00555 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15833863 f miannu "A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Ten genes were preferentially activated by HIF-2alpha, including two (CACNA1A and PTPRZ1) implicated in neurologic diseases." SIGNOR-264332 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr642 TRQPVELtPTDKLFI 9606 17115692 t lperfetto "The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif" SIGNOR-150865 PML protein P29590 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15093545 f gcesareni "The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor" SIGNOR-124320 PRKACA protein P17612 UNIPROT LCP1 protein P13796 UNIPROT up-regulates phosphorylation Ser5 sVSDEEMM 9606 BTO:0000007 16636079 t gcesareni "Phosphorylation on ser5 increases the f-actin-binding activity of l-plastin and promotes its targeting to sites of actin assembly in cells. L-plastin phosphorylation require protein kinase a." SIGNOR-146287 RB1 protein P06400 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 21902831 t gcesareni "Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation." SIGNOR-176563 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR FXR1 protein P51114 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 29142209 t miannu "Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinomaThe Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4. " SIGNOR-272797 PHF12 protein Q96QT6 UNIPROT TLE3 protein Q04726 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11390640 t miannu "We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE." SIGNOR-266993 PIK3R3 protein Q92569 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 32606738 t miannu "N this study, we aimed to explore the interaction of p55PIK with p53 and the role of p55PIK in regulating p53-dependent apoptosis in cancer cells. We found that p55PIK directly binds to the DBD domain of p53 via N24 domain. Moreover, the upregulation of p55PIK expression increases transcriptional levels of p53-dependent apoptosis-related genes including GADD45α, S100A9, MDM2 and AIP1. Furthermore, synthetic N24 translocated to nucleus can significantly inhibit cancer cell growth." SIGNOR-261492 PHF12 protein Q96QT6 UNIPROT SIN3A protein Q96ST3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11390640 t miannu "Pf1 interacts with mSin3A in vivo. Gal4-Pf1 repressed activity of the reporter gene fivefold relative to Gal4 alone (Fig. ​(Fig.5A),5A), suggesting that DNA-bound Pf1 was capable of recruiting functional mSin3A complexes." SIGNOR-266995 HSP90AB1 protein P08238 UNIPROT FLCN protein Q8NFG4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 27353360 t miannu "Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability." SIGNOR-261418 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 14645234 t gcesareni "Pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. Furthermore, phosphorylation of either serine 16 or 63 is sufficient to inhibit op18/stathmin in vitro." SIGNOR-119483 IDH3B protein O43837 UNIPROT IDH complex SIGNOR-C396 SIGNOR "form complex" binding 9606 28139779 t miannu "Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP." SIGNOR-266249 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-252838 GATAD2B protein Q8WXI9 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263857 buprenorphine chemical CHEBI:3216 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258940 FBXO15 protein Q8NCQ5 UNIPROT CRLS1 protein Q9UJA2 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0005816 24703837 t miannu "Fbxo15 Targets CLS1 Protein for Ubiquitination and Degradation to Disrupt Mitochondrial Function. S. aureus infection induces expression of a kinase, PINK1, that phosphorylates an indispensable protein CLS1, which in turn triggers CLS1 ubiquitination and degradation by the F box protein (SCFFbxo15)." SIGNOR-272170 G6PD protein P11413 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI "up-regulates quantity" "chemical modification" 9606 24769394 t miannu "G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress" SIGNOR-267051 SIRT2 protein Q8IXJ6 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 14522900 f miannu " In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity." SIGNOR-254481 MFGE8 protein Q08431 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" 9606 21901532 f miannu "In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production" SIGNOR-260654 RXRA protein P19793 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 10976919 t gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr)." SIGNOR-81446 JAK2 protein O60674 UNIPROT GTF2I protein P78347 UNIPROT "up-regulates activity" phosphorylation Tyr248 EESEDPDyYQYNIQA 10090 BTO:0000944 11313464 t lperfetto "Jak2 activates tfii-i and regulates its interaction with extracellular signal-regulated kinase the interaction between tfii-i and erk, which is essential for its activity, can be regulated by jak2 through phosphorylation of tfii-i at tyrosine 248" SIGNOR-235313 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 14585074 t amattioni "Trail interacts with tril-r1 and trail-r2 and activetes them" SIGNOR-101313 CREB1 protein P16220 UNIPROT CHGA protein P10645 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001007 12456801 t "Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation." SIGNOR-254276 AKT proteinfamily SIGNOR-PF24 SIGNOR ARHGAP22 protein Q7Z5H3 UNIPROT "up-regulates activity" phosphorylation Ser16 ARRARSKsLVMGEQS 9606 BTO:0000007 21969604 t miannu "Akt phosphorylates RhoGAP22 at the 14-3-3 binding site and is required for insulin-stimulated 14-3-3 binding. we have demonstrated that Akt is the kinase responsible for phosphorylation of Ser16 in order to mediate 14-3-3 binding to RhoGAP22." SIGNOR-262613 MAPK9 protein P45984 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134576 FGF2 protein P09038 UNIPROT ENPP1 protein P22413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004473 19049325 f miannu "FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2." SIGNOR-252191 ITGB1 protein P05556 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253178 SMARCA5 protein O60264 UNIPROT WICH complex SIGNOR-C449 SIGNOR "form complex" binding 9606 16603771 t miannu "We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling." SIGNOR-268827 ADSS2 protein P30520 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI "down-regulates quantity" "chemical modification" 9606 10496970 t miannu "Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP." SIGNOR-267343 AP1 complex SIGNOR-C154 SIGNOR CXCL8 protein P10145 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32446778 f miannu "The up-regulation of the CXCL8 gene expression, could be due to a direct effect of the virus at the cellular level. Indeed, intestinal and lung cells lines infected by SARS-CoV, promptly increase their secretion of CXCL8 [88]. This observation would fit with the notion that the expression of CXCL8 is dependent on the tran-scription factor Activator protein 1 (AP-1), which was shown to bestrongly up-regulated by SARS-CoV" SIGNOR-261029 ECM stimulus SIGNOR-ST20 SIGNOR "AX/b2 integrin" complex SIGNOR-C171 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259053 SMARCC2 protein Q8TAQ2 UNIPROT "Neural progenitor-specific SWI/SNF" complex SIGNOR-C477 SIGNOR "form complex" binding 9606 25195934 t miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270616 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-252606 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL4 protein P05112 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu "Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation" SIGNOR-263822 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "up-regulates activity" BTO:0001103 7532173 f "Simone Vumbaca" "These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds." SIGNOR-255644 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP73 protein O15350 UNIPROT up-regulates 9606 17700533 t miannu "These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated." SIGNOR-255472 MAPK3 protein P27361 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser62 SYTPTPRsPRFIGRR 9606 7901013 t gcesareni "In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11" SIGNOR-34678 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Thr501 QMDSGYNtQNCGSNI 9606 18378770 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178154 ATP5PD protein O75947 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261404 nifedipine chemical CHEBI:7565 ChEBI NR1I2 protein O75469 UNIPROT "up-regulates activity" "chemical activation" 9606 9770465 t miannu "In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR." SIGNOR-259066 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM2 protein P0DP24 UNIPROT up-regulates "chemical activation" 10090 10448861 t miannu "Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1." SIGNOR-266318 PPP1CA protein P62136 UNIPROT CCND3 protein P30281 UNIPROT up-regulates dephosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 t lperfetto "These results support the hypothesis that pp1 constitutively keeps cyclin d3 in a stable, dephosphorylated state" SIGNOR-142884 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9009272 t miannu "For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system." SIGNOR-258580 VTN protein P04004 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 7559467 t lperfetto "The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin." SIGNOR-253307 LMNA protein P02545 UNIPROT SUN2 protein Q9UH99 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 16380439 t Sara "In the case of Sun2, there is some evidence that A-type lamins might contribute to Sun2 localization in the INM. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation." SIGNOR-261310 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI "glycine zwitterion" smallmolecule CHEBI:57305 ChEBI "up-regulates quantity" "precursor of" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269691 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" SIGNOR-236764 miR-155 mirna URS000062749E_9606 RNAcentral TRIB2 protein Q92519 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 20516212 t Luisa "ZEB2 is upregulated by serum and downregulates GAX, while the expression of miR-221 upregulates GAX and downregulates ZEB2." SIGNOR-268956 NEK2 protein P51955 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates phosphorylation 9606 10880350 t lperfetto "Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2" SIGNOR-264655 ATG4B protein Q9Y4P1 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates cleavage 9606 BTO:0000007;BTO:0000567 15187094 t gcesareni "Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16." SIGNOR-125449 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 12054501 t lperfetto "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction" SIGNOR-249166 ATM protein Q13315 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT "up-regulates activity" phosphorylation Ser214 KIQELQAsQEARADH 9606 24728176 t miannu "ATM mediated Mad1 Serine 214 phosphorylation regulates Mad1 dimerization and the spindle assembly checkpoint.|Together, these findings reveal an important role of ATM-mediated Mad1 Serine 214 phosphorylation in mitosis." SIGNOR-278467 GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" 9606 20510530 t fferrentino "GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis" SIGNOR-132949 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser518 PSTSKAVsPPHLDGP 9606 BTO:0000551 16873060 t gcesareni "Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517." SIGNOR-148306 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191481 CAMK2G protein Q13555 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1070 DSFLQRYsSDPTGAL BTO:0000017 1309762 t llicata "The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity. " SIGNOR-250694 YAP1 protein P46937 UNIPROT CDC6 protein Q99741 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001939 30224758 f lperfetto "By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ." SIGNOR-276564 STAT6 protein P42226 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" binding 9606 BTO:0000801 10982806 t lperfetto "STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site" SIGNOR-249553 "AMG 900" chemical CID:24856041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189492 ATIC protein P31939 UNIPROT 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI "up-regulates quantity" "chemical modification" 9606 33179964 t miannu "The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP." SIGNOR-267327 FAM83E protein Q2M2I3 UNIPROT CSNK1D protein P48730 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273767 NCOR2 protein Q9Y618 UNIPROT AR protein P10275 UNIPROT down-regulates acetylation 9606 BTO:0000150;BTO:0001130 12771131 t gcesareni "In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases." SIGNOR-101286 GSPT1 protein P15170 UNIPROT "Translation release factor ERF1-ERF3" complex SIGNOR-C494 SIGNOR "form complex" binding 9606 29735640 t miannu "Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex." SIGNOR-270814 MSH6 protein P52701 UNIPROT BLM protein P54132 UNIPROT up-regulates binding 9606 SIGNOR-C60 15064730 t miannu "We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro" SIGNOR-123705 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI "prostaglandin H2(1-)" smallmolecule CHEBI:57405 ChEBI "up-regulates quantity" "precursor of" -1 10922363 t Luana "Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently." SIGNOR-269767 PINK1 protein Q9BXM7 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates phosphorylation Ser142 VPSPPPAsPRSQYNF 9606 17906618 t gcesareni "Htra2 is phosphorylated on activation of the p38 pathway, occurring in a pink1-dependent mannerwe suggest that pink1-dependent phosphorylation of htra2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress." SIGNOR-158052 IKK-complex complex SIGNOR-C14 SIGNOR MTURN protein Q8N3F0 UNIPROT "down-regulates activity" phosphorylation Ser58 GDNFHVWsESEDCLP 10090 BTO:0002572 28704656 t miannu "Here we report that viral infection induced upregulation of INKIT, an inhibitor for NF-κB and IRF3 that restricted innate antiviral responses by blocking phosphorylation of p65 and IRF3. Viral infection induced IKK-mediated phosphorylation of INKIT at Ser58, resulting in its dissociation from the IKKs. INKIT is associated with IKKα/β and TBK1/IKKɛ and inhibits the recruitment and phosphorylation of p65 and IRF3, respectively. IKKα and TBK1 phosphorylate INKIT at Ser58, which results in disassociation of INKIT from IKKα or TBK1 and thereby allows for the subsequent recruitment and phosphorylation of p65 and IRF3" SIGNOR-273641 midostaurin chemical CHEBI:63452 ChEBI FGR protein P09769 UNIPROT "down-regulates activity" "chemical inhibition" -1 30069632 t Gianni "Midostaurin (PKC412, Rydapt®) is an oral multiple tyrosine kinase inhibitor. Main targets are the kinase domain receptor, vascular endothelial-, platelet derived-, and fibroblast growth factor receptor, stem cell factor receptor c-KIT, as well as mutated and wild-type FLT3 kinase" SIGNOR-261976 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr219 DGSDHPYyNSIPSKM -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273912 TNKS2 protein Q9H2K2 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 19759537 t lperfetto "Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin." SIGNOR-263378 FN1 protein P02751 UNIPROT FN1/SDC4 complex SIGNOR-C210 SIGNOR "form complex" binding 23290138 t apalma "We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells" SIGNOR-255285 RPL27 protein P61353 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262474 VAC14 protein Q08AM6 UNIPROT FIG4 protein Q92562 UNIPROT "up-regulates quantity by stabilization" binding 9534 BTO:0000298 20630877 t miannu "Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction." SIGNOR-253534 CASP7 protein P55210 UNIPROT PARP1 protein P09874 UNIPROT down-regulates cleavage 9606 11058599 t amattioni "Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis." SIGNOR-83703 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248368 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248296 TGFB1 protein P01137 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates activity" binding 9606 16885528 t lperfetto "The active form of TGF-beta is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge." SIGNOR-148605 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT "up-regulates activity" phosphorylation Ser2251 ASPLASSerPVRKNL -1 26051540 t irozzo "Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment." SIGNOR-259119 DAPK1 protein P53355 UNIPROT RPL5 protein P46777 UNIPROT unknown phosphorylation 9606 18283219 t lperfetto "Here we adapted this strategy to successfully screen for dapk substrates. We report the identification of two substrates, ribosomal protein l5 and mcm3." SIGNOR-160954 BCL3 protein P20749 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16384933 f gcesareni "One mechanism by which this inhibition occurs is through bcl-3-mediated induction of the p53 inhibitor hdm2. Both stable and transient overexpression of bcl-3 leads to increased hdm2 expression, and small interfering rna (sirna)-mediated knockdown of bcl-3 blocks expression of hdm2. ( articolo-abstract)" SIGNOR-143403 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 21295084 t amattioni "Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction." SIGNOR-256452 SMURF2 protein Q9HAU4 UNIPROT SMAD7 protein O15105 UNIPROT "down-regulates activity" ubiquitination 9606 18448069 t lperfetto "The association of Smurf2 with Smad7 and its ubiquitination were inhibited by AIMP1, thereby protecting its autocatalytic degradation stimulated by Smad7." SIGNOR-178501 SRGAP2 protein O75044 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260516 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT "down-regulates activity" phosphorylation Ser18 ANRTPPKsPGDPSKD -1 17693641 t miannu "Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP." SIGNOR-262932 BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR "up-regulates activity" phosphorylation 9606 "BTO:0000165;BTO:0002974; BTO:0002809" 9442019 t ggiuliani "In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus." SIGNOR-255830 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR ALDH3B1 protein P43353 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0001078 26124079 t miannu "We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members." SIGNOR-272819 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Ser974 EESLAEMsIMTTELQ 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159574 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 t llicata "Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291." SIGNOR-176871 BCL2L2 protein Q92843 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17452531 t gcesareni "Bcl-w may protect largely via its ability to associate with bax because it could efficiently protect xem from tbid and bid, bad, hrk, and bmf bh3 peptides" SIGNOR-154518 IL33 protein O95760 UNIPROT IL1RL1 protein Q01638 UNIPROT "up-regulates activity" binding 9606 BTO:0001679 16286016 t miannu "We report a member of the IL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs.The binding of IL-33 to cells that express ST2 results in the activation of NF-κB and MAP kinases. Administration of purified IL-33 either in vitro or in vivo leads to the production of TH2-associated cytokines." SIGNOR-277711 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA -1 11313365 t miannu "ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner." SIGNOR-252596 Nalmefene chemical CHEBI:7457 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258811 PGM1 protein P36871 UNIPROT "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI "up-regulates quantity" "chemical modification" 9606 32898648 t miannu "Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P)." SIGNOR-267929 PDK1 protein Q15118 UNIPROT PKN2 protein Q16513 UNIPROT "up-regulates activity" phosphorylation Thr816 GYGDRTStFCGTPEF 9606 BTO:0000007 10753910 t miannu "PDK1 phosphorylates the PRKs at their conserved activation loop threonines (Thr-774 and Thr-816 for PRK1 and PRK2, respectively) both in vitro and in vivo." SIGNOR-250265 PTPN11 protein Q06124 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates dephosphorylation Tyr1023 DLVDAEEyLVPQQGF -1 32024694 t lperfetto "...which in turn suggests the importance SHP2 dephosphorylation of pTyr992 in EGFR and pTyr1023 in HER2 to mediate signaling.|More specifically, we show that acidic residues N-terminal to the substrate pTyr in EGFR and HER2 mediate specific binding by the SHP2 active site, leading to blockade of RasGAP binding and optimal signaling by the two receptors." SIGNOR-262957 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI "up-regulates quantity" "precursor of" 9606 31586547 t miannu "The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG)." SIGNOR-267056 SUN1 protein O94901 UNIPROT TERB1 protein Q8NA31 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 SIGNOR-C303 SIGNOR-C305 33015044 t lperfetto "In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex." SIGNOR-263299 "vitamin K" smallmolecule CHEBI:28384 ChEBI "Reduced Vitamin K" smallmolecule CHEBI:8784 ChEBI "up-regulates quantity" "precursor of" 9606 31226734 t lperfetto "This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)" SIGNOR-265915 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002417 15358865 t gcesareni "Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch." SIGNOR-245315 JUN protein P05412 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 10090 BTO:0000725 17041602 f miannu "These results show that restoration of c-Jun expression rescues the myelomonocytic differentiation block in preleukemic PU.1-knockdown bone marrow cells, suggesting that c-Jun is a critical downstream target in PU.1-knockdown HSCs." SIGNOR-256066 TFIIH complex SIGNOR-C457 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser403 PEEFISLsPPHEALD 9606 10428966 t lperfetto "These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase.  here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain." SIGNOR-269353 AZD1480 chemical CID:16659841 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190167 P2RY1 protein P47900 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257442 CAMK2G protein Q13555 UNIPROT CHAT protein P28329 UNIPROT "up-regulates activity" phosphorylation Thr574 VDNIRSAtPEALAFV BTO:0000932 12486117 t llicata "Using mass spectrometry, we identified threonine 456 as a new phosphorylation site in choline acetyltransferase from A beta-(1-42)-treated cells and in purified recombinant ChAT phosphorylated in vitro by calcium/calmodulin-dependent protein kinase II (CaM kinase II). | This phosphorylation combination was observed in choline acetyltransferase from A beta-(1-42)-treated cells. Treatment of cells with A beta-(1-42) resulted in two phases of activation of choline acetyltransferase, the first within 30 min and associated with phosphorylation by protein kinase C and the second by 10 h and associated with phosphorylation by both CaM kinase II and protein kinase C." SIGNOR-250693 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120084 RUNX2 protein Q13950 UNIPROT VEGFC protein P49767 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001610 22641097 f miannu "Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells." SIGNOR-255081 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser251 GKLGGQDsFESIESY 9606 BTO:0000782 12475968 t lperfetto "Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition" SIGNOR-96330 CRY1 protein Q16526 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR "down-regulates activity" binding 9606 20817722 t miannu "The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop." SIGNOR-267975 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000782 18840653 t gcesareni "Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well." SIGNOR-181550 ULK1 protein O75385 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser227 VQQNMMNsASGPLPD 9606 BTO:0003491 34345207 t miannu "Mechanistically, hypoxia stimulates ULK1 to translocate into nucleus, where it interacts with and phosphorylates yes-associated protein (YAP) at Ser227, resulting in YAP stabilization through blockade of ubiquitin-proteasome system (UPS), which in turn facilitates PKM2 transcription, glycolysis, cell proliferation in vitro as well as PDAC growth in mice." SIGNOR-277570 MYO10 protein Q9HD67 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 27580874 f miannu "Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments." SIGNOR-268283 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr526 LRADENYyKAQTHGK 9606 BTO:0000776 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246621 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-119233 MEST protein Q5EB52 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates "transcriptional regulation" 9606 24827625 f areggio "Our data demonstrate that Mest alleviated CCl4-induced collagen deposition in liver tissue and improved the condition of the liver in rats. Mest also significantly reduced the expression and distribution of β-catenin, α-SMA and Smad3 both in vivo and in vitro, in addition to the viability of HSCs in vitro." SIGNOR-258982 PERP protein Q96FX8 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity" ubiquitination 9606 25860612 t "We identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling" SIGNOR-255843 FKBP15 protein Q5T1M5 UNIPROT ACTB protein P60709 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 19121306 t Giulio "However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin." SIGNOR-260595 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates activity" phosphorylation 9606 SIGNOR-C3 19690328 t lperfetto "The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated." SIGNOR-187611 KAT2A protein Q92830 UNIPROT H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269608 STAT5A protein P42229 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR "form complex" binding 9606 8878484 t fspada "We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter." SIGNOR-44379 PSTPIP1 protein O43586 UNIPROT DNM2 protein P50570 UNIPROT down-regulates binding 9606 18480402 t miannu "We show that pstpip1 associates with the regulator of endocytosis, dynamin 2, and pstpip1 expression impairs transferrin uptake and endocytosis" SIGNOR-178628 ASNS protein P08243 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 29084849 t miannu "Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7." SIGNOR-267534 KCNMA1 protein Q12791 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31152168 t miannu "The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3." SIGNOR-269198 MRPS18B protein Q9Y676 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261452 CD3 complex SIGNOR-C432 SIGNOR NCK1 protein P16333 UNIPROT "up-regulates activity" relocalization 9606 12110186 t "We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck." SIGNOR-259935 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10606744 t gcesareni "Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15." SIGNOR-73266 AIP protein O00170 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates activity" "transcriptional regulation" 9606 BTO:0000093 21984905 t "The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α." SIGNOR-253644 GPS1 protein Q13098 UNIPROT "COP9 signalosome variant 2" complex SIGNOR-C487 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270765 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr301 PPGEDSDtDVDDDSR 9606 18678890 t gcesareni "The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites." SIGNOR-179883 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Ser27 SFGFTRTsARRRLAD 21880142 t miannu "Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266299 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR tRNA(Leu) smallmolecule CHEBI:29169 ChEBI "down-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270411 PRKCQ protein Q04759 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT up-regulates phosphorylation Ser960 KKRVRRSsFLNAKKL 9606 BTO:0000782 18796635 t lperfetto "After t-cell activation, the direct phosphorylation of rapgef2 at ser960 by pkc- theta regulates rap1 activation as well as lfa-1 adhesiveness to icam-1. Pkc- theta and its effector rapgef2 are critical factors in tcr signaling to rap1" SIGNOR-181186 SELE protein P16581 UNIPROT ITGAL protein P20701 UNIPROT up-regulates 9606 BTO:0000130 23994464 f apalma "This deceleration is due to the expression of E-selectins on the inflamed endothelium which provides increased number of binding sites for PSGL-1 and also triggers an intermediate-affinity conformational state of the beta2-integrin LFA-1 on neutrophils." SIGNOR-255968 FGF2 protein P09038 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251796 IL18 protein Q14116 UNIPROT IFNG protein P01579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10653850 f miannu "IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement." SIGNOR-260858 CDKN1A protein P38936 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" 9606 10439039 f gcesareni "P21 may inhibit cell cycle progression by preventing the phosphorylation of prb." SIGNOR-69925 MMP21 protein Q8N119 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272366 MARCHF8 protein Q5T0T0 UNIPROT TNFRSF10A protein O00220 UNIPROT "down-regulates quantity" ubiquitination 9606 23300075 t miannu "The collective data indicate that endogenous MARCH-8 ubiquitinates TRAIL-R1 to attenuate its cell surface expression." SIGNOR-278570 CTNNB1 protein P35222 UNIPROT TRRAP protein Q9Y4A5 UNIPROT up-regulates binding 9606 16510874 t gcesareni "The beta-cat c-terminal activation domain associates with trrap/tip60 and mixed-lineage-leukemia (mll1/mll2) set1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo." SIGNOR-144966 STUB1 protein Q9UNE7 UNIPROT IRS4 protein O14654 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002181 30026872 t miannu "IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP)." SIGNOR-277616 doxorubicin chemical CHEBI:28748 ChEBI ABCC1 protein P33527 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002206 9647783 t "Simone Vumbaca" "Unconjugated Dox and Dau failed to inhibit the transport of LTC4, whereas 30 microM GS-Dox or GS-Dau conjugates completely inhibited the transport." SIGNOR-261085 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates binding 9606 12782713 t miannu "Mif binds to the extracellular domain of cd74, and cd74 is required for mif-induced activation of the extracellular signal-regulated kinase-1/2 map kinase cascade, cell proliferation, and pge2 production." SIGNOR-101526 STAT5A protein P42229 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates "transcriptional regulation" 9606 12540601 f fspada "We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner." SIGNOR-210146 SIRT2 protein Q8IXJ6 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 14522900 f miannu " In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity." SIGNOR-254487 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding -1 9774108 t gcesareni "Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells. It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade." SIGNOR-60663 AKT3 protein Q9Y243 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t gcesareni "We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity." SIGNOR-78693 PPARGC1A protein Q9UBK2 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni "Pgc-1alpha protein is required for ampk action on glut4 gene expression and mitochondrial function." SIGNOR-156769 KAT2A protein Q92830 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269603 CSNK2A1 protein P68400 UNIPROT PTPRCAP protein Q14761 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser153 RAEEARDsDTEGDLV -1 30482149 t miannu "We demonstrated for the first time that LPAP is a substrate for protein kinase CK2 that phosphorylates it at Ser153, presumably ensuring LPAP resistance to degradation." SIGNOR-273629 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 7736585 t gcesareni "D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb," SIGNOR-32295 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250799 KIF13A protein Q9H1H9 UNIPROT TTC19 protein Q6DKK2 UNIPROT "up-regulates activity" binding 9606 20208530 t miannu "We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B." SIGNOR-265540 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 BTO:0000007 BTO:0000671 18270262 t gcesareni "Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)." SIGNOR-160842 PRKCD protein Q05655 UNIPROT VRK1 protein Q99986 UNIPROT "down-regulates activity" phosphorylation Thr355 GLKAKTItKKRKKEI 9606 21346188 t miannu "PKC\u03b4 phosphorylates VRK1 on Ser-355 in vitro.|PKCdelta negatively regulates VRK1 kinase activity in vitro." SIGNOR-278219 teniposide chemical CHEBI:75988 ChEBI TOP2B protein Q02880 UNIPROT "down-regulates activity" "chemical inhibition" 9606 1329225 t miannu "Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme." SIGNOR-259330 RBBP7 protein Q16576 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263848 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257786 PRKAA1 protein Q13131 UNIPROT NR0B2 protein Q15466 UNIPROT up-regulates 9606 17909097 f gcesareni "We have concluded that metformin inhibits hepatic gluconeogenesis through ampk-dependent regulation of shp" SIGNOR-158071 RPL41 protein P62945 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262458 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser1004 SEHDSDEsSDDDSDS 9606 BTO:0000661 10066810 t llicata "Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. " SIGNOR-251029 WNT7B protein P56706 UNIPROT FZD10 protein Q9ULW2 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763;BTO:0001260 15923619 t gcesareni "Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling" SIGNOR-137934 silodosin chemical CHEBI:135929 ChEBI ADRA1D protein P25100 UNIPROT "down-regulates activity" "chemical inhibition" 10029 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258451 HMBOX1 protein Q6NT76 UNIPROT IFNG protein P01579 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002030 21839858 t Luana "Additionally, by luciferase reporter assay, HMBOX1 displayed suppressive effect on the transcription activity of IFN-γ promoter. " SIGNOR-261625 NDN protein Q99608 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000671 24349431 t lperfetto "Deletion mapping demonstrated that the C-terminus of cystin and both termini of necdin are required for their mutual interaction. Speculating that these two proteins may function to regulate gene expression, we developed a luciferase reporter assay and observed that necdin strongly activated the Myc P1 promoter, and cystin did so more modestly." SIGNOR-253381 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1B protein P35368 UNIPROT "up-regulates activity" "chemical activation" 10029 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258443 SLBP protein Q14493 UNIPROT H2BC12 protein O60814 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265383 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Ser2612 MFVETQAsQGTLQTR 9606 BTO:0000773 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249155 ATR protein Q13535 UNIPROT USP20 protein Q9Y2K6 UNIPROT "up-regulates quantity by stabilization" phosphorylation 9606 BTO:0000007 25355518 t miannu "USP20 phosphorylation by ATR is important for its stabilization and checkpoint activation" SIGNOR-272822 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017876 t llicata "Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation." SIGNOR-176862 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CD4 protein P01730 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 11893391 t miannu "Degradation of the HIV receptor CD4 by the proteasome, mediated by the HIV-1 protein Vpu, is crucial for the release of fully infectious virions. To promote CD4 degradation Vpu has to be phosphorylated on a motif DSGXXS, which is conserved in several signalling proteins known to be degraded by the proteasome upon phosphorylation. Such phosphorylation is required for the interaction of Vpu with the ubiquitin ligase SCF-beta-TrCP that triggers CD4 degradation by the proteasome." SIGNOR-272615 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249463 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr1074 QRGSSGHtPPPSGPP 26190112 t "Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-253543 E2F1 protein Q01094 UNIPROT RASGEF1B protein Q0VAM2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18396012 f miannu "We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation." SIGNOR-253851 HNRNPH2 protein P55795 UNIPROT TERF2 protein Q15554 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10116 BTO:0001009 27117401 t miannu "During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels." SIGNOR-266806 "AP-3 complex" complex SIGNOR-C247 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 22203680 f lperfetto "Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes" SIGNOR-265941 USF1 protein P22415 UNIPROT GCK protein P35557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9677331 f miannu "Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element" SIGNOR-255597 SMURF proteinfamily SIGNOR-PF29 SIGNOR BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t "inferred from 70% family members" gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps." SIGNOR-270215 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" binding 9606 10209155 t "Amphiregulin is an autocrine growth factor" lperfetto "ErbB ligands include: EGF, transforming growth factor (TGF)_, and amphiregulin which only bind ErbB1" SIGNOR-67000 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr236 FYDETYDyGGFTMMF 9606 12052863 t lperfetto "We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown)." SIGNOR-88911 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 11901158 t lperfetto "Thus, activation of chk2 in irradiated cells may occur through oligomerization of chk2 via binding of the thr-68-phosphorylated region of one chk2 to the fha domain of another. Oligomerization of chk2 may therefore increase the efficiency of trans-autophosphorylation resulting in the release of active chk2 monomers that proceed to enforce checkpoint control in irradiated cells." SIGNOR-116135 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI "up-regulates quantity" "precursor of" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269690 "8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid" chemical CID:92577 PUBCHEM PTPN6 protein P29350 UNIPROT "down-regulates activity" "chemical inhibition" -1 19233143 t lperfetto "In this study, we screened protein tyrosine phosphatases (PTPs) by in vitro phosphatase assays to identify PTPs that are inhibited by 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), a potent inhibitor of SHP-1 and SHP-2 PTPs." SIGNOR-261978 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser287 EPLSPVSsLQASVPG 9606 16027724 t miannu "ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation" SIGNOR-250093 AMPK complex SIGNOR-C15 SIGNOR RAC1 protein P63000 UNIPROT "up-regulates activity" 9606 BTO:0000584 29572236 f miannu "The discovery that AMPK activation is a general requirement for macropinosome formation in cancer cells dramatically extends our understanding of the regulation of this process. By increasing RAC1-GTP levels, AMPK activation stimulates macropinosome formation (Fig. 2I–K; Supplementary Fig. S5). " SIGNOR-277766 PKC proteinfamily SIGNOR-PF53 SIGNOR PPP1R14B protein Q96C90 UNIPROT "up-regulates activity" phosphorylation Thr57 VRRQGKVtVKYDRKE 10606530 t lperfetto "Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold." SIGNOR-265740 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser160 SSTFDALsPSPAIPS 9606 23166821 t llicata "We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5" SIGNOR-199781 BFAR protein Q9NZS9 UNIPROT TMBIM6 protein P55061 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21068390 t miannu "BAR overexpression promotes BI-1 ubiquitination and proteasomal degradation.We show here that bifunctional apoptosis regulator (BAR) functions as an ER-associated RING-type E3 ligase, interacts with BI-1, and promotes proteasomal degradation of BI-1. " SIGNOR-272778 pictrelisib chemical CHEBI:65326 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000149 21876152 t gcesareni "Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed" SIGNOR-176295 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 phosphorylation:Thr185 HDHTGFLtEYVATRW 16456541 t gcesareni "B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk" SIGNOR-143052 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates activity" phosphorylation Ser853 SSLNSSEsDKDQDYD 10090 10671552 t llicata "Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | Under these conditions, phosphorylation of the E-cadherin double mutant S853A/S855A was reduced by 25% as compared with wt E-cadherin. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion." SIGNOR-250841 APC protein P25054 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity" binding 9606 22083140 t amattioni "Apc binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. APC cooperates with Axin to promote the phosphorylation of _-catenin by GSK3 [which requires priming phosphorylation by casein kinase 1, _-isoform (CK1_)]." SIGNOR-177230 PRKCD protein Q05655 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Thr678 RHIVRKRtLRRLLQE 10090 1860884 t lperfetto "These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling." SIGNOR-248858 SEC23IP protein Q9Y6Y8 UNIPROT "1-acyl-sn-glycerol 3-phosphate" smallmolecule CHEBI:16975 ChEBI "up-regulates quantity" "chemical modification" 9606 22922100 t miannu "Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain." SIGNOR-269657 MSX1 protein P28360 UNIPROT LHX2 protein P50458 UNIPROT "down-regulates activity" binding -1 9697309 t 2 miannu "Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity" SIGNOR-241330 STAT3 protein P40763 UNIPROT KRT17 protein Q04695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 21796151 f miannu "IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms." SIGNOR-255234 calcium(2+) smallmolecule CHEBI:29108 ChEBI SLC25A12 protein O75746 UNIPROT "up-regulates activity" "chemical activation" 9606 12084073 t miannu "Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane." SIGNOR-265152 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT down-regulates phosphorylation 9606 25855382 t miannu "Based on the mechanism of Plk1 mediated degradation of SUZ12 and ZNF198 described in this study (XREF_FIG), we quantified expression levels of Plk1 and HOTAIR RNAs in liver tumors from X/c-myc bitransgenic mice.|We interpret these results to mean that HOTAIR facilitates ubiquitination of Plk1 phosphorylated SUZ12 and ZNF198 proteins, thereby accelerating their proteasomal degradation." SIGNOR-278491 PRKCA protein P17252 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 t lperfetto "Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E ." SIGNOR-248945 MAPK15 protein Q8TD08 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 12169099 t gcesareni "Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation." SIGNOR-91375 APBA1 protein Q02410 UNIPROT STXBP1 protein P61764 UNIPROT "up-regulates activity" binding 10116 9395480 t miannu "Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1." SIGNOR-264035 CUL3 protein Q13618 UNIPROT RHOA protein P61586 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 19782033 t miannu "BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex." SIGNOR-264238 ARNT protein P27540 UNIPROT CYP1B1 protein Q16678 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 16115918 f miannu "Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1." SIGNOR-253740 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser721 TPRLRSVsSYGNIRA 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-252774 ADP chemical CHEBI:16761 ChEBI PRPS1 protein P60891 UNIPROT "down-regulates activity" "chemical inhibition" 29074724 t lperfetto "PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP" SIGNOR-265736 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 BTO:0000567 16371512 t gcesareni "We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell" SIGNOR-143368 CLTCL1 protein P53675 UNIPROT "AP-3/clathrin vescicle" complex SIGNOR-C250 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260673 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1071 SFLQRYSsDPTGALT 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250621 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18936167 t "These results therefore suggest that the autoactivation residues Y1054 and Y1059 are targeted by DEP-1 and that this results in the inhibition of kinase activity and the consequent general dephosphorylation of VEGFR2." SIGNOR-248710 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1654 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248771 JNK proteinfamily SIGNOR-PF15 SIGNOR ATN1 protein P54259 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000142 12812981 t "inferred from 70% family members" lperfetto "Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment," SIGNOR-269978 DOT1L protein Q8TEK3 UNIPROT H3-4 protein Q16695 UNIPROT unknown methylation Lys80 REIAQDFkTDLRFQS 9606 12123582 t miannu "HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase." SIGNOR-267142 RPS6KB1 protein P23443 UNIPROT LTC4S protein Q16873 UNIPROT "down-regulates activity" phosphorylation Ser36 ARRAFRVsPPLTTGP -1 27365393 t miannu "Here, we identified Ser(36) as the major p70S6k phosphorylation site, along with a low frequency site at Thr(40), using an in vitro phosphorylation assay combined with mass spectrometry. Cellular LTC4S activity is suppressed by PKC-mediated phosphorylation, and recently a downstream p70S6k was shown to play an important role in this process." SIGNOR-277256 TFEB protein P19484 UNIPROT CTSA protein P10619 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 28552616 t lperfetto "Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants" SIGNOR-276549 FZR1 protein Q9UM11 UNIPROT DNM1L protein O00429 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000567 21325626 t Barakat "Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1 catalyzed by the APC/Ccdh1 (anaphase-promoting complex/cyclosome and its coactivator (Cdh1) E3 ubiquiting ligase complex" SIGNOR-274127 PJA2 protein O43164 UNIPROT PRKAR1A protein P10644 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21423175 t miannu "Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits" SIGNOR-271855 DAPK1 protein P53355 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Ser1303 NKLRRQHsYDTFVDL 9606 20141836 t miannu "DAPK1 Activation Enhances the NR1 and NR2B Channel Conductance.|Thus, an activated DAPK1 enhances NR1 and NR2B receptor channel conductance by phosphorylating NR2B subunit at Ser 1303." SIGNOR-278397 P2RY10 protein O00398 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257121 "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257717 thymidine smallmolecule CHEBI:17748 ChEBI dTMP(2-) smallmolecule CHEBI:63528 ChEBI "up-regulates quantity" "precursor of" 9606 25215937 t miannu "Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates. " SIGNOR-280585 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu63 LERECVEeTCSYEEA -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263680 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" phosphorylation Tyr449 IIQHCSNySTQELLR 9606 BTO:0000793 29022905 t miannu "In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation." SIGNOR-277327 STK3 protein Q13188 UNIPROT Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates phosphorylation 9606 21808241 t "The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction." SIGNOR-269855 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates activity" dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 t "Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)" SIGNOR-248316 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr176 PFISEGTtLKDLIYD -1 8576253 t "giulio giuliani" "From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s)." SIGNOR-255961 LMP1 protein P03230 UNIPROT UBE2I protein P63279 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 22951831 t scontino "One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452." SIGNOR-266838 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR ULK1 protein O75385 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 26687681 t miannu "Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1" SIGNOR-272417 WNT4 protein P56705 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131835 IL11 protein P20809 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9143707 t gcesareni "Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-4" SIGNOR-48033 CHEK1 protein O14757 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 25486478 t miannu "Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21(Waf1) on T145 and S146 residues and induces its proteasome-dependent proteolysis." SIGNOR-279325 CSNK2A1 protein P68400 UNIPROT CERS4 protein Q9HA82 UNIPROT "up-regulates activity" phosphorylation Ser350 DVEESDSsEEAAAAQ 9606 BTO:0000007 26887952 t miannu "Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. " SIGNOR-273982 MAP4K5 protein Q9Y4K4 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 9606 16914735 t lperfetto "Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3beta and enhance the in vivo phosphorylation of gsk3beta on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3beta at serine 9 and decreases the accumulation of cytosolic _-catenin." SIGNOR-228006 ATG7 protein O95352 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates binding 9606 22170151 t gcesareni "These results indicated that the fap motif of atg7 is indispensable for formation of the atg3-lc3 e2-substrate intermediate through the interaction of atg7 with atg3." SIGNOR-195239 HDAC3 protein O15379 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR up-regulates binding 9606 23213415 t lperfetto "Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes." SIGNOR-217358 NFE2L2 protein Q16236 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000599 26194347 f irozzo "Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes." SIGNOR-256263 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH2 protein Q04721 UNIPROT "up-regulates activity" cleavage 9606 25610395 t lperfetto "The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins." SIGNOR-209723 DAMPS stimulus SIGNOR-ST18 SIGNOR NAIP protein Q13075 UNIPROT "up-regulates activity" 16037825 f lperfetto "Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage" SIGNOR-256420 ponatinib chemical CHEBI:78543 ChEBI LYN protein P07948 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000830 23539538 t miannu "Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells" SIGNOR-259273 FBLN5 protein Q9UBX5 UNIPROT ELN protein P15502 UNIPROT "up-regulates activity" binding 9606 18267938 t miannu "The binding of tropoelastin fragments to fibulin-5 was directly proportional to their propensity to coacervate. Furthermore, the addition of fibulin-5 to tropoelastin facilitated coacervation. Taken together, the present study shows that fibulin-5 enhances elastic fiber formation in part by improving the self-association properties of tropoelastin." SIGNOR-252137 AMPK complex SIGNOR-C15 SIGNOR SLC9A3 protein P48764 UNIPROT "down-regulates activity" phosphorylation Ser563 LAFIRSPsTDNVVNV 9606 BTO:0000195 38047302 t miannu "AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) phosphorylated NHE3 at S555. S555 is the primary site of phosphorylation by protein kinase A (PKA), but AMPK phosphorylated S555 independently of PKA. We conclude that AMPK activation inhibits NHE3 activity and NHE3 inhibition is associated with phosphorylation of NHE3 at S555 and S563." SIGNOR-277848 "AP-1 complex" complex SIGNOR-C248 SIGNOR SORT1 protein Q99523 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 31767632 t miannu "The short intracellular domain of sortilin binds several cytoplasmic adaptor proteins (e.g., the AP-1 complex and GGA1 to -3), most of which target two well-defined motifs: a C-terminal acidic cluster dileucine motif and a YXXΦ motif in the proximal third of the domain. Both motifs contribute to endocytosis as well as Golgi-endosome trafficking of sortilin." SIGNOR-273720 Ub:E2 complex SIGNOR-C497 SIGNOR RNF39 protein Q9H2S5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271223 PLK1 protein P53350 UNIPROT ARHGDIA protein P52565 UNIPROT "up-regulates activity" phosphorylation Thr91 GPLELDLtGDLESFK 9606 BTO:0000567 38355643 t miannu "PLK1 phosphorylates RhoGDI1 at Thr7/91 residue in vitro and in vivo. Collectively, we demonstrate that the phosphorylation of RhoGDI1 by PLK1 promotes cancer cell migration and invasion through RhoA activation." SIGNOR-277882 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19864431 t lperfetto "Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855))" SIGNOR-188920 Ub:E2 complex SIGNOR-C497 SIGNOR RNF216 protein Q9NWF9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270971 CDK7 protein P50613 UNIPROT PCGF6 protein Q9BYE7 UNIPROT unknown phosphorylation Ser30 LPPPPPVsPPALTPA -1 12167161 t llicata "In addition, we find that serine 32 of MBLR is specifically phosphorylated during mitosis, most likely by CDK7, a component of the basal transcriptional machinery. | These results indicate that, at least in vitro, MBLR is a substrate for CDK7 phosphorylation." SIGNOR-250769 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Thr718 KEDLPVItIDPASPQ 9606 11604491 t llicata "Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728." SIGNOR-111051 CERK protein Q8TCT0 UNIPROT "ceramide 1-phosphate(2-)" smallmolecule CHEBI:84404 ChEBI "up-regulates quantity" "chemical modification" 9606 34202192 t miannu "Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P)." SIGNOR-268499 MEIS1 protein O00470 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo "To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells." SIGNOR-256648 "AX/b2 integrin" complex SIGNOR-C171 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257714 FCRL3 protein Q96P31 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding -1 12051764 t miannu "Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2." SIGNOR-274012 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT "down-regulates activity" phosphorylation Tyr217 MAEEKKAyKKAKERE 9606 19059208 t miannu "We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling." SIGNOR-262853 SMARCA4 protein P51532 UNIPROT SMARCC2 protein Q8TAQ2 UNIPROT up-regulates binding 9606 10078207 t miannu "The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added." SIGNOR-65444 MTMR2 protein Q13614 UNIPROT "1-phosphatidyl-1D-myo-inositol 3-phosphate(3-)" smallmolecule CHEBI:58088 ChEBI "down-regulates quantity" "chemical modification" 9606 18429927 t miannu "PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns" SIGNOR-269807 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-34665 8-OH-DPAT chemical CHEBI:73364 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258847 ITPRIPL1 protein Q6GPH6 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates binding 9606 BTO:0000938 21368195 t "Induces Ca2+ release that increases the binding affinity of Shh for Boc." gcesareni "Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores." SIGNOR-172497 sertindole chemical CHEBI:9122 ChEBI HTR1F protein P30939 UNIPROT "down-regulates activity" "chemical inhibition" 9534 BTO:0000298 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258544 SP1 protein P08047 UNIPROT CRX protein O43186 UNIPROT "up-regulates activity" binding 9606 15781457 t miannu "Zinc finger DNA-binding domains of both Sp1 and Sp3 interact with Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains." SIGNOR-225336 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 t lperfetto "These results indicate that cyclin d2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by thr280 phosphorylation by gsk3beta or p38" SIGNOR-154672 ARHGAP20 protein Q9P2F6 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260473 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 BTO:0000150 16504004 t gcesareni "Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover." SIGNOR-144818 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SP3 protein Q02447 UNIPROT up-regulates phosphorylation 9606 17685427 t "inferred from 70% family members" gcesareni "Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73." SIGNOR-270053 "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20565746 f irozzo "These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression." SIGNOR-256126 AURKA protein O14965 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser83 ALREIRYsLLPFANE 9606 15147269 t lperfetto "On the basis of these observations, we conclude that s83 of lats2 is a phosphorylation target of aurora-a and this phosphorylation plays a role of the centrosomal localization of lats2." SIGNOR-124830 TK2 protein O00142 UNIPROT 2'-deoxyuridine smallmolecule CHEBI:16450 ChEBI "down-regulates quantity" "chemical modification" 9606 25215937 t miannu "Thymidine kinase 2 (TK2, EC 27.1.21) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates. " SIGNOR-280586 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR SERPINE1 protein P05121 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001615 22198637 t lperfetto "Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1" SIGNOR-253712 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t "Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation." SIGNOR-248643 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr88 QALEEAAtADLDITE 9606 19530738 t lperfetto "First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form." SIGNOR-186151 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 t lperfetto "The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform." SIGNOR-244971 CSNK1A1 protein P48729 UNIPROT ZRANB1 protein Q9UGI0 UNIPROT "up-regulates activity" phosphorylation Ser209 RWRGSCSsGNSQRRS 9606 BTO:0000007 30686098 t miannu "Interestingly, ZRANB1 is phosphorylated at Thr35, and Ser209 residues by CSNK1A1, and this phosphorylation activates its deubiquitinating activity." SIGNOR-273621 LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor" SIGNOR-45524 ERLIN1 protein O75477 UNIPROT Erlin complex SIGNOR-C532 SIGNOR "form complex" binding 10119 BTO:0003293 19240031 t miannu "Here we report that the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex that binds to IP(3)R tetramers immediately after their activation and is required for their processing. The complex is ring-shaped (diameter approximately 250A(),) and RNA interference-mediated depletion of SPFH1 and SPFH2 blocks IP(3)R polyubiquitination and degradation." SIGNOR-275392 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT "up-regulates activity" phosphorylation Ser723 ELDYPMGsFEPSPYP 9606 BTO:0000567 34198826 t miannu "A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR." SIGNOR-276658 MCU protein Q8NE86 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270865 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT "up-regulates activity" phosphorylation 9606 19620713 t lperfetto "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-255263 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT "down-regulates quantity by destabilization" acetylation Lys594 KEVEDIEkYLEDQVN 9606 BTO:0000007 21726808 t lperfetto "Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1" SIGNOR-267604 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1401 LQGEEIKsQNSQEST 9606 12086603 t lperfetto "These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint" SIGNOR-90109 CENPP protein Q6IPU0 UNIPROT "CCAN complex" complex SIGNOR-C365 SIGNOR "form complex" binding 9606 BTO:0000567 18007590 t lperfetto "CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S)." SIGNOR-265208 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129276 GABRA4 protein P48169 UNIPROT "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263759 ceritinib chemical CHEBI:78432 ChEBI ALK protein Q9UM73 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 24670165 t miannu "Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies." SIGNOR-259263 lapatinib chemical CHEBI:49603 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 21443688 t Luana "YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ." SIGNOR-257898 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni "Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt." SIGNOR-244184 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI AXL protein P30530 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258109 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR Enolase proteinfamily SIGNOR-PF74 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f "inferred from family member" miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-270249 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." SIGNOR-106440 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC18 protein Q5QNW6 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271987 LOX protein P28300 UNIPROT EFEMP2 protein O95967 UNIPROT "up-regulates activity" binding 9606 19570982 t miannu "Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking." SIGNOR-252135 "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg737 LAAALGIrSFRNSSL -1 10026263 t lperfetto "Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545" SIGNOR-263646 DLL1 protein O00548 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 23111325 t gcesareni "In this study, we demonstrate that dll1 can activate notch signaling mostly through notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human mm cells." SIGNOR-199320 BCL2 protein P10415 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 14585074 f amattioni "Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi" SIGNOR-88885 ANGPT1 protein Q15389 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241554 FOXO3 protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0004245 10783894 t gcesareni "AFX transcriptionally activates p27kip1, resulting in increased protein levels." SIGNOR-238610 ARID5B protein Q14865 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29326336 f miannu "We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F)." SIGNOR-256159 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto "Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689)." SIGNOR-236400 HBA1 protein P69905 UNIPROT CD163 protein Q86VB7 UNIPROT "up-regulates activity" binding 9606 16522161 t Regulation miannu "These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells." SIGNOR-251747 Ub:E2 complex SIGNOR-C497 SIGNOR RNF123 protein Q5XPI4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271168 SOCS1 protein O15524 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16628196 f miannu "SOCS1, which is another inducible gene, not only blocks STAT1 activation but also inhibits STAT1-dependent TLR3, IRF-7, and MIP-1α." SIGNOR-255229 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120216 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248522 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser166 EPRSRHLsVSSQNPG 9606 12761204 t lperfetto "Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1" SIGNOR-101211 MAPK14 protein Q16539 UNIPROT KHSRP protein Q92945 UNIPROT "down-regulates activity" phosphorylation Thr692 QAAYYGQtPGPGGPQ 10090 BTO:0000165 16364914 t lperfetto "KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery" SIGNOR-235856 EXOC7 protein Q9UPT5 UNIPROT "Exocyst_EXOC6B variant" complex SIGNOR-C491 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270782 VRK1 protein Q99986 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t miannu "The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells./ Vrk1 knockdown resulted in the defective formation of 53bp1 foci in response to ir both in number and size" SIGNOR-197625 AMPK complex SIGNOR-C15 SIGNOR YAP1 protein P46937 UNIPROT "down-regulates activity" phosphorylation Ser94 RLRKLPDsFFKPPEP 9606 BTO:0002181 25751140 t miannu "Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction." SIGNOR-277638 AMPK complex SIGNOR-C15 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 15866171 t lperfetto "Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest" SIGNOR-216475 TBKBP1 protein A7MCY6 UNIPROT CARD10 protein Q9BWT7 UNIPROT "up-regulates activity" relocalization 9606 31792381 t "TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation" SIGNOR-272470 PIK3R1 protein P27986 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" 10116 21798082 f lperfetto "Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2)." SIGNOR-175678 PRKACA protein P17612 UNIPROT APC protein P25054 UNIPROT "down-regulates activity" phosphorylation Ser2054 MPKKKKPsRLKGDNE 9606 11050185 t miannu "Changing a serine residue (Ser(2054)) to aspartic acid mutated the potential protein kinase A site adjacent to NLS2(APC), resulting in both inhibition of the NLS2(APC)-mediated nuclear import of a chimeric beta-galactosidase fusion protein and a reduction of full-length APC nuclear localization." SIGNOR-250335 PTHLH protein P12272 UNIPROT PTH1R protein Q03431 UNIPROT "up-regulates activity" binding -1 8683730 t lperfetto "Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production." SIGNOR-270549 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" SIGNOR-257878 GSK3B protein P49841 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 16107342 t lperfetto "Gsk3beta Phosphorylates pten at thr-366 in intact cells phosphorylation of pten at thr-366 reduces the activity of pten in cells" SIGNOR-236641 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0001950 25487801 t Luana "Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections. " SIGNOR-262312 KLHL20 protein Q9Y2M5 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 26687681 t miannu "Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1" SIGNOR-272413 NUP42 protein O15504 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262097 Ub:E2 complex SIGNOR-C497 SIGNOR RC3H2 protein Q9HBD1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271006 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser77 GEKGRALsTRCQPLE -1 2584239 t lperfetto "We have now determined that PKC phosphorylated serine 43 (and/or serine 45), serine 78, and threonine 144 in the free Tn-I subunit" SIGNOR-248890 (-)-anisomycin chemical CHEBI:338412 ChEBI FOS protein P01100 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189626 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr1097 SMIRTGEtPTKKRGI 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104695 CEBPB protein P17676 UNIPROT GDF15 protein Q99988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 24086573 t "Promoter analysis and chromatin immunoprecipitation analysis revealed that CEBPB could contribute to K7174-mediated transcriptional activation of GDF15." SIGNOR-254050 UBE2I protein P63279 UNIPROT FOS protein P01100 UNIPROT "down-regulates activity" sumoylation Lys265 SISSMELkTEPFDDF 9606 SIGNOR-C154 16055711 t lperfetto "We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity." SIGNOR-263013 N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI "up-regulates quantity" "precursor of" 9606 33179964 t miannu "The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner." SIGNOR-268103 CAD protein P27708 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "chemical modification" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267421 MLLT10 protein P55197 UNIPROT SS18/MLLT10 complex SIGNOR-C75 SIGNOR "form complex" binding 9606 11423977 t miannu "Based on these results, a model is proposed in which the syt and af10 proteins act in concert as bipartite transcription factors" SIGNOR-108924 "MLL2 complex" complex SIGNOR-C88 SIGNOR KDM6A protein O15550 UNIPROT "up-regulates quantity by stabilization" binding 9606 28669924 t miannu "KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. UTX is the complex’s H3K27 demethylase." SIGNOR-268813 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates activity" dephosphorylation Ser206 SSSTYPHsPTSSDPG 9606 BTO:0000552 17085434 t "Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)" SIGNOR-248315 WDR45B protein Q5MNZ6 UNIPROT TSC complex SIGNOR-C101 SIGNOR "up-regulates quantity" binding 9606 BTO:0001938 28561066 t miannu "WIPI3 associates with the TSC complex and FIP200. The specific interaction between WIPI3 and the TSC complex was demonstrated by immunopurification of both endogenous TSC1 and TSC2 with GFP-WIPI3 (Fig. 5a). These data suggest that WIPI3 functions in association with the TSC complex to regulate mTOR activity in the lysosomal compartment." SIGNOR-268479 IMPDH2 protein P12268 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" binding 9606 BTO:0001616 30518405 t miannu "We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. There is evidence that IMPDH2 interacts with the pleckstrin homology domain of PKB/AKT in the regulation of GTP biosynthesis." SIGNOR-260961 ATF4 protein P18848 UNIPROT TARS2 protein Q9BW92 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269428 FBXW2 protein Q9UKT8 UNIPROT MSX2 protein P35548 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 31548378 t miannu " Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase.  Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation." SIGNOR-272259 SMO protein Q99835 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates activity" 10090 BTO:0000011 16399502 f fferrentino "In mammalian models [...] Hh signaling also inhibits mammalian adipogenesis. Hh signals elicit this function early in adipogenesis, upstream of PPARγ, potentially diverting preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis and toward osteogenesis. Hh may elicit these effects by inducing the expression of antiadipogenic transcription factors such as Gata2." SIGNOR-251656 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT "down-regulates activity" phosphorylation Tyr258 KKSISLMyGGSKRKS 9534 BTO:0001538 24284075 t miannu "Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity" SIGNOR-263141 GRK6 protein P43250 UNIPROT GRK6 protein P43250 UNIPROT unknown phosphorylation Ser484 VLDIEQFsTVKGVEL 9534 BTO:0000298 10334944 t "GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established." SIGNOR-251211 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT "down-regulates activity" "chemical inhibition" -1 29901072 t miannu "AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9." SIGNOR-262218 NRCAM protein Q92823 UNIPROT ANK1 protein P16157 UNIPROT "up-regulates quantity" relocalization 10116 BTO:0000227 7961622 t miannu "Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains." SIGNOR-266721 WNT3A protein P56704 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 19175684 f gcesareni "Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs." SIGNOR-183538 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu76 CSFEEAReVFENTER 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263694 PIAS4 protein Q8N2W9 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 11248056 t gcesareni "First, piasy interacts with stat1 both in vitro and in vivo. The in vivo piasy__stat1 interaction is dependent on cytokine stimulation. Second, piasy can inhibit stat1-mediated gene activation without blocking the dna binding activity of stat1." SIGNOR-105723 TAX1BP1 protein Q86VP1 UNIPROT TNFAIP3 protein P21580 UNIPROT "up-regulates activity" binding 9606 BTO:0000782;BTO:0001271 10435631 t lperfetto "Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb." SIGNOR-69921 CCND3 protein P30281 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000165 21898542 f gcesareni "Our findings suggest that cyclin D3 primes myoblasts for differentiation by enhancing muscle specific gene expression and cell cycle exit" SIGNOR-241960 CREB1 protein P16220 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f gcesareni "In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1" SIGNOR-142103 STAT6 protein P42226 UNIPROT CHI3L1 protein P36222 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 20508200 f lperfetto "Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation." SIGNOR-249537 ESR1 protein P03372 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18588516 f miannu "The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor)." SIGNOR-254230 SALL4 protein Q9UJQ4 UNIPROT ZEB1 protein P37275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 23954296 f miannu "Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1." SIGNOR-255123 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 25287865 t miannu "YAP and TAZ were repeatedly isolated as binding proteins for Smads, key transducer of the TGF- and BMP signaling pathways (2, 207, 208). Cytoplasmic YAP/TAZ participate in Smad2/3 cytoplasmic retention, even overruling the ef- fects of high levels of TGF- ligands" SIGNOR-277662 E2F1 protein Q01094 UNIPROT RASGRP1 protein O95267 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18396012 f miannu "We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation." SIGNOR-253850 POU2F1 protein P14859 UNIPROT MYH10 protein P35580 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15728583 t lperfetto "Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation" SIGNOR-238772 furtrethonium chemical CHEBI:134764 ChEBI CHRM4 protein P08173 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258644 BCL6 protein P41182 UNIPROT CD80 protein P33681 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000776 12860928 f "Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells." SIGNOR-253931 "1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate" smallmolecule CHEBI:18348 ChEBI 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI "up-regulates quantity" "precursor of" 9606 23000145 t scontino "Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)." SIGNOR-268451 aclidinium chemical CHEBI:65346 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000131 19653626 t Luana "This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects." SIGNOR-258049 CDKL1 protein Q00532 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" phosphorylation 9606 28352193 t miannu "We also proved that as a downstream molecule of the P15 pathway, Rb is inhibited after CDKL1 knockdown. Rb is a well-known tumor suppressor in cell cycle regulation.28 Phosphorylation of Rb negatively regulates the cell cycle through E2F repression.29–31 However, Rb contains 13 conserved sites that are phosphorylated by the CDK–P15 complex in cycling cells and phosphorylation will cause site-specific and diverse conformational changes in the complex.32,33 Further studies need to be conducted to decipher the phosphorylated site of Rb related to CDKL1 knockdown." SIGNOR-273863 TRIM27 protein P14373 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102028 PRKD1 protein Q15139 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" phosphorylation Ser154 STLYRTQsSSNLAEL 9606 BTO:0000738 23129748 t miannu " PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration. " SIGNOR-276426 NOS3 protein P29474 UNIPROT "nitric oxide" smallmolecule CHEBI:16480 ChEBI "up-regulates quantity" "chemical modification" 9606 24379783 t lperfetto "Nitric oxide (NO) is a major mediator of endothelial function and is synthesized in endothelial cells by endothelial nitric oxide synthase (eNOS)." SIGNOR-251629 SH2B1 protein Q9NRF2 UNIPROT BLNK protein Q8WV28 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000776 32323266 t scontino "SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK." SIGNOR-268446 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 16829981 t "Cbl binds directly to Tyr1045 receptors" gcesareni "Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2" SIGNOR-147826 SYN1 protein P17600 UNIPROT RAB3A protein P20336 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 15265865 t miannu "Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. The interaction between synapsin I and Rab3A was confirmed by photoaffinity labeling experiments on purified synaptic vesicles and by the formation of a chemically cross-linked complex between synapsin I and Rab3A in intact nerve terminals. The data indicate that synapsin I is a novel Rab3 interactor on synaptic vesicles and suggest that the synapsin-Rab3 interaction may participate in the regulation of synaptic vesicle trafficking within the nerve terminals." SIGNOR-269181 PTK2B protein Q14289 UNIPROT ASAP1 protein Q9ULH1 UNIPROT "down-regulates activity" phosphorylation Tyr323 QLQGNKEyGSEKKGY 9606 BTO:0000007 12771146 t miannu "The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells.Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation." SIGNOR-263186 ATR protein Q13535 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto "Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potentialit is, therefore, likely that atm and atr regulate creb phosphorylation collectively in response to stress stimuli." SIGNOR-124060 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178371 "Dynorphin B" chemical CHEBI:80347 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258796 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t lperfetto "Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. " SIGNOR-249073 lisuride chemical CHEBI:51164 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9205951 t miannu "The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively." SIGNOR-258615 GPR132 protein Q9UNW8 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257341 P2RY2 protein P41231 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257145 Gbeta proteinfamily SIGNOR-PF4 SIGNOR THRB protein P10828 UNIPROT "down-regulates activity" phosphorylation 9606 12809513 t "inferred from 70% family members" llicata "We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay." SIGNOR-270016 6 protein P59634 UNIPROT RAE1 protein P78406 UNIPROT "down-regulates activity" binding 9606 32353859 t miannu "Orf6 of SARS-CoV antagonizes host interferon signaling by perturbing nuclear transport, and the NUP98-RAE1 interaction with Orf6 may perform the same function for SARS-CoV-2." SIGNOR-260975 olanzapine chemical CHEBI:7735 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000529 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258510 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19346248 t lperfetto "The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo." SIGNOR-184959 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser656 RAEFLNKsVQKSSGV 9606 BTO:0000887;BTO:0001260 8182108 t gcesareni "Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase." SIGNOR-36792 FGFR4 protein P22455 UNIPROT GLO1 protein Q04760 UNIPROT "up-regulates activity" phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu "We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D)." SIGNOR-276182 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation 9606 11343802 t gcesareni "Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation" SIGNOR-107692 EPHA4 protein P54764 UNIPROT EPHA4 protein P54764 UNIPROT "up-regulates activity" phosphorylation Tyr596 LNQGVRTyVDPFTYE -1 8622893 t "Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry." SIGNOR-251118 ID2 protein Q02363 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR "down-regulates activity" binding 10090 BTO:0004058 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241146 CDK5 protein Q00535 UNIPROT PARP1 protein P09874 UNIPROT "down-regulates activity" phosphorylation Ser785 LRGGSDDsSKDPIDV -1 21922195 t miannu "These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage." SIGNOR-276358 EPX protein P11678 UNIPROT RNASE2 protein P10153 UNIPROT "up-regulates activity" "post translational modification" 9606 BTO:0000399 18694936 t miannu "Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism." SIGNOR-261704 MIB1 protein Q86YT6 UNIPROT JAG1 protein P78504 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000938 12530964 t lperfetto "Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum." SIGNOR-97388 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM42 protein Q8IWZ5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270978 SYNE3 protein Q6ZMZ3 UNIPROT "LINC complex" complex SIGNOR-C303 SIGNOR "form complex" binding 24481844 t lperfetto "LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM." SIGNOR-263284 PTP4A3 protein O75365 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by destabilization" dephosphorylation 9606 29266303 t lperfetto "As expected, PRL3 clearly reduced PTEN phosphorylation at the tyrosine residue and PTEN protein in PRL3 overexpressing LO2 and HepG2 cell lines, with no significant changes in PRL3 (C104S) mutant cells.|PRL3 down-regulates PTEN expression, a negative regulator of the Akt pathway.11 Phosphorylation of PTEN at Tyr336 is required for maintenance of PTEN protein stability and prevention of PTEN degradation.17 We therefore speculated that PRL3 might dephosphorylate PTEN at tyrosine sites and consequently reduce the PTEN protein level." SIGNOR-277010 USP6 protein P35125 UNIPROT ARF6 protein P62330 UNIPROT up-regulates relocalization 9606 15509780 t miannu "Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs)." SIGNOR-130019 ZNF804A protein Q7Z570 UNIPROT INHBE protein P58166 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 23434502 t miannu "ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3)." SIGNOR-269462 ARMC10 protein Q8N2F6 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" binding 9606 BTO:0000971;BTO:0005814 17904127 t miannu "Co-immunoprecipitation and GST pull-down assays have demonstrated that SVH-B directly interacts with p53. In both BEL-7404 cells and p53-null Saos-2 cells transfected with a temperature-sensitive mutant of p53, V143A, ectopically expressed SVH-B suppresses the transcriptional activity of p53, and suppression of SVH by RNA interference increases the transcriptional activity of p53. Our results suggested the function of SVH-B in accelerating growth and inhibition of apoptosis is related to its inhibitory binding to p53." SIGNOR-266414 ERBB2 protein P04626 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 15173068 t gcesareni "The results presented here show for the first time that er redistribution to the cytoplasm and its interaction with her2 are important downstream effects of her2 overexpression, that erk1/2 is important for er cytoplasmic localization, and that subcellular localization of er may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen." SIGNOR-124962 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Thr43 KVTTVVAtPGQGPDR 9606 BTO:0000150;BTO:0000680 16039586 t lperfetto "Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin." SIGNOR-138894 MAST2 protein Q6P0Q8 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation 9606 15951562 t gcesareni "We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status." SIGNOR-138051 TEF protein Q10587 UNIPROT NPPB protein P16860 UNIPROT unknown "transcriptional regulation" 15837525 f "In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription." SIGNOR-253652 axitinib chemical CHEBI:66910 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150 21297102 t gcesareni "Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine." SIGNOR-171863 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" SIGNOR-252523 GSK3B protein P49841 UNIPROT FCAR protein P24071 UNIPROT "down-regulates activity" phosphorylation Ser284 LTFARTPsVCK 10090 BTO:0001516 30766540 t lperfetto "GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state." SIGNOR-264857 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." SIGNOR-246248 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KAT5 protein Q92993 UNIPROT "up-regulates activity" phosphorylation Ser86 TKNGLPGsRPGSPER 9606 BTO:0000567 12468530 t llicata "Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex." SIGNOR-250641 NFATC2 protein Q13469 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001260 17079331 t lperfetto "The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries." SIGNOR-251731 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI "down-regulates quantity" "chemical modification" 9606 10490932 t Regulation miannu "Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme" SIGNOR-251911 CHUK protein O15111 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation 9606 16612387 t gcesareni "Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production." SIGNOR-146116 "PAS complex" complex SIGNOR-C190 SIGNOR "1-phosphatidyl-1D-myo-inositol 3-phosphate" smallmolecule CHEBI:17283 ChEBI "down-regulates quantity" "chemical modification" -1 18950639 t miannu "PtdIns(3,5)P2 is synthesized from PtdIns(3)P through the action of mammalian PIKfyve or the yeast counterpart Fab1, both sole enzymes for PtdIns(3,5)P2 synthesis. PIKfyve and Fab1, in turn, are activated by the orthologous proteins, mammalian ArPIKfyve and yeast Vac14, to upregulate intracellular PtdIns(3,5)P2 production. PtdIns(3,5)P2 turnover is catalyzed, at least in part, by mammalian Sac3 or its yeast counterpart Fig4" SIGNOR-253533 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni "Downstream of caspase-8 activation, apoptosis induction takes place" SIGNOR-256641 CEP350 protein Q5VT06 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR "form complex" binding 9606 16314388 t miannu "Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring." SIGNOR-142355 TRIM33 protein Q9UPN9 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 16751102 t gcesareni "The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. In human hematopoietic stem/progenitor cells, where tgfbeta inhibits proliferation and stimulates erythroid differentiation, tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses." SIGNOR-146986 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr603 PCCIVTStYGWTANM 9606 24117238 t lperfetto "Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity." SIGNOR-202820 LYST protein Q99698 UNIPROT RAB5B protein P61020 UNIPROT "down-regulates activity" binding 7227 33725482 t lperfetto "Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment" SIGNOR-266002 p38 proteinfamily SIGNOR-PF16 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171062 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 29106906 t Gianni "We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord." SIGNOR-268869 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC4 protein P62807 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271986 RAI1 protein Q7Z5J4 UNIPROT PER2 protein O15055 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22578325 f miannu "Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others." SIGNOR-266840 MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation Thr261 LVDSIAKtRDAGCRP -1 9162092 t "Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4." SIGNOR-251421 AMPK complex SIGNOR-C15 SIGNOR MFF protein Q9GZY8 UNIPROT "up-regulates activity" phosphorylation Ser155 GRLKRERsMSENAVR 9606 BTO:0001938 26816379 t gcesareni "A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission." SIGNOR-245948 PP1 proteinfamily SIGNOR-PF54 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t "inferred from 70% of family members" lperfetto "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases" SIGNOR-269901 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10116 BTO:0001103 21798082 t lperfetto "Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2)." SIGNOR-252694 MAPK8 protein P45983 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11781324 t lperfetto "Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis." SIGNOR-113645 "bisphenol A" chemical CHEBI:33216 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" -1 9751507 t miannu "Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings." SIGNOR-268738 PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR RAF1 protein P04049 UNIPROT "up-regulates activity" dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16239230 t gcesareni "... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259." SIGNOR-243538 CSNK2A2 protein P19784 UNIPROT KLF1 protein Q13351 UNIPROT "up-regulates activity" phosphorylation Thr23 ALGPFPDtQDDFLKW 10090 BTO:0004475 9722526 t 2 miannu "Regulation of erythroid Krppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. the transactivation capability of EKLF is augmented by co-transfection of CKIIalpha. in vitro assays demonstrate that CKIIalpha interacts with EKLF, and that the EKLF interaction domain is phosphorylated by CKII only at Thr-41" SIGNOR-241365 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 20562916 t miannu "We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37." SIGNOR-166262 TGFB2 protein P61812 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 22326956 t miannu "Tgf-? Signaling mediates a wide range of biological activities in development and disease. Tgf-? Ligands signal through heterodimeric type i and type ii receptors (tgf-? Receptor type i [t?RI, also known as alk5 and tgfbr1] and t?RII) that are members of the serine/threonine kinase family." SIGNOR-196025 MAPK3 protein P27361 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Thr614 AFRLEPLtPRGVLTV 9606 BTO:0000150 17311928 t llicata "Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1" SIGNOR-153391 MAPK9 protein P45984 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 t "The effect has been demonstrated using P45984-2" gcesareni "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." SIGNOR-179275 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9335504 t llicata "The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1." SIGNOR-52666 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89201 MECP2 protein P51608 UNIPROT DLX5 protein P56178 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19195802 f "Expression of DLX5 is controlled by MECP2, and defect in MECP2 induced an over-expression of DLX5 in lymphocytes as well as in the brain" SIGNOR-254034 RPS6K proteinfamily SIGNOR-PF26 SIGNOR EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 t gcesareni "S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function." SIGNOR-252783 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1387 GRCPSDPyKHSLPSQ -1 10195142 t lperfetto "To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain." SIGNOR-247159 ATM protein Q13315 UNIPROT KHDC3L protein Q587J8 UNIPROT "up-regulates activity" phosphorylation Thr145 IEVREAGtQRSVEVR 9606 BTO:0001086 31609975 t miannu "Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions. " SIGNOR-273505 NEDD4 protein P46934 UNIPROT GUCD1 protein Q96NT3 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 24743017 t miannu "The E3 ligase NEDD4 regulates GUCD1 degradation. many polyubiquitinylated species of GUCD1 appeared as high molecular weight forms, suggesting that GUCD1 is degraded by the proteasome, after polyubiquitin chain formation, in the presence of NEDD4-1." SIGNOR-272846 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-252330 MAPK1 protein P28482 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 9528799 t gcesareni "Our results provide strong evidence that dsrna binding is required for dimerization of full-length pkr molecules in vivo, leading to autophosphorylation in the activation loop and stimulation of the eif2alpha kinase function of pkr." SIGNOR-56337 NDN protein Q99608 UNIPROT PIAS1 protein O75925 UNIPROT "down-regulates quantity by destabilization" binding 9606 24911587 t lperfetto "Necdin bound to PIAS1 central domains that are highly conserved among PIAS family proteins and suppressed PIAS1-dependent sumoylation of the substrates STAT1 and PML (promyelocytic leukemia protein). Remarkably, necdin promoted degradation of PIAS1 via the ubiquitin-proteasome pathway. In transfected HEK293A cells, amino- and carboxyl-terminally truncated mutants of PIAS1 bound to necdin but failed to undergo necdin-dependent ubiquitination." SIGNOR-253387 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 19737929 t lperfetto "A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity" SIGNOR-216837 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr313 HGSGWAEtPRTDRGG 9606 12105215 t lperfetto "We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1" SIGNOR-216717 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser214 AVDQGNEsIVAKTTV 9606 19468302 t llicata "Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex." SIGNOR-185754 dexchlorpheniramine chemical CHEBI:4464 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7925364 t miannu "The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum." SIGNOR-258873 "UV stress" stimulus SIGNOR-ST7 SIGNOR CDKN2A protein P42771 UNIPROT up-regulates 9606 11830546 f miannu "The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. The increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor." SIGNOR-252376 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 14593115 t gcesareni "We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription." SIGNOR-118936 PAK5 protein Q9P286 UNIPROT AIFM1 protein O95831 UNIPROT "down-regulates activity" phosphorylation Thr281 GAEVKSRtTLFRKIG 9606 33867848 t miannu "Our results show that PAK5 can phosphorylate Thr-281 of AIF, which is included in its NLS1 sequence.|These results suggested that PAK5 inhibited AIF from entering the nucleus through phosphorylation of AIF T281 site, thus inhibiting cell apoptosis." SIGNOR-279085 EGR1 protein P18146 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000574 7565762 f miannu "TPA induced EGR1 binding to the -69/+20 promoter sequences over a time course which correlated with increased MDR1 promoter activity and increased steady-state MDR1 RNA levels. These data suggest a role for EGR1 in modulating MDR1 promoter activity in hematopoietic cells." SIGNOR-253871 CDK2 protein P24941 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "down-regulates activity" phosphorylation 9606 12202491 t lperfetto "Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity" SIGNOR-264650 INS protein P01308 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates activity" 9606 BTO:0000887 9415393 f lperfetto "Studies in adipose cells have demonstrated that insulin stimulates its receptor to phosphorylate tyrosine residues in irs-1, leading to activation of phosphatidylinositol 3-kinase, which plays a necessary role in mediating the translocation of the insulin-responsive glucose transporter glut4 to the cell surface." SIGNOR-236781 ALDH5A1 protein P51649 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI "up-regulates quantity" "chemical modification" 9606 19300440 t miannu "Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix." SIGNOR-266617 MAPK3 protein P27361 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser307 EPPSPPQsPRVEEAS 9606 8940068 t gcesareni "Sequential phosphorylation of hsf1 by mitogen-activated protein kinase and glycogen synthase kinase 3 at ser-303 and ser-307 represses transcriptional activation by heat shock factor-1." SIGNOR-44999 SYNE1 protein Q8NF91 UNIPROT "LINC complex" complex SIGNOR-C303 SIGNOR "form complex" binding 24481844 t lperfetto "LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM." SIGNOR-263287 CHEK1 protein O14757 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" phosphorylation 9606 18243098 t gcesareni "We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c." SIGNOR-265326 N protein P59595 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 18055455 t miannu "In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis." SIGNOR-260434 ribavirin chemical CHEBI:63580 ChEBI IMPDH2 protein P12268 UNIPROT "down-regulates activity" "chemical inhibition" 9606 22555152 t Federica "Ribavirin, a well-known IMPDH inhibitor, was included as a reference drug. As expected, this compound markedly inhibited IMPDH activity in a dose-dependent manner in bothtumour cell lines" SIGNOR-261079 L-tryptophan smallmolecule CHEBI:16828 ChEBI 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI "up-regulates quantity" "precursor of" 9606 31024440 t brain lperfetto "In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]." SIGNOR-264184 TBP protein P20226 UNIPROT LIN28B protein Q6ZN17 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 23494474 f miannu "We conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner." SIGNOR-255252 hsa-miR-200a-5p mirna URS000023B77E_9606 RNAcentral GNA13 protein Q14344 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001061 23329838 t Parnian "Taken together these data indicate that GNA13 is an important target of miR-182 and -200a, which bind to the 3 -UTR of GNA13 and down-regulate its protein expression in PC3 cells." SIGNOR-278022 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr504 AEPLPPSyVACS 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251355 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT "up-regulates activity" phosphorylation Ser548 KSSLEAAsFWGE -1 21880710 t miannu "Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression." SIGNOR-262939 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR BHLHE40 protein O14503 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19032342 f lperfetto "DEC1 (BHLHB2/Stra13/Sharp2)-a basic helix-loop-helix transcription factor-is known to be involved in various biological phenomena including clock systems and metabolism. In the clock systems, Dec1 expression is dominantly up-regulated by CLOCK : BMAL1 heterodimer, and it exhibits circadian rhythm in the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and other peripheral tissues." SIGNOR-253707 BIRC2 protein Q13490 UNIPROT RIPK3 protein Q9Y572 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 21931591 t miannu "CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation." SIGNOR-272711 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "precursor of" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266532 RARA protein P10276 UNIPROT OXT protein P01178 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 6153132 f lperfetto "The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances." SIGNOR-268548 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0002572 28646232 t "inferred from 70% family members" Gianni "We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3Œ≤ at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3Œ≤ activity and restores protein synthesis in Tsc2 ‚àí/‚àí MEFs to normal levels" SIGNOR-270068 EXOC8 protein Q8IYI6 UNIPROT "Exocyst_EXOC6B variant" complex SIGNOR-C491 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270783 "D1-D2-G-X3 complex" complex SIGNOR-C301 SIGNOR CHEK2 protein O96017 UNIPROT "up-regulates activity" 9606 BTO:0000567 23438602 f lperfetto "Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation." SIGNOR-263262 SRC protein P12931 UNIPROT DAPK1 protein P53355 UNIPROT "down-regulates activity" phosphorylation Tyr491 CAAWHGYySVAKALC 9606 BTO:0002181 17803936 t miannu " Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation. " SIGNOR-276073 "NMDA receptor_2B" complex SIGNOR-C348 SIGNOR DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11052931 t miannu "Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor" SIGNOR-264223 hsa-miR-202-5p mirna URS00003D8730_9606 RNAcentral LRP6 protein O75581 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000599 24704686 t Parnian "Taken together, our results suggested that LRP6 mRNA is a direct target of miR-202 in HCC cells." SIGNOR-278841 TFEB protein P19484 UNIPROT MOGAT2 protein Q3SYC2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 30145926 f lperfetto "Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB" SIGNOR-276799 serotonin smallmolecule CHEBI:28790 ChEBI HTR6 protein P50406 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264295 AIP protein O00170 UNIPROT GREB1 protein Q4ZG55 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 21984905 f miannu "We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells." SIGNOR-253735 NFE2L2 protein Q16236 UNIPROT PGD protein P52209 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22789539 f miannu "We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C)." SIGNOR-267355 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 11369754 t gcesareni "These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994." SIGNOR-108260 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates activity" dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 t "Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)" SIGNOR-248801 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258218 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257929 CD19 protein P15391 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 10090 10201980 t lperfetto "Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase." SIGNOR-249608 DOK4 protein Q8TEW6 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 t gcesareni "Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells." SIGNOR-101002 PRKCE protein Q02156 UNIPROT MIIP protein Q5JXC2 UNIPROT "up-regulates activity" phosphorylation Ser303 YHIHRRKsFDASDTL 9606 BTO:0001109 29038521 t done miannu "Here, we show that EGF stimulation induces PKCε-dependent phosphorylation of migration and invasion inhibitory protein (MIIP) at Ser303; this phosphorylation promotes the interaction between MIIP and RelA in the nucleus, by which MIIP prevents histone deacetylase 6 (HDAC6)-mediated RelA deacetylation, and thus enhances transcriptional activity of RelA and facilitates tumor metastasis. " SIGNOR-273828 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21620960 t gcesareni "Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity." SIGNOR-252515 CEP290 protein O15078 UNIPROT RAB8A protein P61006 UNIPROT "up-regulates activity" binding 9606 18694559 t miannu "CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CEP290 recruits Rab8a to centrosomes. Depletion of CEP290 results in a significant decrease of Rab8a at the centrosome and at the cilium, raising the possibility that CEP290 first recruits Rab8a through direct protein-protein interactions to the centrosome in cycling cells and later promotes ciliogenesis by allowing the entry of Rab8a into the cilium" SIGNOR-252146 PRKAA2 protein P54646 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 SIGNOR-C15 17082196 t lperfetto "Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology." SIGNOR-150462 XL-647 chemical CID:10458325 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 22722787 t gcesareni "Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4)." SIGNOR-197962 F2RL1 protein P55085 UNIPROT CTSD protein P07339 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254860 SLC27A5 protein Q9Y2P5 UNIPROT "Fatty acid" stimulus SIGNOR-ST19 SIGNOR "up-regulates quantity" relocalization 9606 28457600 t miannu "Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs)." SIGNOR-264466 CYBB protein P04839 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto "Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS)." SIGNOR-264716 WNT5A protein P41221 UNIPROT GSK3B protein P49841 UNIPROT up-regulates 9606 21078818 f gcesareni "We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3)" SIGNOR-169669 XPA protein P23025 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto "The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275704 MCF2 protein P10911 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260557 PRKACA protein P17612 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation." SIGNOR-70424 GRM6 protein O15303 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264354 APC-c complex SIGNOR-C150 SIGNOR KIFC1 protein Q9BW19 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 24510915 t miannu "Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A)." SIGNOR-266109 LYN protein P07948 UNIPROT PTGS2 protein P35354 UNIPROT "up-regulates activity" phosphorylation Tyr120 PPTYNADyGYKSWEA -1 24970799 t miannu "We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity. FYN and LYN kinases phosphorylate COX2 on two distinct residues in vitro." SIGNOR-276643 MAPK14 protein Q16539 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20162623 f Indirect:regulation miannu "Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6)." SIGNOR-251837 UQCRC2 protein P22695 UNIPROT "CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262191 MAP3K1 protein Q13233 UNIPROT FADD protein Q13158 UNIPROT "down-regulates activity" phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 15001534 t gcesareni "The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells" SIGNOR-123168 BRAF protein P15056 UNIPROT NIBAN2 protein Q96TA1 UNIPROT "down-regulates activity" phosphorylation 9606 33684228 t miannu "Overall, this indicates that BRAF-dependent phosphorylation of FAM129B controls its cellular localization and thus its ability to bind to KEAP1 to block NRF2 degradation." SIGNOR-279595 AKT proteinfamily SIGNOR-PF24 SIGNOR PTPN1 protein P18031 UNIPROT "down-regulates activity" phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 t lperfetto "Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor." SIGNOR-235411 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser103 RGLKRSLsEMEIGMV 10753652 t llicata "Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors." SIGNOR-250638 UBE3A protein Q05086 UNIPROT PSMB1 protein P20618 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 28559284 t lperfetto "Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits." SIGNOR-265131 triazolopyridazine chemical CHEBI:48384 ChEBI "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t brain lperfetto "The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005)." SIGNOR-263803 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 t lperfetto "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex" SIGNOR-118580 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-244719 FBXO2 protein Q9UK22 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 23604317 t miannu " FBXL2 interacts with the pool of p85β that is free of p110 PI(3)K catalytic subunits and targets this pool for ubiquitylation and subsequent proteasomal degradation.This result suggests that FBXL2 localization to cell membranes facilitates substrate binding, which in turn stimulates CUL1 neddylation and activation of ubiquitin ligase activity." SIGNOR-271937 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 17108107 t gcesareni "We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392" SIGNOR-150834 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18593906 t tpavlidou "Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene." SIGNOR-259427 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Ser27 SFGFTRTsARRRLAD -1 21880142 t miannu "Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266311 CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni "Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity" SIGNOR-59655 FGF2 protein P09038 UNIPROT ANKH protein Q9HCJ1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004473 19049325 f miannu "FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2." SIGNOR-252193 ATF2 protein P15336 UNIPROT FGF21 protein Q9NSA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005787 25055037 f miannu "The increased production of reactive oxygen species, subsequent induction of p38 MAPK (mitogen-activated protein kinase) and activation of an ATF2 (activating transcription factor 2)-binding site at the proximal promoter region of the FGF21 gene was found to be a major mechanism linking mitochondrial dysfunction with enhanced FGF21 gene transcription in myogenic cells." SIGNOR-253743 ADSS1 protein Q8N142 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "down-regulates quantity" "chemical modification" 9606 10496970 t miannu "Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP." SIGNOR-267346 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr323 GCHLLVAtPGRLVDM 9606 SIGNOR-C17 16280325 t lperfetto "Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis." SIGNOR-141569 SIRT1 protein Q96EB6 UNIPROT COL10A1 protein Q03692 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21337390 f miannu "The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5." SIGNOR-255141 F2RL1 protein P55085 UNIPROT RAB3A protein P20336 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254836 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1070 DSFLQRYsSDPTGAL 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250620 PTPRA protein P18433 UNIPROT FYN protein P06241 UNIPROT up-regulates dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 17507376 t gcesareni "Ptpalpha is a more widely expressed transmembrane ptp that has been shown to regulate the src family kinases, src and fyn, and is also present in t cells." SIGNOR-154796 PKC proteinfamily SIGNOR-PF53 SIGNOR GAD2 protein Q05329 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000142 15147202 t miannu "Here, we report the effect of phosphorylation on the two well-defined GAD isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 and GAD67. GAD65 was activated by phosphorylation, while GAD67 was inhibited by phosphorylation.We further demonstrate that protein kinase A (PKA) and protein kinase C isoform epsilon are the protein kinases responsible for phosphorylation and regulation of GAD67 and GAD65, respectively." SIGNOR-276010 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser285 NHTLAPAsPAPARPR 9606 BTO:0000142 15262992 t lperfetto "Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd" SIGNOR-126851 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser236 AKRRRLSsLRASTSK -1 1985906 t miannu "The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide." SIGNOR-250232 KLF2 protein Q9Y5W3 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12426306 f fspada "Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta." SIGNOR-95519 AMPK complex SIGNOR-C15 SIGNOR AMPK complex SIGNOR-C15 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 17728241 t lperfetto "Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by ampk" SIGNOR-216411 biphenyl-4,4'-diol chemical CHEBI:34367 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" -1 9751507 t miannu "Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings." SIGNOR-268740 HAX1 protein O00165 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 18971376 t lperfetto "The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels." SIGNOR-262052 NF2 protein P35240 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" binding 10090 BTO:0003324 27402866 t "Hippo pathway" Gianni "NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart." SIGNOR-261956 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 10802669 t gcesareni "We show that atm physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (s343a) does not completely complement radiosensitivity in nbs cells." SIGNOR-77149 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1016 DVVDADEyLIPQQGF 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-236527 ERBB2 protein P04626 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 12049736 t lperfetto "Phosphorylation on tyrosine-15 of p34(cdc2) by erbb2 inhibits p34(cdc2) activation and is involved in resistance to taxol-induced apoptosis" SIGNOR-88671 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser68 GGGAGPVsPQHHELT 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198729 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser383 ELPRRVNsASSSNPP 9606 15341740 t llicata "Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites." SIGNOR-128495 FZD3 protein Q9NPG1 UNIPROT GNGT1 protein P63211 UNIPROT up-regulates binding 9606 17251915 t gcesareni "In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat." SIGNOR-152606 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-51288 ARHGEF28 protein Q8N1W1 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260546 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 19282669 t "inferred from 70% family members" lperfetto "Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway" SIGNOR-270070 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR FBXO15 protein Q8NCQ5 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0005816 24703837 t miannu "Fbxo15 Targets CLS1 Protein for Ubiquitination and Degradation to Disrupt Mitochondrial Function. S. aureus infection induces expression of a kinase, PINK1, that phosphorylates an indispensable protein CLS1, which in turn triggers CLS1 ubiquitination and degradation by the F box protein (SCFFbxo15)." SIGNOR-272172 MAPK1 protein P28482 UNIPROT BCL3 protein P20749 UNIPROT "up-regulates activity" phosphorylation Ser122 CPMEHPLsADIAMAT -1 28689659 t miannu "Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. " SIGNOR-277360 MAPK1 protein P28482 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto "We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity" SIGNOR-203473 RPS6KA1 protein Q15418 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto "Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK." SIGNOR-209871 PA2G4 protein Q9UQ80 UNIPROT KLK3 protein P07288 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16254079 t "Ectopic expression of ebp1, a member of the PA2G4 family, inhibits the proliferation and induces the differentiation of human breast and prostate cancer cell lines. Ebp1 inhibits transcription of E2F1 and androgen receptor regulated genes such as prostate specific antigen (PSA) through its interactions with histone deacetylases (HDACs)" SIGNOR-253662 RHEB protein Q15382 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates binding 9606 18550814 t gcesareni "Rheb binds and activates pld1 in vitro in a gtp-dependent manner, strongly suggesting that pld1 is a bona fide effector for rheb." SIGNOR-178892 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269378 CDK5 protein Q00535 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Ser522 PAPSAKSsPSKHQPP 9606 BTO:0000938 18003833 t lperfetto "These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness." SIGNOR-159314 MAPK15 protein Q8TD08 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 12169099 t gcesareni "Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation." SIGNOR-91371 AKT2 protein P31751 UNIPROT PDK1 protein Q15118 UNIPROT "up-regulates activity" phosphorylation Thr346 APRPRVEtSRAVPLA -1 27505672 t miannu " Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. " SIGNOR-277271 DPY30 protein Q9C005 UNIPROT "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "form complex" binding 9606 24680668 t miannu "Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation." SIGNOR-204747 NF1 protein P21359 UNIPROT ADCY4 protein Q8NFM4 UNIPROT up-regulates 9606 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204091 SF3B1 protein O75533 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000664;BTO:0000565 25428262 f irozzo "Taken together, these data show that SF3B1 knockdown results in inhibition of cell growth, induction of cell cycle arrest and impairment of erythroid differentiation in myeloid cell lines.[…]SF3B1 knockdown compared with the scramble control, suggesting that normal SF3B1 function is required for erythroid differentiation." SIGNOR-256004 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser440 DTSYVIEsDEDLEME 9606 BTO:0000007 24429382 t llicata "Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair." SIGNOR-203737 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75934 DUSP9 protein Q99956 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates binding 9606 21908610 t "inferred from 70% of family members" gcesareni "Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein." SIGNOR-269924 3a protein P59632 UNIPROT CYCS protein P99999 UNIPROT "up-regulates activity" 9606 18632968 f Luana "Thus, caspase-9 activation and cytochrome c release in cells expressing the 3a protein indicated that this viral protein also activates the intrinsic pathway of apoptosis." SIGNOR-260214 PGM2 protein Q96G03 UNIPROT "2-deoxy-alpha-D-ribose 1-phosphate" smallmolecule CHEBI:11563 ChEBI "down-regulates quantity" "chemical modification" 9606 17804405 t miannu "Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses." SIGNOR-267094 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t lperfetto "Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation" SIGNOR-181655 TOPBP1 protein Q92547 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates binding 9606 20068082 t gcesareni "Topbp1 directly activates atr/atrip and promotes atr-mediated chk1 phosphorylation." SIGNOR-163214 CDK2 protein P24941 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 20080565 t gcesareni "We report that grk2 protein levels are transiently down-regulated during the g2/m transition by a mechanism involving cdk2-mediated phosphorylation of grk2 at serine670, which triggers binding to the prolyl-isomerase pin1 and subsequent degradation." SIGNOR-163279 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR BAG3 protein O95817 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0002181 34215846 t miannu "We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377." SIGNOR-277320 Ub:E2 complex SIGNOR-C497 SIGNOR RNF128 protein Q8TEB7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270953 AKT1 protein P31749 UNIPROT PDK1 protein Q15118 UNIPROT "up-regulates activity" phosphorylation Thr346 APRPRVEtSRAVPLA -1 27505672 t miannu " Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. " SIGNOR-277272 EXOC1 protein Q9NV70 UNIPROT "Exocyst_EXOC6B variant" complex SIGNOR-C491 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270776 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Thr317 PTQRMTItEFMNHPW -1 7592979 t miannu "In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction" SIGNOR-250102 TRAF6 protein Q9Y4K3 UNIPROT TDP2 protein O95551 UNIPROT "up-regulates activity" ubiquitination 9606 21980489 t miannu "TTRAP is ubiquitylated by TRAF6 and promotes TRAF6 dependent ubiquitylation of TAK1.|In addition, we noted that the presence of TRAF6 strengthened the interaction between TTRAP and the TGF-\u03b2 receptor complex (see also later)." SIGNOR-278717 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni "Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6." SIGNOR-252618 "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT "up-regulates activity" "chemical activation" 9606 31226734 t lperfetto "The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form" SIGNOR-265914 NFIB protein O00712 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24553933 f miannu "Nfibbinds to the ezh2 promoter and overexpression ofnfibrepresses ezh2 transcription." SIGNOR-204643 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258016 PBRM1 protein Q86U86 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270596 MRPL35 protein Q9NZE8 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262362 SRC protein P12931 UNIPROT TERT protein O14746 UNIPROT down-regulates phosphorylation Tyr707 QDPPPELyFVKVDVT 9606 12808100 t lperfetto "Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via src kinase family-dependent phosphorylation of tyrosine 707" SIGNOR-102097 UCK1 protein Q9HA47 UNIPROT cytidine smallmolecule CHEBI:17562 ChEBI "down-regulates quantity" "chemical modification" 9606 27239701 t miannu "Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively. " SIGNOR-280599 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 22124607 t lperfetto "Moreover, we reported that TCPTP knockdown in PTP1B deficient MEFS further enhanced IR activation, consistent with the two PTPs acting in a coordinated manner to attenuate insulin signalling .|Therefore, the inhibition of PTPs such as PTP1B that attenuate IR activation and signalling might be particularly effective in alleviating insulin resistance.|The prototypic family member PTP1B (encoded by PTPN1) dephosphorylates the IR beta subunit Y1162 and Y1163 activation loop autophosphorylation site to attenuate insulin signalling in vivo ." SIGNOR-276947 PAK6 protein Q9NQU5 UNIPROT SLC25A5 protein P05141 UNIPROT "up-regulates quantity" phosphorylation Thr107 LGGVDKRtQFWLYFA 9606 32194820 t miannu "In the present study, it was demonstrated that ANT2 was phosphorylated by PAK6 at T107.|Moreover, PAK6 overexpression upregulated the protein expression of ANT2, while PAK6 knockdown led to opposing effects." SIGNOR-279473 AKT1 protein P31749 UNIPROT SOX2 protein P48431 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr118 RPRRKTKtLMKKDKY 9606 25042802 t miannu "In contrast, phosphorylation of Sox2 by AKT1 at T118 blocks K119me by Set7 and stabilizes Sox2." SIGNOR-279003 NPM1 protein P06748 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30205049 t miannu "In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation." SIGNOR-260138 PSPH protein P78330 UNIPROT L-serine chemical CHEBI:17115 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000142 12213811 t lperfetto "Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP" SIGNOR-268571 NRXN3 protein Q9HDB5 UNIPROT DAG1 protein Q14118 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626542 t miannu "The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM." SIGNOR-265462 LHX3 protein Q9UBR4 UNIPROT ISL2 protein Q96A47 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 9452425 t lperfetto "a direct NLI-independent interaction between Lhx3 and the related proteins Isl1 and Isl2 was observed. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity" SIGNOR-236836 ERMP1 protein Q7Z2K6 UNIPROT UPR phenotype SIGNOR-PH131 SIGNOR "up-regulates activity" 9606 BTO:0000093 27566589 f "Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation." SIGNOR-261295 ADA protein P00813 UNIPROT ADORA1 protein P30542 UNIPROT "up-regulates activity" binding -1 18680557 t miannu "The results show that human ADA, apart from reducing the adenosine concentration and thus preventing A(1)R desensitization, binds to A(1)R behaving as an allosteric effector that markedly enhances agonist affinity and increases receptor functionality." SIGNOR-269105 SLC9A4 protein Q6AI14 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265594 MSL2 protein Q9HCI7 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0002552 19033443 t miannu "Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization. MSL2 ubiquitination of p53 is required for p53 cytoplasmic localization." SIGNOR-271774 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser54 QPLPPRPsPAALPGG 9606 27308327 t miannu "HIPK2 phosphorylates WIP1 at Ser54 and Ser85, and phosphorylated WIP1 is subject to proteasomal degradation so that WIP1 is maintained at low levels." SIGNOR-278229 EIF2AK2 protein P19525 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 10348343 t gcesareni "The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro." SIGNOR-68033 pemetrexed chemical CHEBI:63616 ChEBI TYMS protein P04818 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205933 PSMA4 protein P25789 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263366 MLLT11 protein Q13015 UNIPROT TCF7 protein P36402 UNIPROT "up-regulates activity" binding -1 26079538 t irozzo "Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. Super-shift and electrophoretic mobility shift assay (EMSA) further confirmed that AF1q directly interacted with TCF7 and enhanced the binding affinity of the complex" SIGNOR-259108 Ub:E2 complex SIGNOR-C497 SIGNOR RNF133 protein Q8WVZ7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271205 FPR1 protein P21462 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256682 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000776 25673924 t lperfetto "CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades." SIGNOR-242891 SMAD6 protein O43541 UNIPROT HOXC8 protein P31273 UNIPROT "up-regulates activity" binding 9606 10722652 t gcesareni "Smad6 interacts with hox transcription factors as part of the negative feedback circuit in the bmp signaling pathway" SIGNOR-75823 UCK1 protein Q9HA47 UNIPROT "cytidine 5'-monophosphate(2-)" smallmolecule CHEBI:60377 ChEBI "up-regulates quantity" "chemical modification" 9606 27239701 t miannu "Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively. " SIGNOR-280600 LTN1 protein O94822 UNIPROT RPS6KA1 protein Q15418 UNIPROT "down-regulates activity" ubiquitination 9606 29540532 t miannu "Ltn1 ubiquitylation of RSK1, RSK2, and TWY3 could either result in degradation or impart a regulatory function on target proteins distinct from degradation." SIGNOR-278757 XIAP protein P98170 UNIPROT TLE3 protein Q04726 UNIPROT "up-regulates activity" ubiquitination 9606 22304967 t miannu "These findings suggest that TLE3 ubiquitylation by XIAP may be required during Wnt pathway activation to facilitate its dissociation from TCF/Lef, allowing subsequent beta-catenin binding and transcriptional activation." SIGNOR-278528 POLA1 protein P09884 UNIPROT "DNA polymerase alpha:primase complex" complex SIGNOR-C262 SIGNOR "form complex" binding -1 24043831 t lperfetto "At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation " SIGNOR-261343 AMER1 protein Q5JTC6 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000038 21498506 t lperfetto "We show that Amer1 binds directly to beta-catenin via a novel interaction motif, the REA repeats. This amino acid motif, including the core sequence arginine, glutamic acid and alanine, and this REA repeats mediate binding of Amer1 to the armadillo repeats of beta-catenin. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the plasma membrane." SIGNOR-217950 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation 10029 BTO:0000246 12907755 t "Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR" SIGNOR-248505 WIPF1 protein O43516 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR up-regulates 9606 19121306 f lperfetto "However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin." SIGNOR-260611 DYRK1A protein Q13627 UNIPROT SRSF1 protein Q07955 UNIPROT unknown phosphorylation Ser238 SRGSPRYsPRHSRSR 9606 BTO:0000142 18658135 t gcesareni "Here, we demonstrate that dyrk1a, a kinase encoded by a gene in the ds critical region, phosphorylates alternative splicing factor (asf) at ser-227, ser-234, and ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion." SIGNOR-179615 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YBX1 protein P67809 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 16797541 t miannu "Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1" SIGNOR-271606 CAMK2A protein Q9UQM7 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser643 CFTPKGSsLKIEERA 9606 BTO:0001260 2170388 t gcesareni "Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii" SIGNOR-22631 TWIST2 protein Q8WVJ9 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 21931630 f miannu "Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2." SIGNOR-255592 TUBA8 protein Q9NY65 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu "We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching." SIGNOR-269729 Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT ACE protein P12821 UNIPROT "up-regulates activity" binding 9606 32201502 t MIANNU "Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I" SIGNOR-260231 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR PROX1 protein Q92786 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002181 36433955 t miannu "Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation." SIGNOR-277610 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269344 CDH11 protein P55287 UNIPROT CTNNA1 protein P35221 UNIPROT unknown binding 9606 BTO:0000150 10029089 t miannu "Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin" SIGNOR-64859 CEBPB protein P17676 UNIPROT KLF5 protein Q13887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16054042 f fspada "Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter." SIGNOR-210004 DNA_damage stimulus SIGNOR-ST1 SIGNOR SLX4 protein Q8IY92 UNIPROT up-regulates -1 10542278 f miannu "HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay." SIGNOR-259063 PPP3CB protein P16298 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f gcesareni "The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c." SIGNOR-84044 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 15774499 t gcesareni "The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain." SIGNOR-134654 DMXL2 protein Q8TDJ6 UNIPROT RAB3GAP1 protein Q15042 UNIPROT "up-regulates quantity" binding 10116 BTO:0000142 11809763 t miannu "We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles." SIGNOR-265582 FYN protein P06241 UNIPROT JUP protein P14923 UNIPROT "up-regulates activity" phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 14517306 t "Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 and that it phosphorylated Tyr133 with a much lower activity" SIGNOR-251176 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr255 EEEGAPDyENLQELN 9606 11368773 t lperfetto "In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127." SIGNOR-247034 ATM protein Q13315 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t llicata "Atm and dna?PK Phosphorylate rpa32 thr21in vitro and in vivo" SIGNOR-121865 AMPK complex SIGNOR-C15 SIGNOR CHKA protein P35790 UNIPROT "up-regulates activity" phosphorylation Ser279 KKLHKLLsYNLPLEL 9606 BTO:0000527 34929314 t lperfetto "Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation." SIGNOR-267647 SIRT7 protein Q9NRC8 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" deacetylation Lys37 APSTGGVkKPHRYRP 30653310 t lperfetto "Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37." SIGNOR-275878 sapitinib chemical CHEBI:132986 ChEBI ERBB3 protein P21860 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190155 NR3C1 protein P04150 UNIPROT NR3C2 protein P08235 UNIPROT up-regulates 9606 11154266 f lperfetto "These results indicate that functional interactions between the glucocorticoid and mineralocorticoid receptors in activating specific gene transcription are probably more complex than has been previously appreciated." SIGNOR-85987 TGFBI protein Q15582 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "up-regulates activity" 10090 BTO:0004093 25786978 t lperfetto "First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs." SIGNOR-253284 TRIM27 protein P14373 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102031 ACTL6A protein O96019 UNIPROT "Muscle cell-specific SWI/SNF ARID1A variant" complex SIGNOR-C481 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270699 IGF1R protein P08069 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 10090 11715022 f lperfetto "We show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy." SIGNOR-235373 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "chemical modification" 9606 31422819 t miannu "This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-267513 CTNNB1 protein P35222 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16510874 f gcesareni "Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp." SIGNOR-19153 Ub:E2 complex SIGNOR-C497 SIGNOR NEURL1 protein O76050 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271043 CTNNB1 protein P35222 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" 9606 16510874 f Luana "Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp." SIGNOR-265358 NFATC1 protein O95644 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates "transcriptional regulation" 9606 BTO:0001103 14729474 f apalma "To summarize, these two studies have generated important insights into the control of skeletal muscle hypertrophy by the calcineurin/NFATc1 signaling pathway" SIGNOR-256215 MAPK9 protein P45984 UNIPROT JUNB protein P17275 UNIPROT down-regulates binding 9606 9405416 t gcesareni "Jnk targets junb ubiquitination" SIGNOR-53827 GPR183 protein P32249 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257110 sabcomeline chemical CHEBI:134846 ChEBI CHRM1 protein P11229 UNIPROT "up-regulates activity" "chemical activation" 10116 9399977 t miannu "SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes" SIGNOR-258678 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRA protein P10827 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000759 2158622 t miannu "We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts." SIGNOR-258385 KMT2D protein O14686 UNIPROT "MLL2 complex" complex SIGNOR-C88 SIGNOR "form complex" binding 9606 24680668 t miannu "The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation." SIGNOR-204816 PD173955 chemical CHEBI:49791 ChEBI ABL1 protein P00519 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258263 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser31 EILGRGVsSVVRRCI -1 7935360 t miannu "Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81." SIGNOR-250388 ITCH protein Q96J02 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates ubiquitination 9606 15350225 t gcesareni "Itch promotes ubiquitination of smad2 and augments smad2 phosphorylation that requires an intact ligase activity of itch. Moreover, itch facilitates complex formation between tgf-beta receptor and smad2 and enhances tgf-beta-induced transcription." SIGNOR-128647 PRKCG protein P05129 UNIPROT EIF4E protein P06730 UNIPROT unknown phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 t lperfetto "Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins." SIGNOR-248947 ZNF503 protein Q96F45 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 25538248 f Monia "We asked whether higher pFAK staining in cells expressing Zpo2 correlates with reduced E-cadherin levels. Immunostaining for E-cadherin in the EpH4.9 and PyMT stable cell lines indicated a decrease in overall E-cadherin staining in Zpo2-overexpressing cells compared with the control (Fig. 6C). Similarly, Western blot analysis indicated a reduction in E-cadherin expression in Zpo2-expressing cells compared with the control (Fig. 6D)." SIGNOR-261190 MDH2 protein P40926 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "chemical modification" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266286 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273089 MAP1LC3C protein Q9BXW4 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f lperfetto "We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation" SIGNOR-219399 EGFR protein P00533 UNIPROT HGS protein O14964 UNIPROT up-regulates phosphorylation Tyr329 IDPELARyLNRNYWE 9606 12953068 t lperfetto "We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation" SIGNOR-86689 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t llicata "We show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro." SIGNOR-121873 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178420 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t "Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings." SIGNOR-255840 carfilzomib chemical CHEBI:65347 ChEBI PSMB5 protein P28074 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000873 19348473 t Luana "Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes." SIGNOR-257818 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2W protein Q96B02 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271340 TLR4 protein O00206 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001545 28137827 f miannu "S100A9 induces differentiation of acute myeloid leukemia cells through TLR4." SIGNOR-261923 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one chemical CID:56597938 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258320 cytidine smallmolecule CHEBI:17562 ChEBI "cytidine 5'-monophosphate(2-)" smallmolecule CHEBI:60377 ChEBI "up-regulates quantity" "precursor of" 9606 27239701 t miannu "Uridine-cytidine kinase (UCK) is a pyrimidine ribonucleoside kinase that catalyses the first step of the pyrimidine salvage pathway, the phosphorylation of uridine and cytidine to UMP and CMP, respectively. " SIGNOR-280601 LTB4R2 protein Q9NPC1 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256817 CACNA1H protein O95180 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000142 30736831 t miannu "Certain types of sensory neurons express Cav3.2 calcium channels [12, 13] These channels belong to the family of low-voltage gated T-type calcium channels" SIGNOR-269278 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser8 MWNSGFEsYGSSSYG 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation" SIGNOR-162164 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 20940307 t gcesareni "Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis" SIGNOR-168469 APBA1 protein Q02410 UNIPROT "CASK-Mint1-Veli complex" complex SIGNOR-C561 SIGNOR "form complex" binding 9606 BTO:0000938 16842202 t miannu "The CASK-Mint1-Veli complex acts as an adaptor protein complex interacting with beta-neurexin, the current model proposes that the CASK- Mint1-Veli complex functions as a nucleation site for the assembly of proteins involved in synaptic junctions and synaptic vesicle exocytosis (Fig. 3a)." SIGNOR-278898 BCAR1 protein P56945 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 18321991 t gcesareni "In this study, we show that, after tyrosine phosphorylation of p130cas mediated by integrin signaling, the phosphorylated p130cas is able to interact with phosphorylated smad3 and in turn prevent transcriptional activation by smad3" SIGNOR-161265 EPHB1 protein P54762 UNIPROT CASKIN1 protein Q8WXD9 UNIPROT "up-regulates activity" phosphorylation Tyr296 TKDYCNNyDLTSLNV 9534 BTO:0000298 23181695 t miannu "EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation." SIGNOR-262860 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser170 RDSEGFNsPKQCDSS -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265958 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 BTO:0000944 12052829 t lperfetto "Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms." SIGNOR-263047 PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" 9606 21798082 t lperfetto "Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2)." SIGNOR-252722 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser262 GHGLRRSsKFCLKEH -1 1848190 t lperfetto "We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling." SIGNOR-248855 INSIG2 protein Q9Y5U4 UNIPROT SCAP protein Q12770 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 12242332 t "insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi." SIGNOR-256209 RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" binding 9606 12887920 t amattioni "Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex" SIGNOR-104255 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CTTN protein Q14247 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 20444238 t "inferred from 70% family members" gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-270164 PPP1CB protein P62140 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t "Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1." SIGNOR-248571 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT "up-regulates activity" phosphorylation Ser345 PLVSDEKsSELIITD -1 26119734 t miannu "Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro" SIGNOR-276198 DIO1 protein P49895 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI "down-regulates quantity" "chemical modification" 9606 1400883 t scontino "The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production." SIGNOR-266944 UBAC1 protein Q9BSL1 UNIPROT KPC complex SIGNOR-C523 SIGNOR "form complex" binding 10090 BTO:0000944 15531880 t miannu " We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation. " SIGNOR-271512 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKAR2A protein P13861 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258761 MIB2 protein Q96AX9 UNIPROT JAG2 protein Q9Y219 UNIPROT up-regulates ubiquitination 9606 15920166 t gcesareni "Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2." SIGNOR-137922 ADCY2 protein Q08462 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "chemical modification" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-265004 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4B protein O94953 UNIPROT "up-regulates activity" "chemical activation" 29981745 t lperfetto "Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3." SIGNOR-273466 "Fatty acid" stimulus SIGNOR-ST19 SIGNOR PPARG protein P37231 UNIPROT up-regulates 9606 29369787 t miannu "Omega 3 fatty acids and fibrates are considered as natural and pharmacological ligands of PPARα, respectively, that reduce inflammation and arteriosclerosis in cardiovascular system" SIGNOR-256189 RNF4 protein P78317 UNIPROT KDM5C protein P41229 UNIPROT "up-regulates activity" sumoylation 9606 33859667 t SaraGualdi "Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015)." SIGNOR-271576 SMARCC2 protein Q8TAQ2 UNIPROT "Muscle cell-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C483 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex." SIGNOR-270735 ILK protein Q13418 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA -1 11313365 t miannu "ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner." SIGNOR-250261 PEX14 protein O75381 UNIPROT PEX7 protein O00628 UNIPROT "up-regulates activity" binding -1 15798189 t miannu "The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7." SIGNOR-253028 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 14711813 t llicata "Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. taken together, the results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity." SIGNOR-121165 Ub:E2 complex SIGNOR-C497 SIGNOR CHFR protein Q96EP1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271061 Ub:E2 complex SIGNOR-C497 SIGNOR MEX3B protein Q6ZN04 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271174 CIAO2B protein Q9Y3D0 UNIPROT "CIAO2B cytosolic iron-sulfur protein assembly complex" complex SIGNOR-C630 SIGNOR "form complex" binding 9606 23585563 t miannu " The MMS19 complex consists of a core complex (MMS19-MIP18-CIAO1) and an external component (IOP1). The core complex catches and holds IOP1 via interaction with CIAO1. MMS19 in the core complex binds apoproteins. MIP18 connects CIAO1 and MMS19." SIGNOR-281026 SLBP protein Q14493 UNIPROT H2AC6 protein Q93077 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265400 EIF2AK2 protein P19525 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 25360179 t miannu "Silencing PKR gene expression in HepG2 cells with siRNA reduced STAT3 phosphorylation at Tyr705 and Ser727 (XREF_FIG).|The results also revealed that PKR activates STAT3, a transcription factor associated with primary liver tumors, which is suggested to promote tumor cell proliferation." SIGNOR-279613 MAPK3 protein P27361 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser643 KILIASPsPTHIHKE 9606 BTO:0000567 18519666 t lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-178735 NFE2 protein Q16621 UNIPROT HBE1 protein P02100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000426 16287851 f "Regulation of expression" miannu "NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells." SIGNOR-251842 ABL1 protein P00519 UNIPROT RAPGEF1 protein Q13905 UNIPROT unknown phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 20581864 t llicata "Activation of endogenous c-abl by oxidative stress was associated with phosphorylation of cellular c3g on y504. Inhibition of c3g expression and function using rnai or dominant-negative approaches inhibited c-abl-mediated cell death." SIGNOR-166422 PTPRG protein P23470 UNIPROT ITGB2 protein P05107 UNIPROT "down-regulates activity" 9606 25624455 f miannu "PTPRG activation inhibits chemoattractant induced LFA-1 affinity triggering and mediated adhesion in human primary monocytes.we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation." SIGNOR-254735 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr203 SSLATPPtLSSTVLI 9606 BTO:0001938 12815053 t lperfetto "Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation." SIGNOR-249220 TLR8 protein Q9NR97 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity" 9606 BTO:0004721;BTO:0002900 15661881 f miannu "TLR8 functions in monocytes and myeloid DC and is involved in the production of proinflammatory cytokines such as TNF-α." SIGNOR-259249 PRKACA protein P17612 UNIPROT PTPN11 protein Q06124 UNIPROT "down-regulates activity" phosphorylation Thr73 YGGEKFAtLAELVQY 9606 BTO:0002181 25802336 t miannu " We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity. " SIGNOR-276891 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR IFITMs proteinfamily SIGNOR-PF49 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 25599080 f miannu "The IFITM (interferon-induced transmembrane) proteins comprise a family of interferon-induced antiviral cell-intrinsic restriction factors with high constitutive expression in many cells, including barrier epithelial cells. As their names imply, the expression of human IFITM1, IFITM2, and IFITM3 is also strongly upregulated by both type I and type II interferons" SIGNOR-260220 GATA2 protein P23769 UNIPROT ETV2 protein O00321 UNIPROT "up-regulates activity" binding 10090 24583263 t irozzo "Transcriptional assays with the Spi1 promoter-reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2.The protein-protein interaction between Etv2 and Gata2 is mediated by the Ets and Gata domains. Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation." SIGNOR-256008 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 t lbriganti "Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis." SIGNOR-210176 "NLRC4 inflammasome" complex SIGNOR-C223 SIGNOR "Caspase 1 complex" complex SIGNOR-C220 SIGNOR "up-regulates activity" cleavage 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256384 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0002035 11948419 t miannu "MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e)." SIGNOR-275984 BIRC7 protein Q96CA5 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates binding 9606 BTO:0000848 15485396 t gcesareni "These results suggest that ml-iap might regulate apoptosis by sequestering smac and preventing it from antagonizing xiap-mediated caspases, rather than by direct caspases." SIGNOR-129869 SSTR1 protein P30872 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256958 SNAI1 protein O95863 UNIPROT HPGD protein P15428 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19010907 f miannu "We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression." SIGNOR-254237 Ub:E2 complex SIGNOR-C497 SIGNOR IRF2BPL protein Q9H1B7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271003 RELA protein Q04206 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "form complex" binding 9606 9450761 t gcesareni "Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna" SIGNOR-55381 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser352 TRPTALTsPELSSWS 9606 BTO:0001109 28945223 t miannu "In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation. " SIGNOR-276743 LRFN3 protein Q9BTN0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu "This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments." SIGNOR-264101 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9606 BTO:0000007 20048145 t lperfetto "Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha." SIGNOR-252785 PRKAA2 protein P54646 UNIPROT CDC27 protein P30260 UNIPROT unknown phosphorylation Ser379 NALPRRSsRLFTSDS 9606 SIGNOR-C15 22137581 t lperfetto "Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379, respectively) resulted in an almost complete loss of ampk phosphorylation in these proteins" SIGNOR-195106 FES protein P07332 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15003822 t miannu "Fes also induced Tyr 705 phosphorylation and DNA binding activity of STAT3, in agreement with the idea that Fes can regulate transcriptional activation through Fes dependent phosphorylation of transcription factors.On the basis of these findings, we propose that Fes activation of critical transcriptional regulators such as PU.1 is part of the mechanism by which this kinase induces macrophage differentiation of myeloid progenitors.|We conclude that Fes may regulate granulocytic differentiation at least in part through activation of C/EBP-alpha and STAT3.In 32D cells, Fes activated STAT3 and C/EBP-alpha, two important regulators of granulocytic differentiation [14,15]." SIGNOR-278937 ARID1B protein Q8NFD5 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t lperfetto "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-241713 CASP3 protein P42574 UNIPROT PARP1 protein P09874 UNIPROT "down-regulates activity" cleavage 10090 BTO:0000331 11907276 t amattioni "Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process" SIGNOR-116178 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" relocalization 9606 20515759 t lperfetto "Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor." SIGNOR-59145 RAD18 protein Q9NS91 UNIPROT TP53BP1 protein Q12888 UNIPROT "up-regulates activity" ubiquitination Lys1268 DGTEVERkVTEETEE 9606 19228710 t miannu "RAD18 associates with 53BP1 and is recruited to DSB sites in a 53BP1 dependent manner specifically during G1-phase, RAD18 monoubiquitinates KBD domain of 53BP1 at lysine 1268 in vitro.|These results suggest that RAD18 directed modification at Lysine 1268 of 53BP1 promotes the retention of 53BP1 at DSBs." SIGNOR-278593 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT unknown phosphorylation Tyr706 RDVYSTDyYRVGGHT 10090 BTO:0000944 10533983 t miannu "TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785." SIGNOR-250206 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation Ser189 DEEFREPsTGKTCLP 9606 19661060 t Manara "We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4." SIGNOR-260884 CDK1 protein P06493 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" phosphorylation Ser242 IPNGFGTsPLTPSAR -1 12556484 t done miannu "In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites" SIGNOR-274073 PPM1E protein Q8WY54 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 11864573 t "The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX." SIGNOR-248761 SMURF1 protein Q9HCE7 UNIPROT TRIB2 protein Q92519 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0002181 24089522 t miannu " In this study, we found that TRIB2 was up-regulated and exhibited high stability in liver cancer cells compared with other cells. We performed a structure-function analysis of TRIB2 and identified a domain (amino acids 1-5) at the N terminus that interacted with the E3 ubiquitin ligase Smurf1 and was critical for protein stability. Deletion of this domain extended TRIB2 half-life time accompanied with a more significant malignant property compared with wild type TRIB2." SIGNOR-275432 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser435 TLASERSsPQRKSQR -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414. An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262747 N-(2-(4-(7-Methoxy-1-naphthalenyl)-1-piperazinyl)ethyl)-2-thiophenecarboxamide chemical CID:131907 PUBCHEM HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258866 GSK3B protein P49841 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser160 KRPATDDsSTQNKRA 9606 21439087 t miannu "GSK-3\u03b2 phosphorylates p27 Kip1 at S160 and S161, resulting in increased p27 Kip1 stability [ xref ]." SIGNOR-278938 GSK3B protein P49841 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser161 RPATDDSsTQNKRAN 9606 21439087 t miannu "GSK-3\u03b2 phosphorylates p27 Kip1 at S160 and S161, resulting in increased p27 Kip1 stability [ xref ]." SIGNOR-278939 MID1 protein O15344 UNIPROT PPP2CA protein P67775 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0004725 11685209 t miannu "MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation" SIGNOR-271467 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT "up-regulates activity" phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu "AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. " SIGNOR-277894 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" phosphorylation 9606 21902831 t lperfetto "As a permissive environment is created at these loci, p38 further stimulates gene expression through the phosphorylation of additional myogenic transcription factors, including mef2c and e47." SIGNOR-176551 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75938 NRXN2 protein P58401 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626545 t miannu "The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites" SIGNOR-265455 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser19 KGFRRAVsELDAKQA -1 11359875 t miannu "MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation." SIGNOR-250149 ARHGAP23 protein Q9P227 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260480 EGFR protein P00533 UNIPROT LYN protein P07948 UNIPROT "up-regulates activity" phosphorylation Tyr32 RNTERTIyVRDPTSN 9606 23764002 t miannu "EGFR phosphorylates p56 Lyn at Y32.|In the presence of EGFR, p56 Lyn -mediated MCM7 phosphorylation was significantly augmented, suggesting that EGFR signaling potentiates p56 Lyn kinase activity for MCM7 phosphorylation." SIGNOR-279369 ASTN2 protein O75129 UNIPROT ASTN1 protein O14525 UNIPROT "down-regulates quantity" binding 9606 BTO:0000007 20573900 t miannu "Biochemical and flow cytometry experiments show that ASTN2 forms a complex with ASTN1 and regulates surface expression of ASTN1. Coexpression with ASTN2 reduces the cell surface localization of ASTN1." SIGNOR-269813 PRKCA protein P17252 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates phosphorylation Ser132 GGDAPSPsKRPWARQ 9606 18710826 t tpavlidou "Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity." SIGNOR-180199 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CAD protein P27708 UNIPROT up-regulates phosphorylation 9606 15890648 t "inferred from 70% family members" lperfetto "Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol" SIGNOR-269998 SRC protein P12931 UNIPROT RRAS protein P10301 UNIPROT "down-regulates activity" phosphorylation Tyr66 DPTIEDSyTKICSVD 9606 BTO:0000007 11682467 t lperfetto "The small gtpase, r-ras, affects cell adhesion by maintaining integrin activity. Activated src oncogene phosphorylates r-ras and suppresses integrin activity. the src phosphorylation site in r-ras was tyrosine 66" SIGNOR-111189 EVL protein Q9UI08 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu "Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance." SIGNOR-268391 NOTCH4 protein Q99466 UNIPROT MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 12386158 t gcesareni "We show here identification of two new members of human mam family (human mastermind-2 (hmam-2) and human mastermind-3 (hmam-3)), which retain characteristics similar to human mastermind-1 (hmam-1) and drosophila mastermind. Both hmam-2 and hmam-3 stabilize and participate in the dna-binding complex rbp-j/cbf-1 protein and the notch intracellular domains that serve as intermediates of the signaling. Both hmam-2 and hmam-3 enhanced the activation of transcription from a target promoter by notch signaling. However, we also show evidence that the activation of the target promoter by notch3 and notch4 is more efficiently potentiated by hmam-2 than by hmam-1 or -3." SIGNOR-94279 CSK protein P41240 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Tyr1218 MVSTFEQyQFLYDVI 9606 BTO:0000782 7507203 t llicata "Tyrosine phosphorylation of cd45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase." SIGNOR-26785 GSTA1 protein P08263 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000018 29928434 f irozzo "Accordingly, downregulation of GSTA1 suppressed tumor growth. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line." SIGNOR-256296 ADNP protein Q9H2P0 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR "form complex" binding 10090 BTO:0002896 29795351 t miannu "Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. we have discovered ChAHP, a gene-regulatory complex that consists of the chromatin remodeller CHD4, the DNA-binding factor ADNP, and the heterochromatin proteins HP1β and HP1γ. By locally restricting access to DNA, ChAHP prevents endodermal gene transcription in mouse ES cells and during neuroectodermal differentiation." SIGNOR-266751 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-119366 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12151396 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro." SIGNOR-91067 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT "up-regulates activity" phosphorylation Ser418 TTENRFHsLPFSLTK 9606 24614225 t lperfetto "Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity." SIGNOR-25329 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR "up-regulates activity" 9606 23685857 f "Tumor necrosis factor α (TNF-α, also known as cachectin) is a strong pro-inflammatory cytokine which plays an important role in the immune system during inflammation, cell proliferation, differentiation and apoptosis" SIGNOR-258988 GNAI1 protein P63096 UNIPROT ADCY5 protein O95622 UNIPROT "down-regulates activity" binding 7108 BTO:0001240 8119955 t "Marta Tosoni" "Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3" SIGNOR-278074 Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 16440056 f lperfetto "Axonemal dyneins are responsible for the movement of cilia and flagella." SIGNOR-265021 PRKCI protein P41743 UNIPROT FBXW7 protein Q969H0 UNIPROT "down-regulates activity" phosphorylation Ser18 KRRRTGGsLRGNPSS 9606 BTO:0000567 28850619 t miannu "Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation." SIGNOR-277250 KDM5D protein Q9BY66 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264310 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273924 NRP1 protein O14786 UNIPROT PHACTR1 protein Q9C0D0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21939755 f miannu "Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect." SIGNOR-260061 AGTR1 protein P30556 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000007 20181817 f "Stimulation of AT1 R Induces Membrane Blebbing." SIGNOR-278126 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR "form complex" binding 9606 23397623 t miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270880 ADSL protein P30566 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" 9606 31729379 f miannu "An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels" SIGNOR-266614 SOX6 protein P35712 UNIPROT COL2A1 protein P02458 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10980415 f miannu "Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1" SIGNOR-251760 PRKG1 protein Q13976 UNIPROT PLCB3 protein Q01970 UNIPROT "down-regulates activity" phosphorylation Ser1105 LDRKRHNsISEAKMR 10116 BTO:0004576 11278298 t lperfetto "PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG." SIGNOR-249077 PIM1 protein P11309 UNIPROT HIF1A protein Q16665 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr455 LAMSPLPtAETPKPL 9606 BTO:0002181 34211090 t miannu "PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes." SIGNOR-277311 hsa-miR-103a-3p mirna URS0000476BE1_9606 RNAcentral GPRC5A protein Q8NFJ5 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002137 24984703 t Parnian "MiR-103a-3p down-regulates GPRC5A protein by binding to the 5′ UTR of GPRC5A’s mRNA" SIGNOR-278004 ITGB1 protein P05556 UNIPROT "a7/b1 integrin" complex SIGNOR-C126 SIGNOR "form complex" binding 9606 BTO:0000222;BTO:0002319 10199978 t lperfetto "The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle." SIGNOR-241512 UPP1 protein Q16831 UNIPROT 2'-deoxyuridine smallmolecule CHEBI:16450 ChEBI "up-regulates quantity" "chemical modification" 9606 21855639 t miannu "Uridine phosphorylase (UPP) catalyzes the reversible conversion of uridine to uracil and ribose-1-phosphate and plays an important pharmacological role in activating fluoropyrimidine nucleoside chemotherapeutic agents such as 5-fluorouracil and capecitabine. Most vertebrate animals, including humans, possess two homologs of this enzyme (UPP1 & UPP2), of which UPP1 has been more thoroughly studied and is better characterized" SIGNOR-280535 COX5B protein P10606 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 BTO:0000165 18701479 f lperfetto "Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS." SIGNOR-253104 CDK2 protein P24941 UNIPROT COIL protein P38432 UNIPROT up-regulates phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 SIGNOR-C16 11102515 t lperfetto "In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1_248) was observed" SIGNOR-84949 hsa-mir-146a-5p mirna URS000050B527_9606 RNAcentral SLAMF6 protein Q96DU3 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002417 25743066 t Tiberia "Luciferase assays, along with published reports, have shown that ectopic expression of miR-146a can lead to the repression of multiple mRNAs expressed by Tfh cells, including Slamf6." SIGNOR-279910 ELK1 protein P19419 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16297876 f irozzo "We demonstrated that both Elk-1 and MZF-1 were highly expressed in human poor differentiated HCC cells and involved in the up-regulation of PKCa, which was essential for cell migration and invasion. Over-expression assay confirmed that the PKCa expression may be modulated by these two factors at the transcriptional level." SIGNOR-256282 gemcitabine chemical CHEBI:175901 ChEBI RRM1 protein P23921 UNIPROT "down-regulates activity" "chemical inhibition" -1 2233693 t miannu "Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase." SIGNOR-258386 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "GABA-A (a4-b2-d) receptor" complex SIGNOR-C326 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000938 26136660 t miannu "The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current." SIGNOR-264924 CHUK protein O15111 UNIPROT COPS5 protein Q92905 UNIPROT "down-regulates activity" phosphorylation Ser201 KPPDEGPsEYQTIPL -1 31950832 t lperfetto "Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro." SIGNOR-275507 TGFA protein P01135 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252281 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT3 protein Q9Y243 UNIPROT "down-regulates activity" "chemical inhibition" 25309440 t lperfetto "Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway." SIGNOR-262012 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr839 DTQGRNStPLHLAAG 9606 BTO:0000567 21818122 t miannu "Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. " SIGNOR-276245 CASP3 protein P42574 UNIPROT GSN protein P06396 UNIPROT "down-regulates activity" cleavage Asp403 WRDPDQTdGLGLSYL 9606 9671712 t miannu "We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death." SIGNOR-256357 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1D protein P25100 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258460 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 9606 BTO:0000801 10973958 f lperfetto "NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters." SIGNOR-249554 FBXO3 protein Q9UK99 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272442 BAG6 protein P46379 UNIPROT PCK1 protein P35558 UNIPROT "down-regulates quantity by destabilization" acetylation 9606 BTO:0000007 21726808 t lperfetto "These results indicate that BAT3 and P300 can both exist in the PEPCK1 protein complex, suggesting the possibility that BAT3 could be an enhancer of PEPCK1 acetylation. | indicating a synergistic effect of BAT3 and P300 to promote PEPCK1 acetylation." SIGNOR-267598 "bisphenol A" chemical CHEBI:33216 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -1 31995776 t miannu "This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. ." SIGNOR-268732 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Ser313 TALHRSKsHEFQLGH 10090 19560418 t "These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3" SIGNOR-248527 TP53 protein P04637 UNIPROT AIFM2 protein Q9BRQ8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12135761 t miannu "The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identified PRG3 (p53-responsive gene 3), which is induced specifically under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. these results support the hypothesis that the expression of the PRG3 gene in cells undergoing p53‐dependent apoptosis involves direct activation of its promoter by p53." SIGNOR-261808 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr305 IDYGKVAtQCTCRKD 9606 BTO:0001109 28945223 t miannu "In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation. " SIGNOR-276741 hsa-miR-29c-5p mirna URS0000497496_9606 RNAcentral PTP4A1 protein Q93096 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000675 25193986 t Parnian "These data provide evidence that PTP4A1 and GNA13 are direct targets of miR-29c, and that their expression is negatively regulated by miR-29c in CRC cells. | miR-29c directly targets PTP4A1 and GNA13 3'-UTR." SIGNOR-278025 Riluzole chemical CHEBI:8863 ChEBI KCNN2 protein Q9H2S1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258020 IGF1R protein P08069 UNIPROT PIK3C2A protein O00443 UNIPROT up-regulates phosphorylation 9606 7692086 t gcesareni "Analysis of the ability of the full-length igfr and its mutant receptors described above to associate with phosphatidylinositol 3 kinase indicated that the association required ptk activity and tyrosine [?] Phosphorylation of the receptors and correlated well with their transforming activities" SIGNOR-32076 ETV3 protein P41162 UNIPROT DDX20 protein Q9UHI6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 22028472 t miannu "ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation." SIGNOR-262779 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159466 JAK2 protein O60674 UNIPROT IFNGR1 protein P15260 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 23898330 t lperfetto "In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation" SIGNOR-249490 IFNG protein P01579 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18647246 f miannu "NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B." SIGNOR-252410 CTNNA1 protein P35221 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23431053 t milica "The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation." SIGNOR-201173 SMURF1 protein Q9HCE7 UNIPROT RAD23A protein P54725 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272691 EFNA1 protein P20827 UNIPROT EPHA6 protein Q9UF33 UNIPROT up-regulates binding 9606 9576626 t tpavlidou "Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity" SIGNOR-56962 CDR2 protein Q01850 UNIPROT AURKA protein O14965 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 20383333 f lperfetto "Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology" SIGNOR-252023 CDK1 protein P06493 UNIPROT MORC2 protein Q9Y6X9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr717 PSPKVIKtPVVKKTE 9606 BTO:0000567 36967563 t miannu "Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation." SIGNOR-277837 PCGF2 protein P35227 UNIPROT "Polycomb repressive complex 1" complex SIGNOR-C408 SIGNOR "form complex" binding 9606 31608994 t miannu "PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b" SIGNOR-266813 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t gcesareni "Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion." SIGNOR-181327 HACD proteinfamily SIGNOR-PF86 SIGNOR ELOVL proteinfamily SIGNOR-PF93 SIGNOR "up-regulates activity" binding 18554506 t miannu "Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle." SIGNOR-267915 MSX2 protein P35548 UNIPROT SPEN protein Q96T58 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000661 19835636 t gcesareni "Furthermore, in addition to msx2, both tlx1 and nkx2-5 proteins interacted with notch-pathway repressors, spen/mint/sharp and tle1/grg1, representing a potential mechanism for (de)regulation." SIGNOR-188572 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 10116 7535768 t "We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively" SIGNOR-248465 asparagine smallmolecule CHEBI:22653 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI "up-regulates quantity" "precursor of" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270468 CSNK2A1 protein P68400 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates phosphorylation Ser1364 DDLNNYDsDDQEKQS 9606 20664522 t lperfetto "Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis" SIGNOR-167168 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2G2 protein P60604 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271310 diazepam chemical CHEBI:49575 ChEBI "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t brain lperfetto "The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5." SIGNOR-263797 Diprenorphine chemical CHEBI:4650 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9262330 t miannu "We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine." SIGNOR-258662 POMC protein P01189 UNIPROT MC3R protein P41968 UNIPROT "up-regulates activity" binding BTO:0000614 17702843 t lperfetto "Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases." SIGNOR-253073 SLRP proteinfamily SIGNOR-PF31 SIGNOR ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t "Proteoglycans are ubiquitous in connective tissue, and muscle ECM is no exception. A number of PGsare present in muscle ECM, and many belong to the family of small leucine-rich proteoglycans (SLRPs)." SIGNOR-255345 "JNJ-28312141 free base" chemical CID:11676971 PUBCHEM FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259749 NFATC3 protein Q12968 UNIPROT PTGS2 protein P35354 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21871017 t miannu "NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration" SIGNOR-264028 NR3C1 protein P04150 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8639160 t gcesareni "We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins" SIGNOR-251680 UBE2D2 protein P62837 UNIPROT UBR5 protein O95071 UNIPROT "up-regulates activity" ubiquitination -1 11714696 t miannu "Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks." SIGNOR-272668 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Ser239 LIRGVKSsGKVVYFT 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262918 TRIM32 protein Q13049 UNIPROT POU5F1 protein Q01860 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 26307407 t miannu "This further supports that TRIM32 and Oct4 do physically interact, so that TRIM32 can specifically ubiquitinate Oct4 and thereby target it for degradation." SIGNOR-278620 BRCA1 protein P38398 UNIPROT SAFB protein Q15424 UNIPROT "up-regulates quantity by stabilization" ubiquitination 9606 21950761 t miannu "These results suggest that the BRCA1 and BARD1 heterodimer ubiquitinates SAFB and increases SAFB protein levels." SIGNOR-278624 PRKCH protein P24723 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t gcesareni "Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9" SIGNOR-115730 UCHL5 protein Q9Y5K5 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" deubiquitination 9606 16027725 t lperfetto "Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases" SIGNOR-232101 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Thr345 GADSDVEtPSNFGKY 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262986 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 7961936 t "We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck." SIGNOR-251395 AZD-8055 chemical CHEBI:91329 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor mTOR" gcesareni SIGNOR-190215 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263432 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation Ser46 PASYSFCsGKGVGIK 9606 SIGNOR-C110 12000790 t gcesareni "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45)" SIGNOR-87437 INS protein P01308 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates 9606 22521266 f gcesareni "In conclusion,insulinlikely promotes mkp-3 protein degradation" SIGNOR-197203 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr443 REHPYGRy 9606 BTO:0000567 16179349 t lperfetto "We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal." SIGNOR-249292 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "down-regulates activity" phosphorylation Ser146 MEPERRDsQDGSSYR -1 12432067 t miannu "Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146" SIGNOR-250074 PTPRO protein Q16827 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Ser727 NTIDLPMsPRTLDSL 9606 24708807 t miannu "In addition, this group found that PTPRO dephosphorylated STAT3 at Y705 and S727 then attenuated STAT3 signalling." SIGNOR-277061 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 t lperfetto "Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation" SIGNOR-216546 FZD3 protein Q9NPG1 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 22944199 t amattioni "When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp." SIGNOR-134288 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT "up-regulates activity" phosphorylation Tyr199 RKGQRDLySGLNQRR 9534 11855827 t "Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways." SIGNOR-251369 lenalidomide chemical CHEBI:63791 ChEBI IKZF3 protein Q9UKT9 UNIPROT "down-regulates quantity by destabilization" "chemical inhibition" 9606 24328678 t gcesareni "Members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3 respectively), are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment." SIGNOR-236925 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 10581258 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-72703 SP3 protein Q02447 UNIPROT IFITM5 protein A6NNB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23530031 f miannu "Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation." SIGNOR-254220 ABL1 protein P00519 UNIPROT GMNN protein O75496 UNIPROT "up-regulates activity" phosphorylation Tyr150 EVAEHVQyMAELIER 9606 24789045 t miannu "Taken together, suggests that c-Abl binds and phosphorylates geminin on Y150 in G2/M/early G1 phases." SIGNOR-278505 GATA1 protein P15976 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004475 19825991 f miannu "Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors." SIGNOR-254189 TG101209 chemical CHEBI:90304 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207260 TACR1 protein P25103 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257316 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates "transcriptional regulation" 10090 BTO:0000165 11073979 f ggiuliani "As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B)" SIGNOR-255835 PGD protein P52209 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI "up-regulates quantity" "chemical modification" 9606 24769394 t miannu "The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle" SIGNOR-267053 SMURF1 protein Q9HCE7 UNIPROT CCDC69 protein A6NI79 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272704 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr502 TPGTGLGtSPALAGD -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-251077 SNTB1 protein Q13884 UNIPROT DGC complex SIGNOR-C217 SIGNOR "form complex" binding BTO:0001103 29681515 t apalma "Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated" SIGNOR-255979 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT "up-regulates activity" phosphorylation Ser181 RAKGPSEsSKERNTP -1 25258324 t done miannu " Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D)." SIGNOR-273966 VAV2 protein P52735 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10618391 t tpavlidou "Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo." SIGNOR-73874 (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI "up-regulates quantity" "precursor of" 9606 32439610 t lperfetto "Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions." SIGNOR-268225 USP5 protein P45974 UNIPROT UBC protein P0CG48 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000567 26235645 t miannu "Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors." SIGNOR-270822 HAUS3 protein Q68CZ6 UNIPROT "HAUS complex" complex SIGNOR-C281 SIGNOR "form complex" binding 9606 BTO:0000567 19369198 t lperfetto "Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)" SIGNOR-262322 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." SIGNOR-251146 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" phosphorylation Thr309 SDGATMKtFCGTPEY 9606 15743829 t lperfetto "Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation." SIGNOR-134485 MAPK14 protein Q16539 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser347 FTGLKCPsLAGKPKV 9606 BTO:0000130 14970175 t amattioni "P38-mapk can directly phosphorylate and inhibit the activities of caspase-8" SIGNOR-122103 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser12 TKRTADSsSSEDEEE 9606 21245376 t gcesareni "Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability." SIGNOR-171699 MYOG protein P15173 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001103 7739551 t "Simone Vumbaca" "[...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site." SIGNOR-255642 MYO9B protein Q13459 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260510 CTNNB1 protein P35222 UNIPROT KLF4 protein O43474 UNIPROT "up-regulates activity" binding 10090 24482235 t flangone "The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes." SIGNOR-242100 SCNN1G protein P51170 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 26772908 t miannu "The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity." SIGNOR-269277 COL18A1 protein P39060 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto "There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3" SIGNOR-252269 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni "Rsk1/2 phosphorylates the transcription factor c-fos on s362 and increases its activity." SIGNOR-37216 MARCHF5 protein Q9NX47 UNIPROT FIS1 protein Q9Y3D6 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 16874301 t Barakat "MITOL associates with and ubiquitinates mitochondrial fission protein hFis1. (A) Ubiquitination of hFis1 by MITOL. Thus, MITOL may control the protein expression level of hFis1 through the ubiquitin‚Äìproteasome pathway." SIGNOR-274141 PRKCD protein Q05655 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 1677563 t lperfetto "Of four other protein kinases tested only protein kinase C (PKC) phosphorylated P(45-56), with complete dependence on phosphatidylserine. Only the residue corresponding to serine-51 in eIF-2 alpha was phosphorylated by HCR, dsI or PKC." SIGNOR-248853 OXTR protein P30559 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256936 cytidine smallmolecule CHEBI:17562 ChEBI "cytidine 5'-monophosphate(2-)" smallmolecule CHEBI:60377 ChEBI "up-regulates quantity" "precursor of" 11306702 t lperfetto "Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides." SIGNOR-275857 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu61 EFVQGNLeRECMEEK 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263688 ABT-737 chemical CID:11228183 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates "chemical inhibition" 9606 Other t "The effect has been demonstrated using Q07817-1" gcesareni SIGNOR-189171 DYRK1A protein Q13627 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates quantity" phosphorylation Ser312 TESITATsPASMVGG 9606 31723029 t miannu "DYRK1A interacts with IRS-1 and phosphorylates IRS-1 at Ser-312 and Ser-616.|We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing the turnover of IRS-1 protein." SIGNOR-279520 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser369 AKKAKADsPVNGLPK 9534 BTO:0000298 14623875 t llicata "DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase." SIGNOR-251089 MAPK1 protein P28482 UNIPROT PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation Ser21 LEAGDLEsPLSEEFL 9606 BTO:0000599 10187842 t lperfetto "We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution." SIGNOR-249434 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249678 SPRY2 protein O43597 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates 9606 12414790 f gcesareni "Therefore, we conclude that an increase in soluble ptp1b activity contributes to the anti-migratory, but not anti-mitogenic, actions of hspry2." SIGNOR-95313 CRH protein P06850 UNIPROT KRT14 protein P02533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15468147 t Regulation miannu "CRH stimulated the expression of cytokeratin 1 and involucrin, and inhibited cytokeratin 14 on both mRNA and protein levels." SIGNOR-251899 CAPN1 protein P07384 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Phe59 GVTVETVfSVDEFSA -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263580 ABL2 protein P42684 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Tyr79 GAPAPGVyPGPPSGP 9606 20150913 t llicata "The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3." SIGNOR-163747 BBS5 protein Q8N3I7 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262559 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser487 AQLAGSDsDLDSDDE 9606 23263282 t lperfetto "Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)" SIGNOR-200202 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser196 EKSPSVCsPLNMTSS 9606 BTO:0005043 22798426 t miannu " Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation." SIGNOR-276102 PPP1CB protein P62140 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t "Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway." SIGNOR-248572 regorafenib chemical CHEBI:68647 ChEBI ABL1 protein P00519 UNIPROT "down-regulates activity" "chemical inhibition" 9606 24756792 t miannu "In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically." SIGNOR-259209 STUB1 protein Q9UNE7 UNIPROT CBX4 protein O00257 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys178 LQYQGGHkEAPSPTC 9606 BTO:0002181 32111827 t miannu "The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. " SIGNOR-277513 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176833 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252742 GAD2 protein Q05329 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "down-regulates quantity" "chemical modification" 9606 32041144 t miannu "Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions." SIGNOR-267554 BECN1 protein Q14457 UNIPROT USP10 protein Q14694 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0003704 21962518 t lperfetto "Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities." SIGNOR-260298 POU5F1 protein Q01860 UNIPROT SOX2/POU5F1 complex SIGNOR-C73 SIGNOR "form complex" binding 9606 7590241 t miannu "Sox2 can form a ternary complex with either the ubiquitous oct-1 or the embryonic-specific oct-3 protein on fgf-4 enhancer dna sequences. However, only the sox2/oct-3 complex is able to promote transcriptional activation." SIGNOR-29509 TRAF6 protein Q9Y4K3 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates polyubiquitination 9606 20047764 t miannu "Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1" SIGNOR-271428 FOXO3 protein O43524 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "down-regulates quantity" "transcriptional regulation" 10090 BTO:0002314 24749067 f gcesareni "We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration." SIGNOR-254320 SCN5A protein Q14524 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu "The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons." SIGNOR-253447 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT "up-regulates activity" cleavage Arg494 CAKTKQLrVVNGIPT -1 12372819 t miannu "the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain." SIGNOR-256514 Galanin smallmolecule CHEBI:80161 ChEBI GALR1 protein P47211 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257494 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr647 RDVHNLDyYKKTTNG 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3 the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3." SIGNOR-106730 Ub:E2 complex SIGNOR-C497 SIGNOR PDZRN3 protein Q9UPQ7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271069 USF1 protein P22415 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 28624438 t miannu "The promoter region of ADAM10 contains several transcription factor binding sites that can stimulate its transcription. These include binding sites for transcription factors SP1 and USF, and the spliced form of the X-box binding protein (XBP)-1 as well as a retinoic acid-responsive element" SIGNOR-259837 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT "down-regulates activity" dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 11323411 t "These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro." SIGNOR-248675 PDGFRB protein P09619 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 7535778 t miannu "Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production." SIGNOR-28179 "Neurofibrillary tangle formation" phenotype SIGNOR-PH58 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11578751 f lperfetto "Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death" SIGNOR-251641 ZMIZ1 protein Q9ULJ6 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 BTO:0001321 14609956 t miannu "Our results demonstrate that hZimp10 is a novel AR interacting protein that augments AR-mediated transcription. Moreover, hZimp10 co-localized with AR and SUMO-1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo." SIGNOR-263935 H4C1 protein P62805 UNIPROT "Nucleosome_H2A.Z.2 variant" complex SIGNOR-C323 SIGNOR "form complex" binding -1 24311584 t miannu "In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined." SIGNOR-263712 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT "up-regulates activity" phosphorylation Ser394 EDAVHEDsGDEDGED 9606 BTO:0000567 12082111 t llicata "HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2." SIGNOR-251001 E2F1 protein Q01094 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253855 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr242 FFQQQMIyDSPPSRA 10090 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251310 PRKCA protein P17252 UNIPROT GJB1 protein P08034 UNIPROT "up-regulates activity" phosphorylation Ser229 QRRSNPPsRKGSGFG -1 8390988 t lperfetto "Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b)." SIGNOR-248919 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni "Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability." SIGNOR-157093 ADAM10 protein O14672 UNIPROT EGF protein P01133 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin" SIGNOR-259840 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 12110590 t "inferred from 70% family members" gcesareni "Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway." SIGNOR-270073 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Thr269 GGKRSRLtPVSPESS 9606 BTO:0000551 20974803 t lperfetto "Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis." SIGNOR-216936 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2516 FLTPSPEsPDQWSSS -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273177 NFKB2 protein Q00653 UNIPROT RELB protein Q01201 UNIPROT "up-regulates activity" binding 9606 19098713 t lperfetto "The map3k14-activated chuk/ikka homodimer phosphorylates nfkb2/p100 associated with relb, inducing its proteolytic processing to nfkb2/p52 and the formation of nf-kappa-b relb-p52 complexes. The nf-kappa-b heterodimeric relb-p52 complex is a transcriptional activator." SIGNOR-182835 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Ala86 PLQKQLPaFISEDAS -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263566 pipamperone chemical CHEBI:78549 ChEBI HTR1B protein P28222 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0001311 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258573 TGFB1 protein P01137 UNIPROT SLC20A1 protein Q8WUM9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000249 20930330 f miannu "TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line." SIGNOR-252202 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto "Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export." SIGNOR-252831 SMOC1 protein Q9H4F8 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20359165 f Giorgia "The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells" SIGNOR-260385 CKMT2 protein P17540 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI "up-regulates quantity" "chemical modification" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265789 FGFR1 protein P11362 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT "up-regulates activity" phosphorylation Tyr107 KGEELPTyEEAKAHS 9606 BTO:0000007 21937427 t lperfetto "These data support an idea that Amotl2 Tyr-103 can be phosphorylated by FGF receptor tyrosine kinase activity. We then determined whether Amotl2 Tyr-103 is required for its interaction with c-Src. |Amotl2 promotes MAPK/ERK activation via c-Src, which is dependent on phosphorylation of tyrosine residue at position 103 but independent of the C-terminal PDZ-binding domain." SIGNOR-271869 PIM1 protein P11309 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT "up-regulates activity" phosphorylation Thr362 GEKKKKItVFKEISY 9606 BTO:0001130 18056989 t lperfetto "Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells|This is further corroborated by our finding that the plasma membrane localization and drug-resistant activity of BCRP were compromised by T362A mutation." SIGNOR-264420 CUDC-101 chemical CID:24756910 PUBCHEM HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20143778 t miannu "By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively." SIGNOR-262256 CNOT8 protein Q9UFF9 UNIPROT "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR "form complex" binding 9606 19558367 t lperfetto "In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules." SIGNOR-268310 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT "down-regulates activity" phosphorylation Ser126 RKETSARsLGSPLLH 9534 BTO:0000298 10759890 t miannu "IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex" SIGNOR-262715 TFE3 protein P19532 UNIPROT PIP4P1 protein Q86T03 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 29146937 f lperfetto "TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes" SIGNOR-276806 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH3 protein P22223 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265843 EGF protein P01133 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 9168989 f Regulation miannu "We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin." SIGNOR-251782 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273075 OPALIN protein Q96PE5 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 18490449 f SimoneGraziosi "Opalin protein is a type 1 transmembrane sialylglycoprotein and an oligodendrocyte-specific component of myelin membranes." SIGNOR-269229 KDM5B protein Q9UGL1 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264302 FFAR1 protein O14842 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257338 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NOS2 protein P35228 UNIPROT up-regulates "transcriptional regulation" BTO:0001103 20219869 f "Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6." SIGNOR-256250 KLF3 protein P57682 UNIPROT KLF8 protein O95600 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000759 18687676 t Luana "Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly. " SIGNOR-266049 "Immune complexes" stimulus SIGNOR-ST15 SIGNOR FCGR1A protein P12314 UNIPROT "up-regulates activity" 9606 BTO:0000801 18064051 f lperfetto "Immune complexes bind to activating Fc receptors (FcR) and inhibitory FcRs that are expressed by innate immune effector cells such as basophils, mast cells, neutrophils, monocytes and macrophages, in which they trigger the indicated effector responses." SIGNOR-249521 TRIM27 protein P14373 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 BTO:0000671 12807881 f "inferred from 70% of family members" miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-269915 ANXA1 protein P04083 UNIPROT IL1B protein P01584 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 27426034 f miannu "Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups" SIGNOR-261940 IGF1 protein P05019 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9606 BTO:0000150;BTO:0000680 16039586 t lperfetto "Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. This pathway is a general signal, as it was also observed in cell lines in which erk-primed inactivation of gsk-3beta was regulated by igf-1, tgf-beta, and receptor tyrosine kinase her2" SIGNOR-227948 SP3 protein Q02447 UNIPROT SLC9A3 protein P48764 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 16464174 f "Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity" SIGNOR-254271 FYN protein P06241 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 16938345 t gcesareni "Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk." SIGNOR-148931 MAL protein P21145 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 15337780 f SimoneGraziosi "Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes" SIGNOR-269228 NR4A3 protein Q92570 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30455429 t miannu "Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax." SIGNOR-259397 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr751 SKDESVDyVPMLDMK -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248668 PPARGC1A protein Q9UBK2 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f lperfetto "Furthermore, ampk directly phosphorylates pgc-1?, And this phosphorylation mediates an increase in pgc-1? Protein action on the pgc-1? Promoter." SIGNOR-156783 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15109499 t "The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression." SIGNOR-252926 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr511 SKLQNLSyTEILKIR 9606 15952790 t llicata "We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts." SIGNOR-138154 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2S protein Q16763 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271343 FANCL protein Q9NW38 UNIPROT "Fanconi anemia core complex" complex SIGNOR-C300 SIGNOR "form complex" binding 9606 BTO:0000567 17396147 t lperfetto "This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo " SIGNOR-263245 AKT proteinfamily SIGNOR-PF24 SIGNOR BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser694 QTSKRHDsDTFPELK 9606 BTO:0000150 20085797 t lperfetto "We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation" SIGNOR-244164 HOXA7 protein P31268 UNIPROT IVL protein P07476 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 11435435 f miannu "Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes." SIGNOR-254473 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000298 8974401 t lperfetto "A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively." SIGNOR-236116 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation 9606 17396146 t gcesareni "The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells." SIGNOR-154178 AKT proteinfamily SIGNOR-PF24 SIGNOR CDCA7 protein Q9BWT1 UNIPROT down-regulates phosphorylation Thr163 SRRPRRRtFPGVASR 9606 23166294 t llicata "The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus." SIGNOR-199776 PRKD1 protein Q15139 UNIPROT DLC1 protein Q96QB1 UNIPROT down-regulates phosphorylation Ser1244 NTLKRENsSPRVMQR 9606 21087603 t gcesareni "The tumor suppressor protein dlc1 is regulated by pkd-mediated gap domain phosphorylation.Our results thus show that pkd-mediated phosphorylation of dlc1 on serine 807 negatively regulates dlc1 cellular function." SIGNOR-169994 KU-55933 chemical CID:5278396 PUBCHEM ATM protein Q13315 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000793 28341201 t miannu "KU-55933 blocked phosphorylation of ATM in H2O2 and Dox models of cell damage. the neuroprotective efficacy of KU-55933, a potent inhibitor of ATM, against cell damage evoked by oxidative stress (hydrogen peroxide, H2O2) has been studied in human neuroblastoma SH-SY5Y cells and compared with the efficacy of this agent in models of doxorubicin (Dox)- and staurosporine (St)-evoked cell death." SIGNOR-262536 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser110 SFSEQTRsLDGRLQV 9606 SIGNOR-C8 11027280 t gcesareni "Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgf-beta-dependent smad2-smad3 interactions." SIGNOR-82966 PI3K complex SIGNOR-C156 SIGNOR Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 23994464 f apalma "The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release" SIGNOR-255012 CLU protein P10909 UNIPROT LRP2 protein P98164 UNIPROT "up-regulates quantity" binding 10090 32332780 t miannu "Our results demonstrate that circulating ApoJ is retained in muscle via LRP2 and that LRP2 signaling could play a role in the maintenance of ApoJ homeostasis in circulation, at least in part." SIGNOR-265256 ARHGAP12 protein Q8IWW6 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260469 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Thr507 FGESRAStFCGTPDY 10090 BTO:0000944 11959144 t "PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex" SIGNOR-248594 PRKCD protein Q05655 UNIPROT PPP1R14B protein Q96C90 UNIPROT "up-regulates activity" phosphorylation Thr57 VRRQGKVtVKYDRKE 10606530 t lperfetto "Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold." SIGNOR-265739 BLOC1S6 protein Q9UL45 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265931 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR SMURF1 protein Q9HCE7-2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination LYS355 YERDLVQkLKVLRHE 9606 BTO:0000007 21572392 t miannu "Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation.  FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells." SIGNOR-271911 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20712774 f Regulation miannu "BCL11A maintains silencing of gamma-globin expression in adult erythroid cells and functions as a direct transcriptional regulator of the fetal to adult hemoglobin switch in humans. we found that BCL11A plays a central role in the evolutionarily divergent globin gene switches of mammals. As a factor critical for gamma-globin gene silencing, BCL11A should be considered as a therapeutic target to increase HbF in a directed manner in beta-thalassemia patients." SIGNOR-251775 KIRREL3 protein Q8IZU9 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" binding 10090 BTO:0004032 28381988 t miannu "We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons." SIGNOR-269079 USP13 protein Q92995 UNIPROT UBL4A protein P11441 UNIPROT "up-regulates activity" deubiquitination Lys48 QRLLFKGkALADGKR 9606 BTO:0000007 24424410 t miannu "USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding." SIGNOR-272857 MECP2 protein P51608 UNIPROT DLL1 protein O00548 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 25420914 t Luana "As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1 " SIGNOR-264674 AMPK complex SIGNOR-C15 SIGNOR MFF protein Q9GZY8 UNIPROT "up-regulates activity" phosphorylation Ser172 GQLVRNDsLWHRSDS 9606 BTO:0001938 26816379 t gcesareni "A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission." SIGNOR-249655 CDK11A protein Q9UQ88 UNIPROT SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser238 SEESWTDsEVDSSCS 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273020 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176809 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity." SIGNOR-129288 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 10090 BTO:0000944 12169099 t lperfetto "c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells" SIGNOR-235526 PTK2B protein Q14289 UNIPROT STAP1 protein Q9ULZ2 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10518561 t miannu "In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling." SIGNOR-261818 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273045 OXGR1 protein Q96P68 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256770 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT "up-regulates activity" phosphorylation Tyr426 LLRASGIyYVPKGKA -1 20417104 t miannu "Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C)." SIGNOR-262606 ADAM17 protein P78536 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000782 9034190 t lperfetto "We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified." SIGNOR-46754 TLE2 protein Q04725 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates binding 9606 19460168 t gcesareni "Mapping studies reveal that groucho/tle binds two regions in lef-1." SIGNOR-185736 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM75 protein A6NK02 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271139 EPHB2 protein P29323 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates quantity" phosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 33661095 t miannu "In addition, EPHB2 signaling leads to phosphorylation of GluN2B at tyrosine residue 1472 preventing clathrin dependent endocytosis, and increasing the surface retention of GluN2B containing NMDARs." SIGNOR-279710 MYC protein P01106 UNIPROT CCNE1 protein P24864 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9188852 f gcesareni "Our results suggest that this activation may involve at least two myc-dependent steps: the induction of cyclin e gene transcription followed by accumulation of cyclin e mrna in a protein synthesis-independent manner and the p27(kip1) association with cyce/cdk2 complexes containing newly synthesised cyce." SIGNOR-49130 LPAR4 protein Q99677 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257258 APC-c complex SIGNOR-C150 SIGNOR REV1 protein Q9UBZ9 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23287467 t miannu " Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1." SIGNOR-272895 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 9606 17360704 t gcesareni "We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism." SIGNOR-153618 IRF2 protein P14316 UNIPROT CIITA protein P33076 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 11464288 t lperfetto "In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays." SIGNOR-271681 HSD17B2 protein P37059 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI "up-regulates quantity" "chemical modification" -1 8099587 t Luana "17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone. " SIGNOR-269762 MAPK14 protein Q16539 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15824134 f Andrea "Inhibition of p38 / MAPKs (a) promotes exit from the cell cycle, (b) prevents differentiation, and (c) insulates the cell from most external stimuli allowing the satellite cell to maintain a quiescent state. Activation of satellite cells and p38 / MAPKs occurs concomitantly, providing further support that these MAPKs function as a molecular switch for satellite cell activation" SIGNOR-255745 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr52 DSSKPAVyNYPEGAA 9606 BTO:0000150 20101225 t gcesareni "Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes." SIGNOR-163566 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI HTR1A protein P08908 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190687 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-A (a3-b1-g2) receptor" complex SIGNOR-C332 SIGNOR "up-regulates activity" "chemical activation" 9606 18790874 t brain lperfetto "Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS)." SIGNOR-263788 KDM4B protein O94953 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001109 28073943 f miannu "JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B." SIGNOR-263730 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 t lperfetto "Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor." SIGNOR-26590 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR INCA1 protein Q0VD86 UNIPROT unknown phosphorylation Ser191 GRAQLLWsPWSPLDQ -1 15159402 t miannu " GST-INCA1 was phosphorylated in vitro by cyclin A2-CDK2 but not by CDK2 or either cyclin alone.  Mutation of Ser23, Thr167, and Ser176 strongly reduced in vitro phosphorylation of INCA1.Cyclin A1 and Cyclin A2 in Complex with CDK2 Phosphorylated INCA1 in Vitro Predominantly at Ser176" SIGNOR-273592 clofarabine chemical CHEBI:681569 ChEBI POLG protein P54098 UNIPROT "down-regulates activity" "chemical inhibition" 9606 1707752 t miannu "Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase." SIGNOR-258361 TUBA3C protein P0DPH7 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu "We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching." SIGNOR-269724 3-(9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione chemical CID:10029385 PUBCHEM GSK3B protein P49841 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000183 31562256 t miannu "Indeed, we demonstrated that the selective GSK3 inhibitor LY2090314 significantly reduced cell proliferation in control pancreatic cancer cell lines" SIGNOR-262539 PRKAA1 protein Q13131 UNIPROT GFPT1 protein Q06210 UNIPROT down-regulates phosphorylation Ser242 SKFTRWGsQGERGKD 9606 19170765 t lperfetto "Amp-activated protein kinase phosphorylates glutamine : fructose-6-phosphate amidotransferase 1 at ser243 to modulate its enzymatic activityhe 2-dg induced phosphorylation of gfat1 . The assay of the gfat enzymatic activity in the cell lysates indicated that the 2-dg-treatment inhibited the enzymatic activity" SIGNOR-183528 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275787 GATAD2A protein Q86YP4 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes." SIGNOR-263858 PPP2CA protein P67775 UNIPROT FCAR protein P24071 UNIPROT "up-regulates activity" dephosphorylation Ser284 LTFARTPsVCK -1 30766540 t lperfetto "Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail" SIGNOR-264858 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000007;BTO:0000567 SIGNOR-C14 SIGNOR-C13 15489227 t lperfetto "Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter." SIGNOR-129931 PYGB protein P11216 UNIPROT "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI "up-regulates quantity" "chemical modification" 9606 3346228 t miannu "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267396 BBOX1 protein O75936 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI "up-regulates quantity" "chemical modification" 9606 11802770 t miannu "In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine." SIGNOR-269700 EPHB1 protein P54762 UNIPROT EPHB1 protein P54762 UNIPROT "up-regulates activity" phosphorylation Tyr928 SAIKMVQyRDSFLTA 10029 BTO:0000246 12223469 t " Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity." SIGNOR-251123 MAML3 protein Q96JK9 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 12370315 t gcesareni "We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors." SIGNOR-94100 Ub:E2 complex SIGNOR-C497 SIGNOR PCGF5 protein Q86SE9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271184 SPATA13 protein Q96N96 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260576 STAT1 protein P42224 UNIPROT SOCS1 protein O15524 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19482358 f miannu "Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1" SIGNOR-226484 PRKCA protein P17252 UNIPROT FMNL2 protein Q96PY5 UNIPROT "up-regulates activity" phosphorylation 9606 26256210 t miannu "In contrast, endogenous FMNL2 or FMNL2-GFP remained membrane associated, arguing that PKCalpha activation triggers FMNL2 relocation into intracellular membranes.|We demonstrate that PKCalpha phosphorylates the FMNL2 C terminus to control its localization and autoinhibition, thus uncovering a mode of formin activation by PKCs." SIGNOR-279098 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 t gcesareni "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-55310 Ub:E2 complex SIGNOR-C497 SIGNOR HECW2 protein Q9P2P5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271289 NCBP2 protein P52298 UNIPROT "Cap-binding complex" complex SIGNOR-C440 SIGNOR "form complex" binding 9606 26382858 t lperfetto "The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization." SIGNOR-268358 GPR35 protein Q9HC97 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256996 NGF protein P01138 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0001676 16190874 f miannu "We examined intracellular signals required for NGF-induced expression of the GCH gene in PC12D cells. The activity of GCH was increased up to 5-fold after the NGF treatment. The human GCH promoter activity was significantly enhanced by NGF treatment." SIGNOR-252228 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser565 VISSSEDsDAENSSS 9606 BTO:0000551 16873060 t llicata "Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517." SIGNOR-148310 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 t llicata "CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin." SIGNOR-250948 FLT3 protein P36888 UNIPROT SIRT1 protein Q96EB6 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 9606 26049753 f "SIRT1 protein but not mRNA expression is increased in CD34+ cells from FLT3-ITD positive AML patients compared to FLT3 wild-type AML patients" SIGNOR-261555 AKT1 protein P31749 UNIPROT TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 t gcesareni "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." SIGNOR-67313 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT "up-regulates activity" phosphorylation 10090 20921139 t lperfetto "When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation." SIGNOR-219388 AMPK complex SIGNOR-C15 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 20647423 t lperfetto "Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions." SIGNOR-216471 SPI1 protein P17947 UNIPROT B-Lymphocyte_diff phenotype SIGNOR-PH113 SIGNOR "up-regulates activity" 10090 10203717 f "PU.1 regulates the expression of several genes, including those encoding immunoglobulins, receptors and enzymes. The expression of these genes is crucial for macrophage and B-cell differentiation and for the functional activity of neutrophils." SIGNOR-259955 Gbeta proteinfamily SIGNOR-PF4 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18519666 t "inferred from 70% family members" lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-270095 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT "up-regulates activity" phosphorylation Thr244 AETHSSStPVQHPIK 9606 BTO:0000567 30021153 t lperfetto "Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry." SIGNOR-265032 PAPOLB protein Q9NRJ5 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 19224921 f lperfetto "Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner." SIGNOR-268326 "Survival Factors" stimulus SIGNOR-ST8 SIGNOR BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 9346240 f lperfetto "Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death MachineryAkt phosphorylates BAD in vitro and in vivo, and blocks the BAD-induced death of primary neurons in a site-specific manner." SIGNOR-209693 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 t lperfetto "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) ." SIGNOR-217367 SMO protein Q99835 UNIPROT GNB2 protein P62879 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-199177 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1035 IETDKEYyTVKDDRD 10090 11909529 t "The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP" SIGNOR-248396 "U2 snRNP complex" complex SIGNOR-C479 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 f lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270676 verteporfin chemical CHEBI:32293 ChEBI SFN protein P31947 UNIPROT "up-regulates quantity" "chemical activation" 9606 BTO:0005079 27073720 t "Verteporfin increases the level of 14-3-3σ, which promotes the translocation of YAP from nucleus to cytoplasm." SIGNOR-278129 FBXO45 protein P0C2W1 UNIPROT PAWR protein Q96IZ0 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 24992930 t miannu "Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis.Fbxo45 forms an atypical ubiquitin ligase complex that contains Skp1 and the Ring-finger protein PAM (protein-associated with myc) also known as MYCBP2 (myc-binding protein 2)." SIGNOR-272223 DLL1 protein O00548 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11006133 t gcesareni "These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors." SIGNOR-82398 HBP1 protein O60381 UNIPROT NCF1 protein P14598 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 15024088 t Luana "Together, these results indicate that HBP1 may contribute to the regulation of NADPH oxidase-dependent superoxide production through transcriptional repression of the p47phox gene. " SIGNOR-261614 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr256 SQMKSMStFIEEAYK 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265229 cyproheptadine chemical CHEBI:4046 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7925364 t miannu "The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum." SIGNOR-258869 dopamine smallmolecule CHEBI:18243 ChEBI DRD5 protein P21918 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257481 PPP2CA protein P67775 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Ser12 KSKPKDAsQRRRSLE 9606 BTO:0001938 18069897 t gcesareni "We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC" SIGNOR-247970 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro." SIGNOR-164667 CXCR4 protein P61073 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 33073183 t "Marta Tosoni" "Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner" SIGNOR-278104 CIITA protein P33076 UNIPROT HLA-DRA protein P01903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002417 10886240 f "These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma." SIGNOR-254008 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 8940173 t lperfetto "Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor" SIGNOR-45130 MIPOL1 protein Q8TD10 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 31609475 f miannu "In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9" SIGNOR-261135 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248690 MAPK8 protein P45983 UNIPROT EEF1A2 protein Q05639 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser205 GDNMLEPsPNMPWFK 9606 BTO:0002181 23608534 t miannu "Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome. " SIGNOR-276491 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates phosphorylation Tyr284 LPQNDDHyVMQEHRK 9606 14506255 t llicata "Purified ack1 undergoes autophosphorylation, and autophosphorylation enhances kinase activity. We identified tyr284 in the activation loop of ack1 as the primary autophosphorylation site using mass spectrometry." SIGNOR-118201 PTPRB protein P23467 UNIPROT CDH5 protein P33151 UNIPROT "up-regulates activity" dephosphorylation 9606 19015309 t miannu "Because we had shown previously that VE-PTP supports VE-cadherin function when exogenously expressed in transfected cells, we expected it to be expressed at endothelial cell contacts.|Indeed, tyrosine phosphorylation of VE-cadherin is reduced by VE-PTP in COS-7 and CHO cells." SIGNOR-277131 IRX1 protein P78414 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002392 20440264 f Luana "We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed." SIGNOR-261661 N protein P59595 UNIPROT EEF1A2 protein Q05639 UNIPROT "down-regulates activity" binding 9606 18448518 t lperfetto "The nucleocapsid protein of severe acute respiratory syndrome coronavirus inhibits cell cytokinesis and proliferation by interacting with translation elongation factor 1alpha" SIGNOR-260260 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 t "16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition." lperfetto "Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b." SIGNOR-235910 PCDHA10 protein Q9Y5I2 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-265664 CLTA protein P09496 UNIPROT "AP-3/clathrin vescicle" complex SIGNOR-C250 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260672 CSNK1A1 protein P48729 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates activity" phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 t lperfetto "Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846" SIGNOR-274045 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Thr590 PALLEHRtGRYAPTI 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262921 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" 9606 BTO:0001103 15829723 t apalma "GSK-3beta activity can be inhibited by Akt phosphorylation (12), which may provide a mechanism for Akt to promote muscle growth through inhibition of the negative regulator GSK-3beta." SIGNOR-255109 SMAD3 protein P84022 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" 9606 BTO:0000599 10890911 f lperfetto "Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity" SIGNOR-229308 SLC36A1 protein Q7Z2H8 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI "up-regulates quantity" relocalization 9606 12748860 t lperfetto "Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut." SIGNOR-264737 FYN protein P06241 UNIPROT PTPRJ protein Q12913 UNIPROT "up-regulates activity" phosphorylation Tyr1320 NTTAMTIyENLAPVT 9606 BTO:0000007 22898603 t miannu " We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin." SIGNOR-276374 ETFBKMT protein Q8IXQ9 UNIPROT ETFB protein P38117 UNIPROT "down-regulates activity" methylation Lys200 ATLPNIMkAKKKKIE -1 25416781 t miannu "Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases." SIGNOR-269450 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000567 15642743 t lperfetto "Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P" SIGNOR-226620 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR DYSF protein O75923 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136497 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT "up-regulates activity" phosphorylation Thr125 MIPQKNQtASGDSLD 9606 BTO:0001938 22535524 t lperfetto "We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors." SIGNOR-252049 RBP1 protein P09455 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "up-regulates quantity" relocalization 31963453 t lperfetto "Once in the cytosol, retinol molecules are sequestered by membrane systems and bind to Cellular retinol-binding protein 1 (CRBP1), which plays a role in vitamin A cytoplasmic trafficking" SIGNOR-265108 TRIM47 protein Q96LD4 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates quantity" ubiquitination 10090 BTO:0000575 29291351 t gianni "CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity" SIGNOR-266443 PALB2 protein Q86YC2 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 19369211 t lperfetto "The BRCA1-PALB2 interaction is required for homologous recombination repair.Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex." SIGNOR-244487 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 t gcesareni "The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2)." SIGNOR-59639 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" phosphorylation Ser58 ESETNQNsSSDSEAE -1 11711551 t llicata "We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4." SIGNOR-250962 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT "up-regulates activity" binding 9606 19008118 t FFerrentino "Perhaps through Wnt5a acting via FZD2, might also inhibit adipocyte differentiation." SIGNOR-253520 IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 15084260 t lperfetto "Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation." SIGNOR-216407 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT "down-regulates activity" phosphorylation Thr352 PSEPMMStPPPASEL 9606 BTO:0000567 26080397 t miannu "ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68." SIGNOR-266204 tRNA(Asn) smallmolecule CHEBI:29172 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI "up-regulates quantity" "precursor of" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270467 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1784 TPTSPNYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248826 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Ser577 RKPGLRRsPIKKVRK 9606 9840932 t lperfetto "The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5" SIGNOR-217252 H3C1 protein P68431 UNIPROT "Nucleosome_H2A.Z.1 variant" complex SIGNOR-C322 SIGNOR "form complex" binding -1 24311584 t miannu "In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined." SIGNOR-263717 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr203 HQHYYYDtHTNTYYL 9606 12145304 t gcesareni "The secretory na-k-cl cotransporter nkcc1 is activated by secretagogues through a phosphorylation-dependent mechanism. three phosphoacceptor sites were identified in the n-terminal domain of the protein (at thr184, thr189, and thr202) none of these residues occurs in the context of strong consensus sites for known ser/thr kinases." SIGNOR-90927 PI3K complex SIGNOR-C156 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-252706 SCF(TBL1) complex SIGNOR-C533 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys666 LFRMSEDkPQDYKKR 9606 BTO:0000007 20181957 t miannu "Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC). " SIGNOR-271946 PRKCG protein P05129 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates phosphorylation Ser415 QRKITRPsQRPKTPP 9606 17911614 t gcesareni "Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover." SIGNOR-158133 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 18570871 t gcesareni "In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function." SIGNOR-179084 KIF13A protein Q9H1H9 UNIPROT ZFYVE26 protein Q68DK2 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 20208530 t miannu "We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B." SIGNOR-265539 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18719589 f "induction of mitochondrial biogenesis" fspada "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-180314 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR ARF6 protein P62330 UNIPROT "down-regulates quantity by destabilization" 9534 BTO:0000298 18094045 t miannu "Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A)." SIGNOR-271766 LYN protein P07948 UNIPROT BTK protein Q06187 UNIPROT up-regulates phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 BTO:0000776 8630736 t lperfetto "Phosphorylation at y551 requires lyn kinase activity, indicating that y551 is a transphosphorylation site \ this transphosphorylation at y551 is followed by phosphorylation at a second site, which is dependent on btk catalytic activity." SIGNOR-41607 ARSA protein P15289 UNIPROT HBB protein P68871 UNIPROT "up-regulates activity" acetylation 9606 237937 t Regulation miannu "ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction." SIGNOR-251772 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT "up-regulates activity" phosphorylation Ser696 KKRARRGsSSDEEGG -1 14657015 t lperfetto "Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin." SIGNOR-271843 JAK2 protein O60674 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation 9606 15007095 t miannu "Jak2 and Lyn coimmunoprecipitated with Btk and phosphorylated Btk on tyrosine (XREF_FIG C)." SIGNOR-279196 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT "down-regulates activity" phosphorylation Ser49 REQQEQLsLQQTIID 9534 BTO:0000298 10759890 t miannu "IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex" SIGNOR-262722 HDAC1 protein Q13547 UNIPROT HSPA5 protein P11021 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19417144 f miannu "We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275 but also by exogenous overexpression and small interfering RNA knockdown of specific HDACs." SIGNOR-254227 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 BTO:0000007 17761173 t lperfetto "We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3" SIGNOR-260615 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser233 VSSQHRYsTPHAFTF 9534 12801936 t miannu "Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259)." SIGNOR-250040 DAG1 protein Q14118 UNIPROT DGC complex SIGNOR-C217 SIGNOR "form complex" binding 9606 15117830 t apalma "The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink)." SIGNOR-255983 PRKCD protein Q05655 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation 9606 10698949 t miannu "As shown for serum, phosphorylation of 4E-BP1 by PKCdelta inhibits the interaction between 4E-BP1 and eIF4E and stimulates cap-dependent translation.|Here we demonstrate that protein kinase Cdelta (PKCdelta) associates with RAFT1 and that PKCdelta is required for the phosphorylation and inactivation of 4E-BP1." SIGNOR-279100 RPS6K proteinfamily SIGNOR-PF26 SIGNOR PPP1R3A protein Q16821 UNIPROT "up-regulates activity" phosphorylation Ser46 PQPSRRGsDSSEDIY -1 10648825 t lperfetto "The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates." SIGNOR-252777 FAM83F protein Q8NEG4 UNIPROT CSNK1A1 protein P48729 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273751 PRKCE protein Q02156 UNIPROT ALDH2 protein P05091 UNIPROT "up-regulates activity" phosphorylation Ser296 KSPNIIMsDADMDWA -1 28056995 t lperfetto "Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes." SIGNOR-271864 MAML1 protein Q92585 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" acetylation 9606 17300219 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" gcesareni "The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin." SIGNOR-153038 EIF3A protein Q14152 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266400 MAP3K12 protein Q12852 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation Ser257 ISGQLVDsIAKTRDA 9606 25594179 t miannu "As expected, DLK significantly increased MKK4 phosphorylation on Ser257 / Thr261, and myrAKT1 enhanced MKK4 phosphorylation on Ser78 (XREF_FIG).|While MKK4 activated by DLK had strong activity in phosphorylating JNK3, MKK4 expressed with DLK and AKT1 together exhibited little activity, even though the two samples had similar levels of Ser257 / Thr261 phosphorylation (XREF_FIG)." SIGNOR-279629 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Thr446 LKNDGKRtRSKGTLR 4932 11337501 t "Trans-autophosphorylation of Thr-446 and Thr-451 by the two kinase moieties in a PKR dimer. autophosphorylation in the activation loop would promote proper alignment of key catalytic residues, or the correct orientation of the two lobes of the PKR kinase domain, required for substrate binding or phosphoryl transfer" SIGNOR-251110 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204724 PRKD3 protein O94806 UNIPROT SSH1 protein Q8WYL5 UNIPROT "down-regulates activity" phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 t lperfetto "Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase" SIGNOR-275938 NUAK2 protein Q9H093 UNIPROT LATS1 protein O95835 UNIPROT down-regulates phosphorylation Ser464 NIPVRSNsFNNPLGN 9606 19927127 t gcesareni "Phosphorylation at ser-464 by nuak1 and nuak2 leads to decreased protein level and is required to regulate cellular senescence and cellular ploidy" SIGNOR-161796 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA7 protein Q9Y5G6 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265709 BMP7 protein P18075 UNIPROT BMP7 protein P18075 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 t lperfetto "Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interac- tion with receptors" SIGNOR-236172 ITGA4 protein P13612 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253175 ACAT1 protein P24752 UNIPROT PDP1 protein Q9P0J1 UNIPROT "down-regulates activity" acetylation 34289383 t lperfetto "We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)" SIGNOR-267635 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB2 protein Q00653 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000567 14676825 t lperfetto "Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase." SIGNOR-217175 ITK protein Q08881 UNIPROT BTK protein Q06187 UNIPROT "down-regulates activity" phosphorylation Tyr223 LKKVVALyDYMPMNA -1 12573241 t "Btk-SH3 mutant Y223A was not phosphorylated by Itk. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role" SIGNOR-251333 Dihydromorphine chemical CHEBI:4575 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258786 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser794 QHLRLSTsSGRLLYA 9606 12624099 t gcesareni "These results suggest that highly expressed sik2 in insulin-stimulated adipocytes phosphorylates ser794_ of irs-1 and, as a result, might modulate the efficiency ofinsulinsignal transduction" SIGNOR-99055 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser641 KVTSKCGsLGNIHHK 9606 BTO:0000590 7706316 t lperfetto "Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262." SIGNOR-249342 MAPK1 protein P28482 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser770 MMRSKETsSPGTDDV 9606 17209041 t miannu "We have demonstrated that the map kinases extracellular signal-regulated kinases 1 and 2 (erk1/2) are implicated in growth factor activation of nhe1. / our results suggest that amino acids ser770 and ser771 mediate erk-dependent activation of the na+/h+ exchanger in vivo." SIGNOR-151925 CNOT7 protein Q9UIV1 UNIPROT "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR "form complex" binding 9606 19558367 t lperfetto "In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules." SIGNOR-268307 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 9606 10660621 t lperfetto "Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene." SIGNOR-74880 STK11 protein Q15831 UNIPROT NUAK2 protein Q9H093 UNIPROT up-regulates phosphorylation Thr208 HQGKFLQtFCGSPLY 9606 14976552 t llicata "A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold." SIGNOR-122717 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser574 NSNSCRSsTTTCPEQ 9606 BTO:0000007 16862148 t lperfetto "ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2)." SIGNOR-249303 SIRT6 protein Q8N6T7 UNIPROT ME1 protein P48163 UNIPROT "down-regulates activity" deacetylation Lys337 KIWLVDSkGLIVKGR 31735643 t lperfetto "PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation." SIGNOR-275572 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser29 FLGLHIAsPPNFRLT 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250125 GPER1 protein Q99527 UNIPROT GNG2 protein P59768 UNIPROT "up-regulates activity" binding 10696571 t "GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNG2 stands for the subunit γ, which dissociates from the receptor after the binding of GTP on α-subunit." SIGNOR-251104 SCRIB protein Q14160 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 19458197 f miannu "Our data supports a model by which scribble functions downstream of beta-catenin to cluster synaptic vesicles at developing synapses." SIGNOR-265827 MYC protein P01106 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR "up-regulates quantity" "transcriptional regulation" 10116 10823814 t "inferred from family member" miannu "C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway." SIGNOR-267785 PI3K complex SIGNOR-C156 SIGNOR IRS1 protein P35568 UNIPROT "down-regulates activity" 9606 11160134 f lperfetto "Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307" SIGNOR-252717 EGFR protein P00533 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 22693070 t lperfetto "The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation" SIGNOR-235689 "PAN2-PAN3 deadenylation complex" complex SIGNOR-C553 SIGNOR "messenger RNA" smallmolecule CHEBI:33699 ChEBI "down-regulates quantity by destabilization" "chemical modification" 9606 34280615 t miannu "There are two major deadenylase complexes, Ccr4-Not and Pan2-Pan3, which shorten the 3′ poly(A) tail of mRNA and are conserved from yeast to human.The Ccr4-Not complex has two catalytic subunits including the Ccr4 (Carbon catabolite repressor 4) and Pop2 (PGK promoter directed overproduction). The Pan2-Pan3 complex comprises the catalytic subunit Pan2, a member of the RNase D family, and the regulatory subunit Pan3. Degradation of mRNA begins with either shortening of the poly(A) tail by deadenylases or removal of 5′ cap structure by the decapping enzyme Dcp1-Dcp2." SIGNOR-273872 CBX1 protein P83916 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264491 TAF13 protein Q15543 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263923 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 20940307 t gcesareni "Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis" SIGNOR-168473 GPR119 protein Q8TDV5 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257366 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT "up-regulates activity" phosphorylation Ser90 GLFNELAsPFENEFK 9606 BTO:0000599 10085140 t miannu "P38 directly phosphorylates ATF-2 at Thr-69, Thr-71, and Ser-90, resulting in stimulation of its trans-activating capacity." SIGNOR-250090 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser276 VHPATPIsPGRASGM 9606 BTO:0002181 16046550 t miannu "We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation." SIGNOR-268221 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207944 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 t lperfetto "We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2." SIGNOR-244349 BICDL1 protein Q6ZP65 UNIPROT KIF1C protein O43896 UNIPROT "up-regulates activity" binding -1 20360680 t miannu "BICDR-1 interacts with the dynein/dynactin motor complex. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. These results show that BICDR-1 regulates recruitment and/or activity of the anterograde kinesin motor Kif1C on Rab6 secretory carriers." SIGNOR-266876 MRAP2 protein Q96G30 UNIPROT MC5R protein P33032 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252369 NR2E3 protein Q9Y5X4 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates binding 9606 15190009 t gcesareni "All four proteins, nr2e3, nr1d1, nrl and crx, could be co-immunoprecipitated from the bovine retinal nuclear extract, suggesting their existence in a multi-protein transcriptional regulatory complex in vivo." SIGNOR-125661 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT down-regulates phosphorylation Tyr981 LPLDKDYyVVREPGQ 9606 9391116 t gcesareni "We found that jak3 is autophosphorylated on multiple sites including y980 and y981. Compared with the activity of wild-type (wt) jak3, mutant y980f demonstrated markedly decreased kinase activity, and optimal phosphorylation of jak3 on other sites was dependent on y980 phosphorylation. The mutant y980f also exhibited reduced phosphorylation of its substrates, gammac and stat5a. In contrast, mutant y981f had greatly increased kinase activity, whereas the double mutant, yy980/981ff, had intermediate activity." SIGNOR-53594 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser733 TVREQDQsFTALDWS 9606 18957422 t lperfetto "Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma" SIGNOR-181798 5-{3-[4-(2,3-Dichlorophenyl)piperidin-1-yl]propoxy}-1,3-benzothiazole chemical CID:56599142 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258322 BDNF protein P23560 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32603820 f miannu "BDNF is a central driver of synaptic plasticity and memory formation and its decreased levels may contribute to the degeneration of specific neuronal populations and progressive atrophy of neurons in the AD-affected brain" SIGNOR-265063 FYN protein P06241 UNIPROT CD300LB protein A8K4G0 UNIPROT "up-regulates activity" phosphorylation Tyr188 EPGEQPIyMNFSEPL 9534 16920917 t lperfetto "As CD300b phosphorylation was occurring only in the presence of both c-Fyn and DAP-12, we addressed whether tyrosine phosphorylation was required for association of CD300b and DAP-12. For this purpose, we generated a set of HA-tagged CD300b mutants affecting the transmembrane lysine (K158L), the cytoplasmic tyrosine (Y188F) or both residues.|As expected, the CD300b double mutant could neither recruit DAP-12 nor become phosphorylated in the presence of c-Fyn kinase (Fig. 5⇑C). Association between CD300b and DAP-12 was maintained in absence of the c-Fyn kinase, indicating that phosphorylation of the adaptor was not essential for the formation of the complex (data not shown)" SIGNOR-264771 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257935 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR CBFB protein Q13951 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f irozzo "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins." SIGNOR-255852 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 20219869 f apalma "Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6." SIGNOR-255356 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 9606 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257457 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1A protein P35348 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258454 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM38 protein O00635 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271141 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser1798 GQRKRLIsSVEDFTE 9606 BTO:0000007 15342917 t lperfetto "The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1" SIGNOR-252801 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser43 FGYQRRAsDDGKLTD 10090 BTO:0000944 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-249439 SREBF1 protein P36956 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12923220 t lperfetto "IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells|evidence that IDH1 may regulate lipogenesis in hepatic cells" SIGNOR-253132 VEGFC protein P49767 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252277 IFNL1 protein Q8IU54 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 12469119 t gcesareni "Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha." SIGNOR-96177 hexestrol chemical CHEBI:31669 ChEBI AKR1C2 protein P52895 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193300 RNF11 protein Q9Y3C5 UNIPROT STAMBP protein O95630 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 14755250 t miannu "RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome." SIGNOR-272953 AKAP11 protein Q9UKA4 UNIPROT IQGAP2 protein Q13576 UNIPROT "up-regulates activity" binding 9606 21776420 t miannu "We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP." SIGNOR-273740 RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT "up-regulates activity" binding 9606 23151663 t gcesareni "Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization." SIGNOR-199542 TADA1 protein Q96BN2 UNIPROT "SAGA complex" complex SIGNOR-C465 SIGNOR "form complex" binding 9606 34811519 t lperfetto "Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module" SIGNOR-269583 Cyclopamine chemical CHEBI:4021 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9534 BTO:0000298 12414725 t gcesareni "The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent derivatives, that this inhibitory effect is mediated by direct binding of cyclopamine to the heptahelical bundle of Smoothened (Smo)" SIGNOR-95270 CDK5 protein Q00535 UNIPROT KALRN protein O60229 UNIPROT "up-regulates activity" phosphorylation 9606 18628310 t miannu "We then demonstrated that Cdk5 phosphorylates Kalirin 7 on Thr 1590 , increasing its GEF activity slightly and changing its solubility properties." SIGNOR-279603 EPM2A protein O95278 UNIPROT GSK3B protein P49841 UNIPROT unknown dephosphorylation Ser9 SGRPRTTsFAESCKP 10090 16959610 t "Epm2a-encoded laforin is a phosphatase for GSK-3beta and an important repressor in the Wnt signaling pathway| only GSK-3β phosphorylation on Ser9 was affected by overexpression of laforin|Although GSK-3β is inactivated by phosphorylation at the Ser9 position, it is unclear if the inactivated enzyme can be reactivated by dephosphorylation." SIGNOR-248345 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr487 SLSNIDFyAQVSDIT 10029 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248419 MAPK1 protein P28482 UNIPROT NR4A1 protein P22736 UNIPROT "up-regulates activity" phosphorylation Thr143 CSAPSPStPSFQPPQ 10116 BTO:0001009 11883936 t lperfetto "NGFI-B is an inducible orphan nuclear receptor that initiates apoptosis. Growth factors such as EGF activate the MAP kinase ERK, whose activity may determine if a cell survives or undergoes apoptosis. EGF stimulation of cells leads to phosphorylation of threonine in NGFI-B. Thr-142 of NGFI-B is comprised in a consensus MAP kinase site and was identified as a preferred substrate for ERK2 (but not ERK1) in vitro." SIGNOR-249430 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257403 CSNK2A2 protein P19784 UNIPROT IL16 protein Q14005 UNIPROT "up-regulates activity" phosphorylation Ser743 MPLQPNAsLNEEEGT -1 12450396 t llicata "We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation." SIGNOR-251009 HTR7 protein P34969 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257168 POT1 protein Q9NUX5 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 17237768 t miannu "We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme." SIGNOR-152327 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser202 EEDSRPRsQSSKAAI 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. Clk1 promotes SPF45-induced exon 6 exclusion" SIGNOR-262705 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation Ser166 TYSDEHFsPGSHPSH 9606 12556497 t gcesareni "Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk." SIGNOR-97808 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 9687510 t gcesareni "Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth." SIGNOR-59435 PLAGL1 protein Q9UM63 UNIPROT ABCC6 protein O95255 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007;BTO:0000599 18850323 f miannu "We identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins. Both these factors are shown to bind to the same single consensus-binding element in the ABCC6 proximal promoter in cell lines of hepatic and renal origin by reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. PLAG-mediated ABCC6 transactivation may play an important role in determining the level of tissue-specific expression of this gene. The described mechanism can also find potential application in therapeutic interventions in forms of PXE related to impaired ABCC6 expression." SIGNOR-254926 DYRK1B protein Q9Y463 UNIPROT NKX3-1 protein Q99801 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser185 KTKRKQLsSELGDLE 9606 25777618 t miannu "In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover." SIGNOR-279610 BTRC protein Q9Y297 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 9606 11359933 t gcesareni "An e3 ubiquitin ligase complex roc1-scffbw1a consisting of roc1, skp1, cullin1, and fbw1a (also termed trcp1) induces ubiquitination of smad3." SIGNOR-108237 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB6 protein Q9Y5F9 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265706 GSK3B protein P49841 UNIPROT HNRNPD protein Q14103 UNIPROT "down-regulates activity" phosphorylation Ser83 DEGHSNSsPRHSEAA 9606 BTO:0001271 11903055 t lperfetto "In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation." SIGNOR-102582 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 20871233 f "Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation." SIGNOR-255343 GMNN protein O75496 UNIPROT CDT1 protein Q9H211 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 11125146 t "Here we show that geminin interacts tightly with Cdt1, a recently identified replication initiation factor necessary for MCM loading." SIGNOR-261680 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT "up-regulates activity" phosphorylation Ser793 PRPSPLPsPQPAPRR 9606 20005250 t miannu "Further, investigation revealed that MLK3 was phosphorylated at two residues Ser789 and Ser793 by GSK3\u03b2 ( xref ).|When, these two sites on MLK3 were mutated to non-phosphorable Ala, the activation of MLK3 by GSK3\u03b2 was blocked, and neuronal cell death upon NGF withdrawal also prevented ( xref )." SIGNOR-279615 AURKB protein Q96GD4 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser184 GKKSGKKsYLSGGAG 9606 23226345 t lperfetto "Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1" SIGNOR-200079 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr659 VADERVDyVVVDQQK 10090 BTO:0000944 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251317 Osmotic_stress stimulus SIGNOR-ST28 SIGNOR FUS protein P35637 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000312 33172210 f "We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne" SIGNOR-262815 HOXC13 protein P31276 UNIPROT LAMB2 protein P55268 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0000298 10835276 t Luana "The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells." SIGNOR-261644 zotepine chemical CHEBI:32316 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258553 MAGT1 protein Q9H0U3 UNIPROT "OST-B complex" complex SIGNOR-C536 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272071 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser342 LAHDRAPsRKDSLES 9606 23337587 t gcesareni "Interestingly, sufu stability is regulated via dual phosphorylation at ser342/ser346 by pka and gsk3, and blocking sufu phosphorylation either by mutating ser346 to ala or by treating cultured cells with pka inhibitors attenuates sufu ciliary accumulation, whereas phospho-mimetic forms of sufu exhibits increased ciliary localization" SIGNOR-200492 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Ser548 MRKSQRSsKGSEILL -1 21642394 t miannu "In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475." SIGNOR-276333 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser287 SVKSPVSsPNNVTLR 9606 BTO:0005043 22798426 t miannu " Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation." SIGNOR-276104 CDH2 protein P19022 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265864 7a protein P59635 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 9606 17428862 t Luana "In this study, we show that the overexpression of Bcl-XL, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family." SIGNOR-261075 E protein P59637 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" 9606 BTO:0000661 16048439 f Luana "SARS-CoV E protein induces apoptosis by ‘sequestering’ Bcl-xL to the membranes of ER and Golgi, where the SARS-CoV E protein is located. As a consequence, the existing balance between pro-survival protein Bcl-xL and pro-apoptotic proteins, including Bax and BH3-domain-only proteins, is tipped by SARS CoV E protein, so that sequestered Bcl-xL could not fulfil its normal function in inhibition of apoptosis. | This result implied that SARS-CoV E protein might induce T-cell apoptosis via a pathway antagonistic to the mitochondrion-dependent mechanism of Bcl-xL." SIGNOR-260586 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12226093 t "The effect has been demonstrated using P10636-8" lperfetto "Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease." SIGNOR-92607 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258416 MRPS18C protein Q9Y3D5 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261450 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" phosphorylation Tyr204 HTGFLTEyVATRWYR 1712480 t lperfetto "Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|" SIGNOR-249472 ULK2 protein Q8IYT8 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT "up-regulates activity" phosphorylation 9606 33135781 t miannu "When mTOR is inhibited, ULK1 and ULK2 activate and phosphorylate ATG13 and FIP200." SIGNOR-280159 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser197 DRVSRSSsPLKTGEQ 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250124 BID protein P55957 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 9606 BTO:0000093 22464442 t lperfetto "Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer." SIGNOR-209675 AKT1 protein P31749 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Thr1462 GLRPRGYtISDSAPS 10090 BTO:0000944 12150915 t lperfetto "We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines." SIGNOR-235515 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t "Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity" SIGNOR-251358 EFNA5 protein P52803 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou "Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor" SIGNOR-52473 "1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate" smallmolecule CHEBI:18348 ChEBI RAB21 protein Q9UL25 UNIPROT "down-regulates activity" binding 9606 19693279 t miannu "It was demonstrated that wild-type Rab21 was transiently associated with macropinosomes. Rab21 was recruited to the macropinosomes after a decrease in PI(4,5)P(2) and PI(3,4,5)P(3) levels. Although Rab21 was largely colocalized with Rab5, the recruitment of Rab21 to the macropinosomes lagged a minute behind that of Rab5, and preceded that of Rab7." SIGNOR-277781 MAPK9 protein P45984 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t "JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8" gcesareni "Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-189" SIGNOR-124027 wortmannin chemical CHEBI:52289 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 BTO:0001271 7503989 t gcesareni "Wortmannin inhibited the activity of partially purified pi3-kinase from calf thymus, as well as the pi3-kinase activity in anti-pi3-kinase p85 immunoprecipitates from rbl-2h3 cells, at a concentration as low as 1.0 nm and with ic50 values of 3.0 nm." SIGNOR-252663 TFE3 protein P19532 UNIPROT ATG9B protein Q674R7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 24448649 f lperfetto "The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells" SIGNOR-276808 GPR35 protein Q9HC97 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257204 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr59 GETRFTDtRKDEQER 9606 phosphorylation:Thr59 GETRFTDtRKDEQER 8386634 t gcesareni "Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2" SIGNOR-38566 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 t lperfetto "Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation." SIGNOR-249162 LPCAT4 protein Q643R3 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI "down-regulates quantity" "chemical modification" 9606 21498505 t miannu "Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. " SIGNOR-272773 ketoconazole chemical CHEBI:47519 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258060 PRKCA protein P17252 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t lperfetto "Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway." SIGNOR-115714 propionyl-CoA(4-) smallmolecule CHEBI:57392 ChEBI (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI "up-regulates quantity" "precursor of" 9606 15890657 t miannu "Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively." SIGNOR-267185 CDC42 protein P60953 UNIPROT CDC42BPA protein Q5VT25 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9418861 t lperfetto "Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization|MRCK alpha and Cdc42V12 colocalize, particularly at the cell periphery in transfected HeLa cells. Microinjection of plasmid encoding MRCK alpha resulted in actin and myosin reorganization." SIGNOR-262593 DVL3 protein Q92997 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates binding 9606 10535959 t gcesareni "Ckiepsilon was in a complex with axin and other downstream components of the wnt pathway, including dishevelled." SIGNOR-71759 NRXN1 protein Q9ULB1 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626542 t miannu "The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites." SIGNOR-265452 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys122 SPVEDNEkDLVKLAK -1 19240029 t miannu "S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10)." SIGNOR-272739 DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" binding 9606 19365405 t gcesareni "B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1." SIGNOR-185268 risperidone chemical CHEBI:8871 ChEBI HTR1B protein P28222 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0001311 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258526 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC15 protein Q99877 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271993 MARCHF9 protein Q86YJ5 UNIPROT PTPRA protein P18433 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001522 19457934 t miannu "MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. " SIGNOR-271540 PTPN11 protein Q06124 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" dephosphorylation Ser727 TDNLLPMsPEEFDEV 9606 BTO:0000007 12270932 t "SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity." SIGNOR-248673 Quadazocine chemical CID:115077 PUBCHEM OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258419 DMPK protein Q09013 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata "Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. " SIGNOR-236982 LTB protein Q06643 UNIPROT LTBR protein P36941 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 BTO:0000975 7995952 t lperfetto "These experiments point toward the lt-alpha 1/beta 2 complex as the predominant membrane form of lt on the lymphocyte surface, and this complex is the primary ligand for the lt-beta receptor." SIGNOR-35759 formestane chemical CHEBI:75172 ChEBI CYP19A1 protein P11511 UNIPROT "down-regulates activity" "chemical inhibition" -1 7083195 t miannu "Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes." SIGNOR-258407 PTPRF protein P10586 UNIPROT LCK protein P06239 UNIPROT up-regulates dephosphorylation 9606 12496362 t flangone "We confirmed that lar dephosphorylated the phosphorylated tyrosine residues of lck..Activation Of lck and fyn involves tyrosine dephosphorylation of the cooh-terminal regulatory domain of kinases, followed by autophosphorylation of the kinase domain." SIGNOR-96771 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT "up-regulates activity" phosphorylation Ser644 NLMFRKFsLERPFRP -1 24548923 t miannu "Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro. " SIGNOR-276255 SGK1 protein O00141 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Ser1130 GARDRVRsMSGGHGL -1 27451907 t miannu "SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2. " SIGNOR-277266 CASP3 protein P42574 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates cleavage 9606 11283607 t gcesareni "Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity." SIGNOR-106546 "DNA polymerase epsilon" complex SIGNOR-C377 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 10801849 f lperfetto "HeLa pol epsilon was initially purified as a soluble factor that restored repair synthesis to cytosol-depleted, UV-irradiated permeabilized human fibroblasts (11). By reconstituting the nucleotide excision repair (NER) process from purified proteins, Shivji et al. (12) further showed that mammalian pol epsilon was the most efficient enzyme in performing gap-filling DNA synthesis during NER." SIGNOR-265722 TNC protein P24821 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "up-regulates activity" binding 9606 BTO:0001521 38058842 t miannu "TNC is shown to bind to integrin receptors expressed in adjacent PAAD cells, thereby inducing EMT. In addition, TNC expression in CAFs had significant positive correlations with ITGαV, ITGβ1, or ITGβ3 expression in cancer cells, which supports our speculations that the TNC-integrin signaling axis promotes the EMT pathway in cancer cells." SIGNOR-277736 RXRG protein P48443 UNIPROT GLI2 protein P10070 UNIPROT "up-regulates quantity" "transcriptional regulation" 31390799 f SimoneGraziosi "Despite RXRγ being heavily down-regulated upon silencing (average silencing was about 80%), the reduction in Gli2 expression levels was statistically significant only for Clobetasol-treated but not for Gefitinib-treated cells." SIGNOR-269267 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." SIGNOR-84975 KSR1 protein Q8IVT5 UNIPROT ARAF protein P10398 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 29433126 t miannu "In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically." SIGNOR-273876 ATM protein Q13315 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t lperfetto "Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro." SIGNOR-121861 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271 21697284 t gcesareni "Cocrystallization of the met kinase domain in complex with nvp-bvu972 revealed a key role for y1230 in binding of nvp-bvu972, as previously reported for multiple other selective met inhibitors." SIGNOR-174555 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2I protein P63279 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271346 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" sumoylation Lys606 EELLAEEKSKPIPIM 9606 BTO:0000007 19638400 t Barakat "Through detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms." SIGNOR-274129 PTPN1 protein P18031 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 15632081 t gcesareni "Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs" SIGNOR-132959 NRF1 protein Q16656 UNIPROT RETREG3 protein Q86VR2 UNIPROT up-regulates 9606 BTO:0000934 23939472 f lperfetto "We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. " SIGNOR-261489 ATF4 protein P18848 UNIPROT CARS2 protein Q9HA77 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269417 CDC25C protein P30307 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" dephosphorylation 9606 32518522 t miannu "At the interval CDC25C inhibits ASK1, dephosphorylating pThr838 in its activation loop.|CDC25C dephosphorylates ASK1 to inhibit its activity during the interphase." SIGNOR-277100 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI PIP5K1A protein Q99755 UNIPROT up-regulates "chemical activation" 9606 17245604 t gcesareni "All pip5k isoforms are stimulated by pa." SIGNOR-152542 AR protein P10275 UNIPROT ARG1 protein P05089 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321 20711410 f miannu "The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression." SIGNOR-253738 MRGPRX1 protein Q96LB2 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256929 belinostat chemical CHEBI:61076 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257748 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation Thr255 ITTPELTtPCGSAEY 9606 9155017 t gcesareni "Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38." SIGNOR-48346 SKP1 protein P63208 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243554 MAPK13 protein O15264 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation 9606 9199504 t miannu "Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in the ability of tau to promote microtubule assembly." SIGNOR-278313 SRC protein P12931 UNIPROT HK1 protein P19367 UNIPROT "up-regulates activity" phosphorylation Tyr732 YDRLVDEySLNAGKQ 9606 BTO:0002181 28054552 t miannu "Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation. " SIGNOR-277335 Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR ATP smallmolecule CHEBI:15422 ChEBI "down-regulates quantity" "chemical modification" 9606 11376933 t miannu "To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis." SIGNOR-267843 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT "down-regulates activity" phosphorylation Ser794 SGGARAKsKSVSFNL 9606 BTO:0000007 21734191 t miannu "We show that TRPC5 channels may become directly phosphorylated by PKA at serine residues 794 and 796, and that this phosphorylation abolishes the receptor-operated nonselective cation current mediated by TRPC5 channels in HEK-293 cells." SIGNOR-276340 CSNK1E protein P49674 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni "However, ck1epsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the beta-catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated ck1epsilon as a candidate s45-kinase in several assays, both in vitro and in vivo." SIGNOR-87448 hsa-miR-146a mirna URS00005E1F00_9606 RNAcentral CXCR4 protein P61073 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001949 20023696 t "Expression of CXCR4 was downregulated in clinical samples of KS and this was accompanied by increased expression of miR-146a. Our results demonstrate that K13-induced NF-κB activity suppresses CXCR4 via upregulation of miR-146a. Downregulation of CXCR4 expression by K13 may contribute to KS development by promoting the premature release of KSHV-infected endothelial progenitors into the circulation." SIGNOR-277938 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 21084559 t gcesareni "Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal." SIGNOR-169841 MRPS24 protein Q96EL2 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261436 CALM2 protein P0DP24 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t miannu "The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases" SIGNOR-266328 HTR3A protein P46098 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu "The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. " SIGNOR-264316 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5A protein P29375 UNIPROT "up-regulates activity" "chemical activation" 29981745 t lperfetto "Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3." SIGNOR-273467 MAPK14 protein Q16539 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation 10029 BTO:0005787 25815583 t "TTP appears to be a p38α/β MAPK target and pretreating skeletal muscle with a p38α/β MAPK inhibitor reduces TTP phosphorylation." SIGNOR-253596 CAMK2D protein Q13557 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates phosphorylation Thr554 RGLSRQEtFDSETQE 9606 20194790 t "The effect has been demonstrated using Q08289-2" gcesareni "We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells." SIGNOR-164067 CSNK1D protein P48730 UNIPROT PER1 protein O15534 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 11165242 t miannu "Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2)." SIGNOR-268001 EGFR protein P00533 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Tyr21 IENEEQEyVQTVKSS 9606 24103589 t lperfetto "The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf" SIGNOR-202776 IDH complex SIGNOR-C396 SIGNOR 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "chemical modification" 9606 28139779 t miannu "Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP." SIGNOR-266252 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 16403219 t miannu "Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells." SIGNOR-250395 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259794 SMO protein Q99835 UNIPROT ARRB1 protein P49407 UNIPROT up-regulates binding 9606 23074268 t "The binding occours if Smo is phosphorylated" gcesareni "Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2" SIGNOR-199150 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg534 KSRSLDRrGIQRAAD -1 7989361 t lperfetto "The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994." SIGNOR-263629 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT "down-regulates activity" phosphorylation Ser313 LDLEESSsSDHAERP 10029 BTO:0000246 7876239 t "The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization." SIGNOR-251442 FLT3 protein P36888 UNIPROT PARP1 protein P09874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 21228325 f "Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls " SIGNOR-261554 PIPP smallmolecule CID:24755493 PUBCHEM LRP6 protein O75581 UNIPROT up-regulates 9606 18772438 f gcesareni "Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490" SIGNOR-180797 AGTR1 protein P30556 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 32201502 f MIANNU "Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis." SIGNOR-260234 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-176373 diphenhydramine chemical CHEBI:4636 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257787 MRGPRX1 protein Q96LB2 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257384 "adenosine 5'-monophosphate" smallmolecule CHEBI:16027 ChEBI IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0001103 1631143 t miannu "AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells." SIGNOR-269774 RORA protein P35398 UNIPROT NPAS2 protein Q99743 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 20817722 t miannu "Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding." SIGNOR-267980 acyl-CoA smallmolecule CHEBI:17984 ChEBI 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 ChEBI "up-regulates quantity" "precursor of" -1 18772128 t miannu "The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils." SIGNOR-267243 ACTR5 protein Q9H9F9 UNIPROT "INO80 complex" complex SIGNOR-C498 SIGNOR "form complex" binding 9606 25016522 t miannu "Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication." SIGNOR-270850 PLAG1 protein Q6DJT9 UNIPROT ABCC6 protein O95255 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007;BTO:0000599 18850323 f miannu "We identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins. Both these factors are shown to bind to the same single consensus-binding element in the ABCC6 proximal promoter in cell lines of hepatic and renal origin by reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. PLAG-mediated ABCC6 transactivation may play an important role in determining the level of tissue-specific expression of this gene. The described mechanism can also find potential application in therapeutic interventions in forms of PXE related to impaired ABCC6 expression." SIGNOR-254925 PRKCD protein Q05655 UNIPROT SDC4 protein P31431 UNIPROT "up-regulates activity" phosphorylation Ser179 MKKKDEGsYDLGKKP 10116 11916978 t lperfetto "The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant." SIGNOR-116265 SMAD6 protein O43541 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 12857866 t lperfetto "Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4" SIGNOR-217706 BIRC5 protein O15392 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 11069302 t amattioni "Survivin (an inhibitor of apoptosis) phosphorylation on thr34 may regulate apoptosis at cell division via an interaction with caspase-9." SIGNOR-84065 UBE3A protein Q05086 UNIPROT SCRIB protein Q14160 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 11027293 t miannu "Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase" SIGNOR-272573 BANP protein Q8N9N5 UNIPROT KHDRBS1 protein Q07666 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 26080397 t miannu "SMAR1 Interacts with Sam68 in a Signal-Dependent Manner. HDAC6 in complex with SMAR1 deacetylates Sam68. Here, we document that SMAR1, in cooperation with histone deacetylase 6 (HDAC6), interacts with Sam68 and maintains it in a deacetylated state, concomitantly inhibiting the inclusion of CD44 alternate exons." SIGNOR-266201 PSMD14 protein O00487 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263346 CREBBP protein Q92793 UNIPROT LHX3 protein Q9UBR4 UNIPROT "up-regulates activity" binding 9606 10931853 t scontino "Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim and CBP Act Synergistically in TRH Stimulation of the Human α-GSU Promoter." SIGNOR-267206 EVX1 protein P49640 UNIPROT GSC protein P56915 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 22178155 f miannu "We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin." SIGNOR-254139 SIRT7 protein Q9NRC8 UNIPROT H3-5 protein Q6NXT2 UNIPROT "up-regulates activity" deacetylation Lys38 K-->P 30653310 t lperfetto "Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37." SIGNOR-275885 Normorphine chemical CHEBI:7633 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258824 SNRPG protein P62308 UNIPROT "U1 snRNP complex" complex SIGNOR-C480 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270683 APC-c complex SIGNOR-C150 SIGNOR PFKFB3 protein Q16875 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000793 20080744 t miannu "We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins." SIGNOR-271435 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr89 VSPLLLTtTNSSEGL 9606 11152499 t tpavlidou "Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites." SIGNOR-85785 ADRA2A protein P08913 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256977 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser443 ATGSGIKsHNSALYS 9606 15574499 t amattioni "Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility." SIGNOR-131451 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR Degranulation phenotype SIGNOR-PH92 SIGNOR up-regulates 9606 16470226 f "Alessandro Palma" "So, the association of aggregated FcεRI with the preferentially activated LYN in lipid rafts might be sufficient to shift the equilibrium of FcεRI from a nonphosphorylated state to a phosphorylated state, thereby initiating FcεRI-mediated degranulation" SIGNOR-254956 MAML1 protein Q92585 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000887 18758483 t gcesareni "Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin)." SIGNOR-180136 IKZF1 protein Q13422 UNIPROT LNPEP protein Q9UIQ6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003420 15894523 f miannu "Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha." SIGNOR-255403 FGFR3 protein P22607 UNIPROT CILK1 protein Q9UPZ9 UNIPROT "down-regulates activity" phosphorylation Tyr15 RQLGDGTyGSVLLGR -1 30782830 t miannu "FGF signaling partially abolished ICK's kinase activity, through FGFR-mediated ICK phosphorylation at conserved residue Tyr15, which interfered with optimal ATP binding." SIGNOR-277436 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER2 protein O15055 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 22750052 f lperfetto "Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins." SIGNOR-253682 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2J1 protein Q9Y385 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271342 FANCI protein Q9NVI1 UNIPROT "Fanconi anemia ID complex" complex SIGNOR-C302 SIGNOR "form complex" binding 9606 BTO:0000007 17412408 t lperfetto "Immunoprecipitation of HA-FLAG-tagged FANCI expressed in 293T cells with antibodies against either HA or FLAG, but not MYC, resulted in coimmunoprecipitation of endogenous FANCD2|The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage." SIGNOR-263269 IFNGR2 protein P38484 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 23898330 t lperfetto "In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation" SIGNOR-249504 PRKCA protein P17252 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser371 AHSSHLKsKKGQSTS -1 9571186 t lperfetto "Here, we demonstrate that cotransfection of p53 with either PKC alpha or PKC zeta increases p53's transcriptional activity. Mutagenesis of p53 indicates that serine 371 is the major site for phosphorylation by PKC alpha in vitro." SIGNOR-248999 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr71 VAFSVDNtIKRPNPA 29383184 t lperfetto "PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8." SIGNOR-275568 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation 9606 16023596 t gcesareni "Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation." SIGNOR-138592 LRRK2 protein Q5S007 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation 9606 22998870 t miannu "We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association." SIGNOR-192068 WNT6 protein Q9Y6F9 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131894 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Ser916 TGEAPTLsPPRDARP 9606 BTO:0000567 31981797 t miannu "CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines." SIGNOR-276832 Ub:E2 complex SIGNOR-C497 SIGNOR RNF151 protein Q2KHN1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271158 TNF protein P01375 UNIPROT CTSK protein P43235 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 11920402 f lperfetto "This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme." SIGNOR-253317 PAK3 protein O75914 UNIPROT SYN1 protein P17600 UNIPROT "up-regulates activity" phosphorylation Ser605 AGPTRQAsQAGPVPR 10116 BTO:0001009 12237306 t miannu "Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release" SIGNOR-250246 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Thr179 FAKTFVGtPYYMSPE 9606 17197699 t gcesareni "Enzymatic activity, inhibited;" SIGNOR-151771 NRF1 protein Q16656 UNIPROT BRK1 protein Q8WUW1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23939472 f miannu "We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons." SIGNOR-261369 RAB6B protein Q9NRW1 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 20360680 f miannu "We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles." SIGNOR-266881 CDC23 protein Q9UJX2 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252008 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding 10090 9442088 t gcesareni "Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s)." SIGNOR-55300 IRS1 protein P35568 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 BTO:0000156 11259577 t lperfetto "Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis." SIGNOR-236614 AKT1 protein P31749 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser345 ELLCLRRsSLKAYGN 9606 11809767 t lperfetto "Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation." SIGNOR-252469 KHK protein P50053 UNIPROT beta-D-fructofuranose smallmolecule CHEBI:28645 ChEBI "down-regulates quantity" "chemical modification" 9606 38971308 t miannu "KHK catalyzes the phosphorylation of the C1 hydroxyl of fructose to generate fructose-1-phosphate (F-1P)" SIGNOR-280238 EGFR protein P00533 UNIPROT ZNRF1 protein Q8ND25 UNIPROT "up-regulates activity" phosphorylation Tyr103 TYAHGNGyQETGGGH 9606 26572619 t miannu "Together, these results demonstrate that EGFR-dependent phosphorylation of ZNRF1 at Y103 promotes degradation of AKT and resultant activation of GSK3\u03b2, which mediates oxidative stress\u2013induced neuronal apoptosis ( xref )." SIGNOR-279522 mTORC1 complex SIGNOR-C3 SIGNOR ULK1 protein O75385 UNIPROT down-regulates phosphorylation 9606 19690328 t lperfetto "The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated." SIGNOR-217133 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0001103 21798082 t lperfetto "Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b)." SIGNOR-252841 "SAE1/SAE2 complex" complex SIGNOR-C294 SIGNOR JUN protein P05412 UNIPROT "down-regulates activity" sumoylation Lys226 HPRLQALkEEPQTVP 9606 BTO:0000567 SIGNOR-C154 16055711 t lperfetto "We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity." SIGNOR-263006 CH5132799 chemical CID:49784945 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190946 ELP5 protein Q8TE02 UNIPROT "Elongator complex" complex SIGNOR-C466 SIGNOR "form complex" binding 9606 28601220 t miannu "Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer." SIGNOR-269712 olanzapine chemical CHEBI:7735 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8""5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3)." SIGNOR-258834 RUNX2 protein Q13950 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001610 22641097 f miannu "Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells." SIGNOR-255084 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr588 QLKPLKTyVDPHTYE 9606 18387945 t lperfetto "The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells." SIGNOR-178169 CSNK2A1 protein P68400 UNIPROT HMOX2 protein P30519 UNIPROT "up-regulates activity" phosphorylation Ser79 TALYFTYsALEEEME 10116 BTO:0003036 14527438 t llicata "Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. | CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2" SIGNOR-250895 "Immunoglobulin lambda-1 light chain" protein P0DOX8 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR "form complex" binding 9606 BTO:0000776 20176268 t scontino "Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes." SIGNOR-268198 IRAK1 protein P51617 UNIPROT GLIPR2 protein Q9H4G4 UNIPROT "up-regulates activity" phosphorylation Ser58 ILKHSPEsSRGQCGE 9606 BTO:0001370 25544559 t miannu "We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion." SIGNOR-262887 BRCA2 protein P51587 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu "Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates" SIGNOR-204538 EIF2AK2 protein P19525 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 10723127 t lperfetto "As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation." SIGNOR-249335 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 23729744 t apalma "Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster), which in turn facilitates a further crucial signaling cleavage within the Notch transmembrane domain by a γ-secretase complex that contains Presenilin (S3 cleavage)" SIGNOR-255372 ITGB4 protein P16144 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9428518 t gcesareni "Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation." SIGNOR-252697 tetra-mu3-sulfido-tetrairon chemical CHEBI:49883 ChEBI "Succinate dehydrogenase-Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR "form complex" binding 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively." SIGNOR-267733 TFAP4 protein Q01664 UNIPROT SALL2 protein Q9Y467 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000452 21228219 f miannu "The transcription factor AP4 increases along with SALL2 in quiescent cells and positively regulates SALL2 expression." SIGNOR-255426 CSNK2A2 protein P19784 UNIPROT CCAR2 protein Q8N163 UNIPROT "up-regulates activity" phosphorylation Thr454 AAEAAPPtQEAQGET 9606 24962073 t lperfetto "CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1" SIGNOR-267667 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation -1 8929531 t lperfetto "The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL." SIGNOR-244497 EP300 protein Q09472 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates binding 9606 24058639 t miannu "P300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380" SIGNOR-202682 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171022 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser910 SLLGRSGsYSYLEER 9606 20354225 t gcesareni "Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity." SIGNOR-22572 OSBP2 protein Q969R2 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI "up-regulates quantity" relocalization 30925160 t lperfetto "CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes." SIGNOR-264879 TPO protein P07202 UNIPROT "L-alanine zwitterion" smallmolecule CHEBI:57972 ChEBI "up-regulates quantity" "chemical modification" 9606 28153798 t scontino "The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines." SIGNOR-267041 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates activity" phosphorylation Thr417 WGIKCRLtLQKPSCL 9606 20663873 t miannu "We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27." SIGNOR-259817 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-169678 SETD1A protein O15047 UNIPROT "Set1-Ash2 HMT complex" complex SIGNOR-C352 SIGNOR "form complex" binding 9606 BTO:0000567 12670868 t miannu "Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles." SIGNOR-264478 UFL1 protein O94874 UNIPROT H4C1 protein P62805 UNIPROT "up-regulates activity" ubiquitination Lys32 DNIQGITkPAIRRLA 9606 BTO:0000007;BTO:0001938 30886146 t lperfetto "Here we report that UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation." SIGNOR-265072 HTR1E protein P28566 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257100 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni "In the absence of hedgehog signaling, gli1 is transcriptionally repressed, gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation, and gli3 is processed to a cleaved repressor." SIGNOR-154222 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" cleavage Ile847 LQPDVTGiRLLSLGA -1 9242537 t lperfetto "Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex." SIGNOR-263637 WNK3 protein Q9BYP7 UNIPROT WNK1 protein Q9H4A3 UNIPROT "up-regulates activity" phosphorylation Ser382 KRASFAKsVIGTPEF 9606 22032326 t Manara "We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro." SIGNOR-260789 AKT1 protein P31749 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser346 LLCLRRSsLKAYGNG 9606 11809767 t lperfetto "Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation." SIGNOR-252470 LRRK2 protein Q5S007 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23754980 t gcesareni "Subsequent assays confirmed a direct interaction between the lrrk2 roccor domain and all three human dvl proteins, these data are consistent with a role for lrrk2 in the activation of canonical wnt signaling bringing dvl proteins to cellular membranes." SIGNOR-202187 CALM3 protein P0DP25 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 9822657 t miannu "The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk." SIGNOR-266345 PRKD1 protein Q15139 UNIPROT CDH1 protein P12830 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 15695390 t gcesareni "Our study has identified e-cadherin as a novel substrate of pkd1, and phosphorylation of e-cadherin by pkd1 is associated with increased cellular aggregation and decreased cellular motility in prostate cancer." SIGNOR-133856 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Thr1031 ASSTDHQtPPTSPVQ 9606 24089523 t lperfetto "Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1" SIGNOR-202702 P2RY13 protein Q9BPV8 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257231 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-249409 DOK1 protein Q99704 UNIPROT ITGB1 protein P05556 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257669 TSHZ3 protein Q63HK5 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 19343227 t miannu "We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex.Endogenous HDAC1 was co-immunoprecipitated with FE65 when both FE65 and Teashirt3 were co-transfected (lane 4), but not when Teashirt3 or FE65 was omitted (lane 5 and 6), confirming that the association of HDAC1 with FE65 is dependent on, and mediated, by Teashirt3." SIGNOR-264814 DDX3X protein O00571 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 33627125 t miannu "DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2" SIGNOR-269202 2-(6-Bromo-1,3-benzodioxol-5-yl)-N-(4-cyanophenyl)-1-[(1S)-1-cyclohexylethyl]benzimidazole-5-carboxamide chemical CID:126961335 PUBCHEM F2RL1 protein P55085 UNIPROT "down-regulates activity" "chemical inhibition" -1 28445455 t "Simone Vumbaca" "The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling." SIGNOR-261119 NME1 protein P15531 UNIPROT NETO2 protein Q8NC67 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255166 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1A protein P50416 UNIPROT "down-regulates activity" binding 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267114 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser191 SRHAIMRsPQMVSAI 9606 18423204 t amattioni "Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt." SIGNOR-178258 OPTN protein Q96CV9 UNIPROT NEFL protein P07196 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259881 AKT proteinfamily SIGNOR-PF24 SIGNOR RNF11 protein Q9Y3C5 UNIPROT "down-regulates quantity" phosphorylation Thr135 DWLMRSFtCPSCMEP 9606 BTO:0003474 16123141 t gcesareni "Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity" SIGNOR-248085 FYN protein P06241 UNIPROT NPHS1 protein O60500 UNIPROT "up-regulates activity" phosphorylation 9606 12668668 t miannu "Fyn directly bound Nephrin via its SH3 domain, and Fyn directly phosphorylated Nephrin.|Similar to Fyn deletion, simultaneous deletion of Fyn and Yes reduced Nephrin phosphorylating activity." SIGNOR-279523 DYRK2 protein Q92630 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 17349958 t llicata "Here, we demonstrate that the dual-specificity tyrosine-phosphorylation-regulated kinase 2 (dyrk2) directly phosphorylates p53 at ser46. these findings indicate that dyrk2 regulates p53 to induce apoptosis in response to dna damage." SIGNOR-153544 PRKCZ protein Q05513 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser311 RTYETFKsIMKKSPF 9606 SIGNOR-C13 17183360 t gcesareni "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k)" SIGNOR-151432 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 9724739 t amattioni "Activated jnk phosphorylates p53" SIGNOR-59812 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 BTO:0000567 27126896 f Luana " Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation." SIGNOR-268017 ABCC9 protein O60706 UNIPROT "KATP channel" complex SIGNOR-C274 SIGNOR "form complex" binding 9606 28842488 t lperfetto "ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits." SIGNOR-262057 haloperidol chemical CHEBI:5613 ChEBI HTR2A protein P28223 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000331 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258520 TP53 protein P04637 UNIPROT G6PD protein P11413 UNIPROT "down-regulates activity" binding 9606 BTO:0001938;BTO:0001109 21336310 t miannu "The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer." SIGNOR-267468 NEK2 protein P51955 UNIPROT LRRC45 protein Q96CN5 UNIPROT "down-regulates activity" phosphorylation Ser661 VLAYVQAsPVRTLSP 9606 BTO:0000567 24035387 t miannu " Moreover, LRRC45 interacts with both C-Nap1 and rootletin and is phosphorylated by Nek2A at S661 during mitosis. After phosphorylation, both LRRC45 centrosomal localization and fiber-like structures are significantly reduced, which subsequently leads to centrosome separation. " SIGNOR-273707 ARHGAP20 protein Q9P2F6 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260472 SRC protein P12931 UNIPROT HLA-A protein P04439 UNIPROT unknown phosphorylation Tyr344 SDRKGGSyTQAASSD 9606 6304688 t lperfetto "Hla-a2 and hla-b7 antigens are phosphorylated in vitro by rous sarcoma virus kinase (pp60v-src) at a tyrosine residue encoded in a highly conserved exon of the intracellular domain." SIGNOR-25566 AURKA protein O14965 UNIPROT TIFA protein Q96CG3 UNIPROT "up-regulates activity" phosphorylation Thr9 TSFEDADtEETVTCL 9606 BTO:0001545 28069801 t miannu "Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. " SIGNOR-273551 AKT1 protein P31749 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Thr779 LYKEATStFTNITYR 9606 BTO:0000132 10896934 t gcesareni "A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta(3) for signaling molecules." SIGNOR-252552 AMPK complex SIGNOR-C15 SIGNOR SREBF1 protein P36956 UNIPROT down-regulates phosphorylation 9606 21892142 t lperfetto "Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation" SIGNOR-216564 MAP4K3 protein Q8IVH8 UNIPROT IQGAP1 protein P46940 UNIPROT "up-regulates activity" phosphorylation Ser480 NTVWKQLsSSVTGLT -1 31431460 t miannu "GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration. " SIGNOR-277479 EIF2B4 protein Q9UI10 UNIPROT EIF2S1 protein P05198 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269127 MLXIPL protein Q9NP71 UNIPROT ACACA protein Q13085 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000759 15496471 t Luana "The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS)" SIGNOR-267946 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser304 YEDDDYVsKKSKHEE 9606 10993082 t lperfetto "Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity" SIGNOR-82033 NMDA proteinfamily SIGNOR-PF56 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). In contrast, group I mGluRs increase the intracellular Ca2+ concentration via a classical Gq-mediated mechanism that triggers release from intracellular stores through IP3 receptors" SIGNOR-264931 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR PSIP1 protein O75475 UNIPROT down-regulates cleavage 9606 BTO:0001130 18708362 t miannu "Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75" SIGNOR-256469 "arachidonic acid" smallmolecule CHEBI:15843 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 1357097 t miannu "These results suggest that the activation of protein kinase c by both arachidonic acid and phorbol esters may play a role in the potentiation of glutamate exocytosis." SIGNOR-17809 RPS5 protein P46782 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262419 GUCY1A1 protein Q02108 UNIPROT GUCY1A3-B2 complex SIGNOR-C139 SIGNOR "form complex" binding 9606 10977868 t gcesareni "This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity" SIGNOR-244116 MAPK3 protein P27361 UNIPROT NCKIPSD protein Q9NZQ3 UNIPROT up-regulates phosphorylation 9606 14559906 t gcesareni "Spin90 was phosphorylated by erk1, which was, itself, activated by cell adhesion and platelet-derived growth factor. Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck" SIGNOR-118747 KIF1C protein O43896 UNIPROT RAB6C protein Q9H0N0 UNIPROT "up-regulates quantity" relocalization -1 20360680 t miannu "Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation." SIGNOR-266879 "ruxolitinib phosphate" chemical CHEBI:66917 ChEBI JAK2 protein O60674 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23061804 t miannu "Ruxolitinib is a selective inhibitor of Janus kinases (JAK) 1 and 2, which are involved in the signalling pathway of various cytokines and growth factors essential to haematopoiesis." SIGNOR-259171 GRM2 protein Q14416 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264349 AKT2 protein P31751 UNIPROT ADARB1 protein P78563 UNIPROT "down-regulates activity" phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 t miannu "AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively" SIGNOR-276196 MDFI protein Q99750 UNIPROT MYOG protein P15173 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 8797820 t 2 miannu "We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals." SIGNOR-240493 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 20679343 t "The effect has been demonstrated using P10636-8" lperfetto "Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3?" SIGNOR-167294 MAPK12 protein P53778 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR "form complex" binding 29681515 t apalma "Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated" SIGNOR-255981 EZH2 protein Q15910 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23836662 f miannu "We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes." SIGNOR-254146 SRC protein P12931 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t lperfetto "Further, we identified an interaction between fak's second pro-rich motif and endophilin a2's sh3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow src phosphorylation of endophilin a2 at tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. Together, these results suggest a regulatory mechanism of cell invasion whereby fak promotes cell-surface presentation of mt1-mmp by inhibiting endophilin a2-dependent endocytosis." SIGNOR-139150 GNA13 protein Q14344 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0004605 37392861 f "Marta Tosoni" "Western blots revealed that GNA13 knockdown and overexpression upregulated and inhibited the phosphorylation of ERKs, respectively. Moreover, GNA13 was the upstream of ERKs signaling to regulating ERKs phosphorylation level" SIGNOR-278049 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 15896703 t gcesareni "We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism." SIGNOR-137241 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 16046550 t "The effect has been demonstrated using Q01196-8" miannu "We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation." SIGNOR-138973 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 t gcesareni "Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway." SIGNOR-90525 GSK3B protein P49841 UNIPROT EIF2B1 protein Q14232 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175436 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT "up-regulates activity" phosphorylation Ser463 SPHNPISsVS 10090 9748228 t gcesareni "Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif, and also regulated Smad5 and Smad8 phosphorylation." SIGNOR-247674 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1120 QPLNPAPsRDPHYQD 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250623 BMP7 protein P18075 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 18719589 f "induction of mitochondrial biogenesis" fspada "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-180308 MAP4K1 protein Q92918 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 8824585 f gcesareni "These results demonstrated that the observed jnk1 activation was from hpk1 and not from other hpkl-associated kinases or from cross-reactive kinases precipitated by anti-hpk1 antibody." SIGNOR-43999 CDC42 protein P60953 UNIPROT USP6 protein P35125 UNIPROT up-regulates relocalization 9606 12612085 t miannu "In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin." SIGNOR-98935 methoxamine chemical CHEBI:6839 ChEBI ADRA1B protein P35368 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258447 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT "up-regulates activity" binding 9606 8548810 t lperfetto "The c-iaps associate with traf1 and traf3" SIGNOR-39527 STAT3 protein P40763 UNIPROT "PDAC-associated neural remodeling (PANR)" phenotype SIGNOR-PH233 SIGNOR up-regulates 9606 BTO:0000584 29269518 f miannu "Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell–promoting factor LIF supports PDAC-associated neural remodeling (PANR).Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling." SIGNOR-278038 NAT8L protein Q8N9F0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI "up-regulates quantity" "chemical modification" 9606 19524112 t miannu "The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA." SIGNOR-267523 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser428 EPAPVLSsPPPADVS 9606 SIGNOR-C17 15037602 t lperfetto "Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain." SIGNOR-123516 DIO2 protein Q92813 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI "up-regulates quantity" "chemical modification" 9606 34674502 t scontino "Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3." SIGNOR-266953 "GABA-A (a4-b2-d) receptor" complex SIGNOR-C326 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268593 dUMP(2-) smallmolecule CHEBI:246422 ChEBI dTMP(2-) smallmolecule CHEBI:63528 ChEBI "up-regulates quantity" "precursor of" 9606 21876188 t lperfetto "In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR." SIGNOR-268236 histamine smallmolecule CHEBI:18295 ChEBI HRH2 protein P25021 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257513 CDK1 protein P06493 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Thr135 TVQQHPStPKRHTVL 9606 BTO:0000007 21209322 t lperfetto "High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. we performed in vitro kinase assays using the tonebp/orebp peptide containing t135 as substrate (figure 3b, right panel) and various recombinant kinases. The peptide is strongly phosphorylated by cdk5, less by cdk1." SIGNOR-170882 FBXO31 protein Q5XUX0 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0002181 29343641 t miannu "FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2." SIGNOR-277380 HDAC1 protein Q13547 UNIPROT "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263839 RIMS3 protein Q9UJD0 UNIPROT RAB3C protein Q96E17 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 31679900 t miannu "N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle" SIGNOR-264380 MRPS18A protein Q9NVS2 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262334 Fibrinogen complex SIGNOR-C311 SIGNOR Fibrin complex SIGNOR-C317 SIGNOR "form complex" cleavage 9606 BTO:0000131 18544683 t lperfetto "A fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel.|Fibrin clots were formed as described for turbidity experiments, in which the fibrinogen, calcium, and polyP (when included) were preincubated for 15 minutes before adding thrombin." SIGNOR-263551 SPDEF protein O95238 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003160 22761428 f miannu "Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells." SIGNOR-255219 vorinostat chemical CHEBI:45716 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257947 SMAD1 protein Q15797 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 16621789 t gcesareni "These results identify a potential mechanism whereby bmp-2 antagonizes wnt signaling in osteoblast progenitors by promoting an interaction between smad1 and dvl-1 that restricts beta-catenin activation." SIGNOR-146131 PIM proteinfamily SIGNOR-PF34 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser166 SSRRRAIsETEENSD 9606 BTO:0000785 18467333 t gcesareni "Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt." SIGNOR-259433 MYO3A protein Q8NEV4 UNIPROT MYO3A protein Q8NEV4 UNIPROT "down-regulates activity" phosphorylation Thr908 INLAKGDtGEATRHA 9534 24214986 t Manara "We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work" SIGNOR-260923 PDPK1 protein O15530 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007;BTO:0001914 23887393 t gcesareni "Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency" SIGNOR-243519 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation 9606 19701891 t miannu "The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway)" SIGNOR-254361 Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270906 MAPKAPK3 protein Q16644 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser179 RRFRRSQsDCGELGD -1 15850461 t miannu "Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263081 TARS1 protein P26639 UNIPROT threonine smallmolecule CHEBI:26986 ChEBI "down-regulates quantity" "chemical modification" 9606 25824639 t miannu "Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding." SIGNOR-270502 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EGR1 protein P18146 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 21983014 f "In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression." SIGNOR-254258 PKA proteinfamily SIGNOR-PF17 SIGNOR PSMD2 protein Q13200 UNIPROT "up-regulates activity" phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu "Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B). " SIGNOR-273898 LCK protein P06239 UNIPROT CD5 protein P06127 UNIPROT "up-regulates activity" phosphorylation Tyr453 ASHVDNEySQPPRNS 9606 BTO:0000782 11298344 t lperfetto "Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck" SIGNOR-106799 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 SIGNOR-C17 8626512 t lperfetto "Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane." SIGNOR-41319 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" 9606 31908417 t miannu "The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs." SIGNOR-262251 NFKB1 protein P19838 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" binding 9606 9450761 t lperfetto "Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna" SIGNOR-55378 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR -1 10557092 t lperfetto "The physical association and phosphorylation of Cdc25C protein phosphatase by Prk. | Further studies reveal that His6-Prk phosphorylates Cdc25C on serine216, a residue also phosphorylated by Chk1 and Chk2. Together, these observations strongly suggest that Prk's role in mitosis is at least partly mediated through direct regulation of Cdc25C." SIGNOR-249030 TYK2 protein P29597 UNIPROT "ISGF3 complex" complex SIGNOR-C124 SIGNOR "up-regulates activity" phosphorylation 9606 15120645 t miannu "Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48)." SIGNOR-260148 PKA proteinfamily SIGNOR-PF17 SIGNOR SEC14L2 protein O76054 UNIPROT "up-regulates activity" phosphorylation Ser289 VQISRGSsHQVEYEI -1 15680919 t done miannu " Thus, phosphorylation of SPF at Ser-289 appears necessary for maximal stimulation of squalene monooxygenase activity in vitro and absolutely required for the stimulation of cholesterol synthesis in cell culture. the 2.3-fold activation of SPF by PKA was reduced by 60% in the S289A mutant, indicating that phosphorylation of this site contributes to the activation of SPF." SIGNOR-273788 SP1 protein P08047 UNIPROT SLC19A3 protein Q9BZV2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 15217784 f miannu "In transiently transfected Drosophila SL2 cells, both SP1 and SP3 transactivated the SLC19A3 minimal promoter in a dose-dependent manner and in combination demonstrated an additive stimulatory effect." SIGNOR-255215 hsa-miR-106a ncrna URS0000D5C047_9606 RNAcentral ATG16L1 protein Q676U5 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 9606 BTO:0003033 33505399 t Tiberia "Overexpression of miR-106a results in a significant decrease in ATG16L1 expression levels. miR-106a inhibitor significantly enhanced luciferase activity in HEK 293T cells confirming that ATG16L1 is a putative target of miR-106a." SIGNOR-281083 PHF6 protein Q8IWS0 UNIPROT UBTF protein P17480 UNIPROT down-regulates binding 9606 BTO:0001271 23229552 t miannu "We demonstrate that phf6 is a nucleolus, ribosomal rna promoter-associated protein. Phf6 directly interacts with upstream binding factor (ubf) through its phd1 domain and suppresses ribosomal rna (rrna) transcription by affecting the protein level of ubf" SIGNOR-200133 MLXIPL protein Q9NP71 UNIPROT ELOVL6 protein Q9H5J4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 27524233 t Luana "In this study, we clearly show that mouse and human Elovl6 are direct targets of ChREBP. " SIGNOR-267945 ADD1 protein P35611 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266037 PRKAA1 protein Q13131 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 t miannu "AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex" SIGNOR-276837 RAC1 protein P63000 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 18423204 t gcesareni "We show that rac1 activates jnk2 that in turn phosphorylates beta-catenin on critical residues and controls its nuclear translocation." SIGNOR-178265 TACR3 protein P29371 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257333 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT "up-regulates activity" phosphorylation Ser250 PTRPQEQsTGDTMGR -1 21775627 t lperfetto "Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition" SIGNOR-265009 HDAC8 protein Q9BY41 UNIPROT SMG5 protein Q9UPR3 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 16809764 t miannu "Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. " SIGNOR-272650 AURKA protein O14965 UNIPROT SPIN1 protein Q9Y657 UNIPROT "up-regulates activity" phosphorylation Ser109 LNKDERVsALEVLPD 9606 BTO:0000567 22258766 t miannu "The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function." SIGNOR-273549 CCNA2 protein P20248 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR "form complex" binding 9606 19056339 t lperfetto "We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2." SIGNOR-182566 LRAT protein O95237 UNIPROT "all-trans-retinyl ester" smallmolecule CHEBI:63410 ChEBI "up-regulates quantity" "chemical modification" 10090 18093970 t lperfetto "We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis" SIGNOR-265111 PAK6 protein Q9NQU5 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Thr158 HLVSRPStSSRRRAI 9606 BTO:0000007 23132866 t miannu "We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation." SIGNOR-276428 BDKRB2 protein P30411 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257281 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT "down-regulates activity" phosphorylation Ser260 SEGGADDsAEEGDLL 9606 15687492 t gcesareni "In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C." SIGNOR-133532 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 t lperfetto "Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation." SIGNOR-252768 PALB2 protein Q86YC2 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates binding 9606 19423707 t miannu "We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage." SIGNOR-185656 PPP1CA protein P62136 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates activity" dephosphorylation Ser127 PQHVRAHsSPASLQL 9606 21909427 t lperfetto "In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.|PP1A dephosphorylates endogenous YAP2 at serine 127." SIGNOR-276999 ABL1 protein P00519 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 22590567 t "inferred from 70% of family members" llicata "We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death." SIGNOR-269946 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120068 PRKCE protein Q02156 UNIPROT ALDH2 protein P05091 UNIPROT "up-regulates activity" phosphorylation Thr429 MQILKFKtIEEVVGR -1 28056995 t lperfetto "Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes." SIGNOR-271866 PRKDC protein P78527 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 20219974 t miannu "DNA-PK phosphorylates ERalpha at Ser-118.|Phosphorylation resulted in stabilization of ERalpha protein as inhibition of DNA-PK resulted in its proteasomal degradation." SIGNOR-279561 Temsirolimus chemical CHEBI:79699 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 21081844 t gcesareni "Temsirolimus, an inhibitor of mammalian target of rapamycin (mtor) complex 1, is approved for the treatment of metastatic renal cell carcinoma (rcc)." SIGNOR-169712 naltrexone chemical CHEBI:7465 ChEBI OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258946 AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t lperfetto "In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis" SIGNOR-251526 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser238 QGTPLTCsPNVENRG 9606 BTO:0005043 22798426 t miannu " Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation." SIGNOR-276101 RPS17 protein P08708 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262434 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257998 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258131 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI "down-regulates quantity" "chemical modification" 9606 33179964 t miannu "The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS)." SIGNOR-267317 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT "up-regulates activity" phosphorylation Ser717 LKEAEEEsSEDD 9606 BTO:0000007 11500362 t llicata "Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. " SIGNOR-250859 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT "up-regulates activity" phosphorylation Ser642 DSFGSLPsPKELSSF 9606 BTO:0002181 25452387 t miannu "The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. " SIGNOR-276444 CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI PGS1 protein Q32NB8 UNIPROT "up-regulates activity" "chemical activation" 9606 29034233 t lperfetto "After activation of PA by the CDP-DAG synthase TAMM41 (Kutik et al., 2008), the phosphatidylglycerol phosphate synthase (PGS1) catalyzes the committed step by converting CDP-DAG to phosphatidylglycerol phosphate (PGP)" SIGNOR-267024 CREB1 protein P16220 UNIPROT FST protein P19883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15130492 f lperfetto "MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA" SIGNOR-251714 retinal smallmolecule CHEBI:15035 ChEBI "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "precursor of" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265121 9b protein P59636 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates quantity by destabilization" 9606 25135833 f miannu "SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6." SIGNOR-260242 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2C protein P18825 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258915 CAMK2A protein Q9UQM7 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 15363394 f miannu "In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively." SIGNOR-268385 MAP3K7 protein O43318 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates activity" phosphorylation 9606 19136967 t miannu "Here we showed that TAK1 directly phosphorylated RCAN1 at two novel sites (serine 94 and -136), resulting in activation of calcineurin-NFAT signaling.|Indeed, low doses of RCAN1 facilitated calcineurin-nuclear factor of activated T cells signaling in the presence of TGF-\u03b2-activated kinase 1+TAB1 ( ), suggesting that TGF-\u03b2-activated kinase 1 augments calcineurin-nuclear factor of activated T cells signaling through RCAN1." SIGNOR-279535 PRKACA protein P17612 UNIPROT AANAT protein Q16613 UNIPROT "up-regulates activity" phosphorylation Thr31 PSCQRRHtLPASEFR -1 11336675 t miannu "AANAT1201 is phosphorylated at Thr-31 by PKA, it binds to 14-3-3. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations. " SIGNOR-250325 PYGL protein P06737 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI "down-regulates quantity" "chemical modification" 9606 3346228 t "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267949 GLUD1 protein P00367 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "down-regulates quantity" "chemical modification" 9913 11254391 t "Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate." SIGNOR-266917 STK4 protein Q13043 UNIPROT SAFB protein Q15424 UNIPROT "down-regulates activity" phosphorylation 9606 23893242 t miannu "In the present study, we demonstrate that the chromatin scaffold protein SAFB1 interacts with and is phosphorylated by MST1 and is a novel regulator of AR capable of integrating signaling between the AR and MST1 networks." SIGNOR-279296 PPP2R2B protein Q00005 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR "form complex" binding 9606 23454242 t gcesareni "[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity." SIGNOR-243507 BLOC-1 complex SIGNOR-C381 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 f lperfetto "BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton." SIGNOR-265940 SLC11A1 protein P49279 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 11909746 f "Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS)" SIGNOR-254037 KIF4A protein O95239 UNIPROT PRC1 protein O43663 UNIPROT "up-regulates activity" binding 9606 15297875 t miannu "These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins" SIGNOR-265988 HUWE1 protein Q7Z6Z7 UNIPROT ATOH1 protein Q92858 UNIPROT "down-regulates quantity" ubiquitination 9606 32336296 t miannu "Huwe1 ubiquitinates and degrades Atoh1, and robustly affects development of GNPs that express this transcription factor [ xref ].|This provides further evidence that phosphorylation of Atoh1 affects Huwe1-mediated degradation, and demonstrates that Huwe1 inhibits Atoh1 to affect cellular differentiation in multiple cell types." SIGNOR-278693 BRAF protein P15056 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity" relocalization 9606 19861538 f miannu "The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression." SIGNOR-251987 MAPK1 protein P28482 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates phosphorylation Ser50 GTLFQDPsFPAIPSA 9606 14993287 t lperfetto "Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo." SIGNOR-123079 TNF protein P01375 UNIPROT COMT protein P21964 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0000099 19291302 f "Regulation of expression" miannu "COMT gene expression is downregulated by TNFα in primary rat astrocytes at both protein and mRNA levels." SIGNOR-251963 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser20 LQYYYSSsEDEDSDH 9606 16717095 t lperfetto "Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2." SIGNOR-146833 GTP smallmolecule CHEBI:15996 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR "form complex" binding 9606 8722040 t miannu "The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions." SIGNOR-270812 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr74 SAHARKEtEFLRLKR 9606 12493777 t lperfetto "We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo" SIGNOR-96687 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" phosphorylation Ser466 SKASSRRsSFSMEEG 10090 23599343 t "This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor." SIGNOR-255315 GABRA6 protein Q16445 UNIPROT "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263771 glycine smallmolecule CHEBI:15428 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264745 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 9606 9840932 t lperfetto "The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk4" SIGNOR-217264 LDHB protein P07195 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "down-regulates quantity" "chemical modification" 9606 24929216 t lperfetto "Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase." SIGNOR-267656 TBK1 protein Q9UHD2 UNIPROT VPS37C protein A5D8V6 UNIPROT "down-regulates activity" phosphorylation 9606 21270402 t miannuccelli "We have identified that TBK1 may target and phosphorylate VPS37C, a structural component of ESCRT-I complex, and serve as a ratelimiting factor in the control of PTAP-dependent (HIV-1, MLV/p6, and EIAV/PTAP), but not PPPY-dependent (MLV, EIAV/PPPY) retrovirus budding, independent of its role in IFN-I signaling." SIGNOR-279768 HSPA5 protein P11021 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT "down-regulates activity" binding 9606 31226023 t miannu "In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation." SIGNOR-260164 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 23290138 t "Simone Vumbaca" "Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions" SIGNOR-255646 GRM8 protein O00222 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264939 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259706 FBXW8 protein Q8N3Y1 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0001109 phosphorylation:Thr286 EEVDLACtPTDVRDV 17205132 t miannu "We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8." SIGNOR-271624 NFIX protein Q14938 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268907 MAPK11 protein Q15759 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 20820849 t gcesareni "Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis." SIGNOR-167848 CTBP1 protein Q13363 UNIPROT VDR protein P11473 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 18485278 f miannu "We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells." SIGNOR-255178 FLI1 protein Q01543 UNIPROT GP6 protein Q9HCN6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001549 12359731 f miannu "Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter." SIGNOR-254157 MAPK8 protein P45983 UNIPROT CDC25B protein P30305 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser101 ASESSLSsESSESSD 9606 BTO:0000567 21807946 t miannu " Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104)." SIGNOR-276352 WNT9A protein O14904 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni "we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase" SIGNOR-195975 ZBTB20 protein Q9HC78 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 23776228 t miannu "Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses α-fetoprotein gene transcription in liver." SIGNOR-266867 Ub:E2 complex SIGNOR-C497 SIGNOR "RING E3 ligase" proteinfamily SIGNOR-PF106 SIGNOR "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270944 creatine smallmolecule CHEBI:16919 ChEBI CKM protein P06732 UNIPROT "up-regulates activity" "chemical activation" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265784 MRPS22 protein P82650 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261434 FAM83D protein Q9H4H8 UNIPROT CSNK1A1L protein Q8N752 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273757 WNT7A protein O00755 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131903 HDAC1 protein Q13547 UNIPROT DNMT1 protein P26358 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23242655 f "Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells." SIGNOR-254028 FBXO31 protein Q5XUX0 UNIPROT "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR "up-regulates activity" binding 9606 BTO:0002181 29343641 t miannu "FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2." SIGNOR-277381 NARS2 protein Q96I59 UNIPROT tRNA(Asn) smallmolecule CHEBI:29172 ChEBI "down-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270461 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Thr329 RALTEDStQTSDTAT -1 7836371 t gcesareni "Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation." SIGNOR-249664 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176817 BLK protein P51451 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr288 YETADGGyMTLNPRA -1 8756631 t lperfetto "To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation." SIGNOR-249311 PPP2R5D protein Q14738 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR "form complex" binding 9606 23454242 t gcesareni "[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity." SIGNOR-243439 RPL5 protein P46777 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 25301064 t miannu "We report that rpl5 and rpl11 can also enhance the transcriptional activity of a p53 homolog tap73" SIGNOR-205517 RORA protein P35398 UNIPROT PCP4 protein P48539 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001011 19381306 t miannu "RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice." SIGNOR-266848 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2G2 protein P60604 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271344 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT "up-regulates activity" phosphorylation -1 9155018 t "These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways" SIGNOR-253011 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159369 UDP-D-glucose smallmolecule CHEBI:18066 ChEBI P2RY14 protein Q15391 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257562 TLR4 protein O00206 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." SIGNOR-261928 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation 9606 16082221 t gcesareni "Atm directly and indirectly induces mdm2 and mdmx phosphorylation, resulting in decreased activity and stability of these proteins. We recently provided a mechanism for the reduced stability of mdm2 and mdmx by showing that atm-dependent phosphorylation lowers their affinity for the deubiquitinating enzyme hausp." SIGNOR-139403 JAK2 protein O60674 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates phosphorylation Tyr738 WDQEAQIyELVAQTV 9606 20098430 t gcesareni "We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1" SIGNOR-163557 C4B protein P0C0L5 UNIPROT "C3 convertase complex" complex SIGNOR-C310 SIGNOR "form complex" binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 t "complement C4b fragment:PRO_0000042703" lperfetto "However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex" SIGNOR-263398 SRC protein P12931 UNIPROT CTNND2 protein Q9UQB3 UNIPROT "up-regulates activity" phosphorylation Tyr1157 SRKDYETyQPFQNST 9606 24412473 t miannu "Furthermore, according to our data from immunoprecipitation to py20 antibody, c-Src can phosphorylate delta-catenin on Y1073, Y1176, Y1179 and Y1112, with the predominant sites being Y1073, Y1112 and Y1176.|Interestingly, we found that c-Src can increase the stability of delta-catenin in MEF cells." SIGNOR-278327 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser85 GSEGDSEsGEEEELG -1 2046671 t llicata "Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Mutation of serine 85 alone had a smaller but significant effect on phosphorylation that may be due to alteration in the protein kinase recognition site." SIGNOR-250957 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18509061 t gcesareni "We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf." SIGNOR-178713 ALK protein Q9UM73 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates activity" phosphorylation 9606 35640677 t miannu "NPM-ALK also directly phosphorylates HES1 protein." SIGNOR-280181 DNMT1 protein P26358 UNIPROT GAD1 protein Q99259 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19029285 f miannu "induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation." SIGNOR-254574 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273054 CX3CL1 protein P78423 UNIPROT CX3CR1 protein P49238 UNIPROT up-regulates binding 9606 11432858 t gcesareni "Fractalkine/cx3cl1 is a membrane-tethered chemokine that functions as a chemoattractant and adhesion protein by interacting with the receptor cx3cr1." SIGNOR-109135 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser358 MHPYQGRsGCSSQSI -1 28130417 t lperfetto "Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3." SIGNOR-264871 POMT complex SIGNOR-C372 SIGNOR DAG1 protein Q14118 UNIPROT "up-regulates activity" glycosylation 9606 BTO:0000007 14699049 t miannu "we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O-mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O-mannosylation is complex. Further, protein O-mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain." SIGNOR-265430 LCK protein P06239 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" phosphorylation Tyr354 SSNQELIyEGRRLVL 9606 BTO:0002181 28618271 t miannu "The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. " SIGNOR-276724 Ub:E2 complex SIGNOR-C497 SIGNOR RNF113B protein Q8IZP6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271193 SPC25 protein Q9HBM1 UNIPROT MYH9 protein P35579 UNIPROT "up-regulates activity" binding 9606 BTO:0000949 39488790 t miannu "This study demonstrates that SPC25 acts as a molecular scaffold, mediating SPC25/RIOK1/MYH9 complex formation and triggering the RIOK1‐mediated phosphorylation of MYH9 at Ser1943.Taken together, these results suggested that SPC25 increases MYH9 phosphorylation at Ser1943, enhancing the nuclear accumulation of MYH9 and consequently modulating the transcription of CTNNB1." SIGNOR-278894 CDH20 protein Q9HBT6 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265859 SUFU protein Q9UMX1 UNIPROT SAP18 protein O00422 UNIPROT up-regulates binding 9606 11960000 t gcesareni "Here we report that the mouse homolog of su(fu) [msu(fu)] specifically interacts with sap18, a component of the msin3 and histone deacetylase complex. In addition, we demonstrate that msu(fu) functionally cooperates with sap18 to repress transcription by recruiting the sap18-msin3 complex to promoters containing the gli-binding element." SIGNOR-117311 AKT1 protein P31749 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 t flangone "Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG." SIGNOR-252545 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR WNK1 protein Q9H4A3 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 23387299 t miannu "CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms." SIGNOR-272100 WNK1 protein Q9H4A3 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates phosphorylation Thr1048 YQEKVHMtWTKDKYM 9606 BTO:0000938 BTO:0000142 19665974 t gcesareni "We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases." SIGNOR-187560 MAP3K13 protein O43283 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 11726277 t gcesareni "Lzk directly phosphorylated and activated mkk7." SIGNOR-112349 MAP3K7 protein O43318 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 9606 9480845 f lperfetto "Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene...[]...These Results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway" SIGNOR-55710 F2RL1 protein P55085 UNIPROT TNFRSF12A protein Q9NP84 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254837 COL1A1 protein P02452 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates binding 9606 9659900 t gcesareni "We report that the collagens serve as ligands for the previously orphan family of discoidin domain-containing receptor-like tyrosine kinases." SIGNOR-58779 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 17197020 t gcesareni "We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of ca2+ influx through trpv6 ca2+ channels in hek293 cells. Co-transfection with src led to tyrosine phosphorylation of trpv6 which could be dephosphorylated by ptp1b. y161/162 are essential for tyrosine phosphorylation-dependent modulation of trpv6-mediated ca2+ entry." SIGNOR-151711 EGR3 protein Q06889 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000848 20506119 f miannu "In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2." SIGNOR-253882 DFFB protein O76075 UNIPROT DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 BTO:0000661 9422513 f "Cleavage of ICAD/DFF-45" amattioni "The specific cleavage of icad/dff-45 by caspase-3 relieves the inhibition and promotes the endonuclease activity of cad, resulting in apoptotic dna fragmentation" SIGNOR-54358 MYC protein P01106 UNIPROT UBTF protein P17480 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000539 15282543 t lperfetto "MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter." SIGNOR-269644 PAK1 protein Q13153 UNIPROT MAP3K1 protein Q13233 UNIPROT "up-regulates activity" phosphorylation Ser67 RQLRKVRsVELDQLP 9606 BTO:0000007 12228228 t lperfetto "We found that pak1 phosphorylated mekk1 on serine 67 of its amino-terminal regulatory domain. mekk1 activity was increased modestly following pak phosphorylation." SIGNOR-236006 AKT1 protein P31749 UNIPROT ZRANB1 protein Q9UGI0 UNIPROT "up-regulates activity" phosphorylation Thr117 QRRTRSPtESPQSSG 9606 BTO:0000007 29748601 t miannu "Our findings also identify an essential role for activation of Trabid by AKT-mediated phosphorylation at Ser78/Thr117 in negatively regulating Twist1 signaling, which further provides insights into the mechanisms by which Trabid regulates Twist1 ubiquitination." SIGNOR-273484 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT "up-regulates activity" phosphorylation Ser330 AGSTISNsHAQPFDF 10116 BTO:0000067 12270943 t lperfetto "We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation)." SIGNOR-249331 TBK1 protein Q9UHD2 UNIPROT IKBKB protein O14920 UNIPROT up-regulates binding 9606 14743216 t fstefani "A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway." SIGNOR-121576 ABL2 protein P42684 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 t lperfetto "Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised" SIGNOR-146589 BRAF protein P15056 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates quantity" phosphorylation Thr219 AEHQYFMtEYVATRW 9606 29483645 t miannu "Our data indicate that oncogenic BRAF increases ERK5 protein level, phosphorylation at several residues and kinase activity.|Overexpression of oncogenic BRAF induced ERK5 phosphorylation at Thr218 and Tyr220, although to a lower level than that induced by MEK5DD." SIGNOR-278352 FGD2 protein Q7Z6J4 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260552 DYRK3 protein O43781 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "down-regulates activity" phosphorylation Ser1330 PAFGRVSsPPNAMMS 9606 BTO:0000578 31066068 t miannu "Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity." SIGNOR-275451 APIP protein Q96GX9 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 15262985 t acerquone "Taken together, these results suggest that apip functions to inhibit muscle ischemic damage by binding to apaf-1 in the apaf-1/caspase-9 apoptosis pathway." SIGNOR-126797 AURKA protein O14965 UNIPROT PHLDA1 protein Q8WV24 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser95 PLCLLRVsLLCALRA 9606 BTO:0006218 21807936 t miannu "Aurora A directly phosphorylates PHLDA1 leading to its degradation. Aurora A phosphorylates PHLDA1 at Ser 98." SIGNOR-273545 SRC protein P12931 UNIPROT PRKAA2 protein P54646 UNIPROT "down-regulates activity" phosphorylation Tyr179 TSCGSPNyAAPEVIS 9606 BTO:0002181 34673141 t miannu "We show here that Src signaling leads to direct phosphorylation of the AMPK-α subunit on a novel site, tyrosine 179, resulting in suppression of AMPK-T172 phosphorylation and autophagy upon integrin-mediated cell adhesion." SIGNOR-277573 PRKDC protein P78527 UNIPROT NR3C1 protein P04150 UNIPROT unknown phosphorylation Ser508 QQATTGVsQETSENP -1 9038175 t lperfetto "Phosphorylation of the GR fusion protein by DNA-PK mapped to a single site, Ser-527. This site occurs adjacent the GR nuclear localization sequence between the DNA and ligand binding domains of GR, and thus its phosphorylation, if confirmed, has the potential to affect receptor function in vivo." SIGNOR-248965 PLK1 protein P53350 UNIPROT ESPL1 protein Q14674 UNIPROT "down-regulates activity" phosphorylation Thr1363 AGPHVPFtVFEEVCP 9606 BTO:0002181 17974570 t miannu "Although mutation of serine 1126 and threonine 1346 to alanine had no effect (lanes 2 and 5), additional mutation of threonine 1363 and serine 1399 rendered separase almost completely resistant to phosphorylation (lane 3). Serine 1399 seems to be the one residue within this large separase fragment that is most efficiently phosphorylated by polo-like kinase, because a corresponding point mutation was sufficient to reduce the labeling by 80% compared with wild type (lane 6)." SIGNOR-276083 SKP2 protein Q13309 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0003725 11439327 t miannu "We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line." SIGNOR-272575 PRPS2 protein P11908 UNIPROT "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "down-regulates quantity" "chemical modification" 9606 16939420 t miannu "PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP." SIGNOR-267081 NRXN1 protein P58400 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626543 t miannu "The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites" SIGNOR-265453 IRX1 protein P78414 UNIPROT SPON1 protein Q9HCB6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002392 20440264 f Luana "We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed." SIGNOR-261669 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203528 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MAP3K8 protein P41279 UNIPROT down-regulates binding 9606 22435554 t lperfetto "Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek" SIGNOR-216289 PTTG1 protein O95997 UNIPROT S100A4 protein P26447 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002430 19351864 f miannu "PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR." SIGNOR-255070 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000527 21419810 t lperfetto "In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer" SIGNOR-172886 AKT1 protein P31749 UNIPROT IMPDH2 protein P12268 UNIPROT "up-regulates activity" phosphorylation 9534 BTO:0004055 10930578 t Federica "Further, we have demonstrated an in vivo association of IMPDH and PKB/Akt by co‐immunoprecipitation from COS cells expressing a constitutively active form of PKB/Akt. Finally, we were able to show that this constitutively active PKB/Akt could phosphorylate IMPDH in vitro. Thus, the interplay between PKB/Akt and IMPDH reported here could suggest that PKB/Akt activation leads to IMPDH type II activation which in turn prepares the cell for entry into S phase." SIGNOR-261262 PLK1 protein P53350 UNIPROT CEP192 protein Q8TEP8 UNIPROT "up-regulates activity" phosphorylation Thr44 GLPVAVStLARDRSS 9606 BTO:0000007 26012549 t miannu "In the presence of AurA binding, Plk1 preferentially phosphorylates and interacts with the T44 motif of Cep192 through the “self-priming and binding” mechanism" SIGNOR-266405 SRC protein P12931 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15695828 t llicata "These data indicate that pyk2 activation via phosphorylation at tyr-402 requires ?V?3 Ligation and src activity." SIGNOR-133870 EIF5B protein O60841 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI "up-regulates activity" relocalization 9606 30551605 t lperfetto "EIF5B was also shown to deliver Met-tRNAi into the P-site of the ribosome in an eIF2-independent translation initiation mechanism utilized by the CSFV and HCV IRESs " SIGNOR-269119 AIFM2 protein Q9BRQ8 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0003000 12135761 f miannu "The PRG3 gene is a potential p53 target gene in a p53‐dependent apoptosis pathway. These results clearly indicate that the ectopic expression of PRG3 induces apoptosis." SIGNOR-261809 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates phosphorylation Ser187 RIMEKADsNKTRIDE 9606 BTO:0000938 18171919 t llicata "Phosphorylation of snap-25 at ser187 mediates enhancement of exocytosis by a phorbol ester in ins-1 cells." SIGNOR-160313 FANCM protein Q8IYD8 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates relocalization 9606 20372056 t gcesareni "The enzymatic activity of fan cm is then required to remodel and stabilize the fork to allow topbp1 access to activate atr , in a 9-1-1-independent manner." SIGNOR-164765 XL765 chemical CHEBI:71958 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207881 AKT1 protein P31749 UNIPROT TSC complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000944 12150915 t lperfetto "We have shown thataktregulates the tsc1-tsc2 complex by directly phosphorylating tsc2. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1akt has been shown to directly phosphorylate two sites on tsc2 (s939 and t1462 on the full-length human protein), which are conserved and phosphorylated in drosophila tsc2, and is likely to phosphorylate two or three additional sites (s981 and s1130/s1132)." SIGNOR-235628 TARS1 protein P26639 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 25824639 t miannu "Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding." SIGNOR-270504 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT "down-regulates activity" phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 t miannu "We show that TRPC5 channels may become directly phosphorylated by PKA at serine residues 794 and 796, and that this phosphorylation abolishes the receptor-operated nonselective cation current mediated by TRPC5 channels in HEK-293 cells." SIGNOR-276339 RASGRF2 protein O14827 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260573 ADRB2 protein P07550 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257081 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161658 FASTKD2 protein Q9NYY8 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu "DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU." SIGNOR-261227 HSD3B2 protein P26439 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000048 2243100 t lperfetto "Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens." SIGNOR-268634 ADRA1B protein P35368 UNIPROT GNA11 protein P29992 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 1334487 t "In this report, we demonstrate that in transfected cos-7 cells Gal4 and Ga16, like Gaq and Ga11, can activate PIPLC j3l and that all three al-ARs, alA, alB and alC, can activate endogenous PI-PLC by coupling to Gaq or Ga11." SIGNOR-278122 PRKCQ protein Q04759 UNIPROT WIPF1 protein O43516 UNIPROT "up-regulates activity" phosphorylation Ser488 RNESRSGsNRRERGA -1 12504004 t lperfetto "TCR engagement also causes PKCtheta-dependent phosphorylation of WIP, causing the disengagement of WASP from the WIP-WASP complex, thereby releasing it from WIP inhibition. These results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation. | These results suggest that phosphorylation at S488 disrupts WIP binding to WASP." SIGNOR-249181 MAPK3 protein P27361 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t llicata "Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro" SIGNOR-173413 NRF1 protein Q16656 UNIPROT RETREG3 protein Q86VR2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23939472 f miannu "We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons." SIGNOR-261367 TFEB protein P19484 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 33176151 f lperfetto "Notably, TFEB regulates genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (for example, Cd36 and Fabps), and the β-oxidation of FFA in mitochondria (for example, Cpt1, Crat, Acadl, Acads and Hdad) and in peroxisomes (Cyp4a genes)." SIGNOR-276707 IL6 protein P05231 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12859689 f miannu "CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA." SIGNOR-252220 PRKAA1 protein Q13131 UNIPROT STIM1 protein Q13586 UNIPROT "down-regulates activity" phosphorylation Ser257 GLHRAEQsLHDLQER 10090 BTO:0000452 31381180 t miannu "STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE" SIGNOR-277299 CORT protein O00230 UNIPROT GHSR protein Q92847 UNIPROT up-regulates binding 9606 12161511 t gcesareni "In human tissues cst-14 as well as cst-17 but not ss-14 bind the gh secretagogue receptor (ghs-r)." SIGNOR-91134 RTN4 protein Q9NQC3 UNIPROT LINGO1 protein Q96FE5 UNIPROT up-regulates binding 9606 BTO:0000938 15694321 t flangone "Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1," SIGNOR-133752 ziprasidone chemical CHEBI:10119 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258504 RPS6KA5 protein O75582 UNIPROT ATXN1 protein P54253 UNIPROT "up-regulates quantity by stabilization" phosphorylation 9606 23719381 t miannu "In summary, the data from the cell based screen, biochemical studies and genetic interactions strongly suggest that MSK1 phosphorylates ATXN1 and regulates its stability." SIGNOR-279109 CDKN1B protein P46527 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "down-regulates activity" binding 9606 17409098 t lperfetto "P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e)." SIGNOR-217505 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Thr86 YTLSRAQtVVVEYTH -1 19264966 t miannu "The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites." SIGNOR-276135 NOD1 protein Q9Y239 UNIPROT ATG16L1 protein Q676U5 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19898471 t miannu "By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease." SIGNOR-252406 PAX3 protein P23760 UNIPROT FGFR4 protein P22455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 t "FGFR4 is a transcriptional target of PAX3 and the PAX3-FOXO1 fusion protein found in ARMS." SIGNOR-251572 DNAJB12 protein Q9NXW2 UNIPROT HSPA8 protein P11142 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21148293 t miannu "JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex" SIGNOR-271491 PBK protein Q96KB5 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation 9606 17631144 t miannu "Phosphorylation of ELK1 or ERK2 increased dramatically compared with controls and suggested that TOPK or ERK2 could enhance ERK2 or TOPK kinase activity by respective and mutual phosphorylation of each other.|The results indicated that active TOPK could strongly phosphorylate ERK2 and very weakly phosphorylate ERK1." SIGNOR-278417 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation 9606 12832467 t lperfetto "Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk" SIGNOR-102645 SHOX protein O15266 UNIPROT NPPB protein P16860 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17881654 f miannu "The ability of SHOX to transactivate the NPPB endogenous promoter was demonstrated in luciferase reporter assays using serial deletions of the NPPB promotor region. Binding of SHOX to the NPPB promoter was also demonstrated in vivo by chromatin fixation and immunoprecipitation. We also demonstrate the lack of promoter activation in two SHOX mutants from patients with Leri-Weill syndrome." SIGNOR-255138 YES1 protein P07947 UNIPROT CDK4 protein P11802 UNIPROT down-regulates phosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 18479465 t lperfetto "We purified tyrosine 17 kinases from hela cells and found that the src family non-receptor tyrosine kinase c-yes contributes a large fraction of the tyrosine 17 kinase activity in hela lysatesthis site is equivalent to tyrosine 15 of cyclin dependent kinase 1, which undergoes inhibitory phosphorylation by wee1 and myt1" SIGNOR-178624 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 4188963 t dermatitis gcesareni SIGNOR-251705 APOBEC3F protein Q8IUX4 UNIPROT "Clearance_of_foreign intracellular_DNA" phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto "The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24)." SIGNOR-261327 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates activity" cleavage 9606 BTO:0000567 10882063 t gcesareni "... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases." SIGNOR-254334 RBM10 protein P98175 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0001938 30403180 f irozzo "Osteosarcoma is the most common malignant bone tumor with high incidence in adolescence and poor prognosis. RBM10, a member of RBPs, was reported to be a tumor suppressor in many kinds of cancers. The results showed that U2OS cell growth was significantly inhibited when RBM10 is overexpressed as compared with negative control cells." SIGNOR-259149 POU5F1 protein Q01860 UNIPROT ID2 protein Q02363 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254937 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 18697834 t "Simone Vumbaca" "Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells" SIGNOR-255650 "NMDA receptor_2D" complex SIGNOR-C350 SIGNOR CAMK2A protein Q9UQM7 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11052931 t miannu "The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD" SIGNOR-264217 CDK1 protein P06493 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Thr609 SAAQLAStPFHKLPV 9606 16760428 t gcesareni "The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609" SIGNOR-147065 ICAM1 protein P05362 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 23994464 f apalma "Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. After finding the place for transmigration, neutrophils migrate to the interstitium through transcellular or paracellular routes and begin chemotaxing towards the site of infection/inflammation within the perivascular and interstitial space." SIGNOR-255042 RIMS3 protein Q9UJD0 UNIPROT CACNA1D protein Q01668 UNIPROT "up-regulates activity" binding 9606 BTO:0005822 28642685 t miannu "Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells." SIGNOR-264357 FOXO proteinfamily SIGNOR-PF27 SIGNOR IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260088 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 t milica "Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects." SIGNOR-202036 CSNK2A1 protein P68400 UNIPROT DEK protein P35659 UNIPROT up-regulates phosphorylation Ser32 MPGPREEsEEEEDED 9606 15199154 t amattioni "Dek is phosphorylated by the protein kinase ck2 in vitro and in vivo on ser32" SIGNOR-125912 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000007 16964285 t amattioni "Casp8 induces apoptosis by directly activating casp3." SIGNOR-256458 HNuRF complex SIGNOR-C448 SIGNOR EN2 protein P19622 UNIPROT "up-regulates quantity by expression" 9606 14609955 f miannu "Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. ) ChIP assays localize hNURF specifically to engrailed-1 (en-1) and engrailed-2 (en-2) promoters." SIGNOR-268840 "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI "up-regulates quantity" relocalization 9606 18790874 t brain lperfetto "GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)" SIGNOR-263811 Ub:E2 complex SIGNOR-C497 SIGNOR WWP2 protein O00308 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271288 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Ala36 PESKATNaTLDPRSF -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus" SIGNOR-263575 "C3 convertase complex" complex SIGNOR-C310 SIGNOR C3 protein P01024 UNIPROT "up-regulates activity" cleavage Arg671 QPAARRRrSVQLTEK 31331124 t lperfetto "This forms the C4b2a complex, which is a classical pathway C3 convertase. C4b2a cleaves C3, which is the central component of the complement cascade, to C3a, and anaphylatoxin, and C3b results in the activation of the lytic pathway" SIGNOR-263449 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2A protein P28223 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257521 MAP3K20 protein Q9NYL2 UNIPROT MAP2K7 protein O14733 UNIPROT "up-regulates activity" phosphorylation 9606 12220515 t gcesareni "This result suggests that ZAK activates JNK/SAPK mediated by downstream target, MKK7" SIGNOR-243342 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1100 QGCRRRHsSETFSST 9606 17360977 t lperfetto "Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223" SIGNOR-235675 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates activity" dephosphorylation Tyr66 LHQEDNDyINASLIK -1 11506178 t "Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions." SIGNOR-248423 ATM protein Q13315 UNIPROT FANCI protein Q9NVI1 UNIPROT unknown phosphorylation Ser730 LDKSADFsQSTSIGI 9606 BTO:0000007 17412408 t "Three phosphorylation sites were detected in a human KIAA1794 protein: S730, T952, S1121, and two other sites in the mouse protein S555, T558. We renamed the KIAA1794 protein as FANCI, since, as shown below, the locus encoding this protein is mutated in an individual with Fanconi anemia complementation group I" SIGNOR-255590 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249004 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Lys32 RARRPESkATNATLD -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus" SIGNOR-263573 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000590 20679343 t lperfetto "Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3?" SIGNOR-167286 PRKCG protein P05129 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 BTO:0000007 14576165 t lperfetto "A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis." SIGNOR-249238 RPS6KA1 protein Q15418 UNIPROT NR4A3 protein Q92570 UNIPROT unknown phosphorylation Ser376 GRRGRLPsKPKSPLQ 9606 BTO:0000007 16223362 t lperfetto "We have established that two related proteins, Nurr1 and Nor1, are also phosphorylated on the equivalent site by RSK in cells in response to mitogenic stimulation. | Similar to Nur77, when FLAG€“Nor1 was expressed in HEK-293 cells, its phosphorylation on Ser377 was stimulated by both PMA and EGF" SIGNOR-249297 PCNA protein P12004 UNIPROT "DNA polymerase delta" complex SIGNOR-C376 SIGNOR "up-regulates activity" binding 9534 BTO:0004055 12930972 t lperfetto "Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA)." SIGNOR-265511 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 15818404 t gcesareni "Akt/pkb ser129 is phosphorylated by ck2 in vitro and in vivo;(4) such a phosphorylation of activated akt/pkb correlates with a further increase in catalytic activity." SIGNOR-135203 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser295 LQASVPGsVPGVLGP 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-250730 SMAD4 protein Q13485 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" 9606 BTO:0000599 10890911 f lperfetto "Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity" SIGNOR-229311 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22863277 t miannu "Lats1/2 inhibit yap by direct phosphorylation at s127, which results in yap binding to 14-3-3 and cytoplasmic sequestration" SIGNOR-198514 ATF4 protein P18848 UNIPROT YARS2 protein Q9Y2Z4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269432 FABP7 protein O15540 UNIPROT "Fatty acid" stimulus SIGNOR-ST19 SIGNOR "up-regulates quantity" relocalization 9606 28457600 t miannu "Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs)." SIGNOR-264461 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR ERBB4 protein Q15303 UNIPROT "up-regulates activity" binding 9606 25287865 t miannu "The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2" SIGNOR-277671 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273064 XBP1 protein P17861-2 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 9606 15598891 f miannu "ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER." SIGNOR-260186 MTNR1A protein P48039 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257101 CDKN2A protein P42771 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR down-regulates binding 9606 8891723 t luana "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." SIGNOR-259810 PRKACA protein P17612 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262751 MAGEL2 protein Q9UJ55 UNIPROT TRIM27 protein P14373 UNIPROT "up-regulates activity" binding 9606 23452853 t miannu "MAGE proteins are a family of proteins that contain a conserved domain known as the MAGE homology domain. Recently, we showed that MAGE proteins function biochemically to bind to and enhance the activity of E3 RING ubiquitin ligases. The E3 RING ubiquitin ligase TRIM27 was identified as a major binding partner of MAGE-L2." SIGNOR-253513 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2638 VAGQIRAtQQQHDFT 9606 BTO:0000773 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249159 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Pro54 NPNDKYEpFWEDEEK -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263578 MYOD1 protein P15172 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001103 16275751 f "andrea cerquone perpetuini" "Together, these results support the notion that Myf5 functions toward myoblast proliferation, whereas MyoD prepares myoblasts for efficient differentiation." SIGNOR-255417 DACH2 protein Q96NX9 UNIPROT MYOG protein P15173 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165 17075071 t Luana "We confirmed Dach2 is a Mgn transcriptional repressor that mediates HDAC-dependent regulation by (i) overexpressing Dach2 in myotubes harboring the 133-bp Mgn promoter and (ii) rescuing TSA-mediated Mgn repression by Dach2 knockdown." SIGNOR-261579 PKA proteinfamily SIGNOR-PF17 SIGNOR SYN3 protein O14994 UNIPROT "down-regulates activity" phosphorylation 9606 10571231 t miannu "Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation" SIGNOR-264110 ULK2 protein Q8IYT8 UNIPROT DENND3 protein A2RUS2 UNIPROT "up-regulates activity" phosphorylation Ser490 ELAPRNSsLRLTDTA 9606 25925668 t lperfetto "ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12." SIGNOR-264733 SGCB protein Q16585 UNIPROT DGC complex SIGNOR-C217 SIGNOR "form complex" binding 9606 15117830 t apalma "The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink)." SIGNOR-255986 fulvestrant chemical CHEBI:31638 ChEBI ESR2 protein Q92731 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000150 12113237 t miannu "Fulvestrant (Faslodex, formerly ICI 182,780) is a potent steroidal antiestrogen that mediates its effects by estrogen receptor downregulation." SIGNOR-259304 ANG protein P03950 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252280 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1195 HGHVSDAsISLGESV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262905 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000007 19126544 t lperfetto "Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1." SIGNOR-236030 CD19 protein P15391 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 10090 25673924 t lperfetto "CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades." SIGNOR-242900 BIRC3 protein Q13489 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates ubiquitination 9606 20682767 t gcesareni "Ciap1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate nik for degradation." SIGNOR-167298 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys365 SLASQATkDGKKDKK -1 19240029 t miannu "S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP." SIGNOR-272745 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT "up-regulates activity" phosphorylation Tyr700 EGEEDTEyMTPSSRP 10090 11997497 t "Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation." SIGNOR-251305 PRKDC protein P78527 UNIPROT PRKAG1 protein P54619 UNIPROT "up-regulates activity" phosphorylation Thr284 LKCYLHEtLETIINR -1 31983282 t miannu "PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity. " SIGNOR-277504 SIRT7 protein Q9NRC8 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" deacetylation Lys19 TGGKAPRkQLATKAA 22722849 t lperfetto "SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression." SIGNOR-275872 ERG protein P11308 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002398 22140532 t miannu "ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability." SIGNOR-259408 LCK protein P06239 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr42 DSMKDEEyEQMVKEL 14534291 t lperfetto "Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors" SIGNOR-249374 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Thr317 EDATLEEtLVKKKKK 9606 20573420 t lperfetto "Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation." SIGNOR-166333 CREBBP protein Q92793 UNIPROT IFNAR2 protein P48551 UNIPROT "up-regulates activity" acetylation Lys399 SGPCERRkSPLQDPF 9606 BTO:0000007 17923090 t lperfetto "By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2." SIGNOR-217783 ITGB3 protein P05106 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253198 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-249639 SLBP protein Q14493 UNIPROT H2AC1 protein Q96QV6 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265401 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 15611135 t gcesareni "We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines." SIGNOR-132555 MET protein P08581 UNIPROT MET protein P08581 UNIPROT up-regulates phosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 8302603 t lperfetto "Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation" SIGNOR-37723 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR TIAM1 protein Q13009 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser329 DVNAGEGsEFADSGI 9606 BTO:0002181 25124033 t miannu "Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site." SIGNOR-276674 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "carbamoyl phosphate(2-)" smallmolecule CHEBI:58228 ChEBI "up-regulates quantity" "precursor of" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267417 PRKCE protein Q02156 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR "up-regulates activity" phosphorylation -1 15894802 t "inferred from family member" lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-270280 GATA6 protein Q92908 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000195 24317510 f lperfetto "Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2." SIGNOR-253152 RNF4 protein P78317 UNIPROT SUMO2 protein P61956 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 18408734 t miannu "Here we demonstrate that the RING-domain-containing ubiquitin E3 ligase, RNF4 (also known as SNURF), targets poly-SUMO-modified proteins for degradation mediated by ubiquitin. RNF4 depletion or proteasome inhibition led to accumulation of mixed, polyubiquitinated, poly-SUMO chains. PML protein accumulated in RNF4-depleted cells and was ubiquitinated by RNF4 in a SUMO-dependent fashion in vitro.RNF4 preferentially binds to and ubiquitinates SUMO-2 polymers over SUMO-2 monomers in vitro" SIGNOR-272640 sorafenib chemical CHEBI:50924 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258285 PNMT protein P11086 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI "down-regulates quantity" "chemical modification" 9606 7961964 t brain lperfetto "In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline)." SIGNOR-264008 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser662 GLGRSITsPTTLYDR 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104683 CDK1 protein P06493 UNIPROT USP9X protein Q93008 UNIPROT "up-regulates activity" phosphorylation Ser2547 YEGSEEVsPPQTKDQ 32152317 t "Phosphosites were derived from Figure S1" lperfetto "Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis." SIGNOR-275608 NMBR protein P28336 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256918 WNT10B protein O00744 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131628 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM61 protein Q5EBN2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271163 MITF protein O75030 UNIPROT MLANA protein Q16655 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000848 12819038 f miannu "The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels." SIGNOR-254590 PIAS1 protein O75925 UNIPROT PRDM1 protein O75626 UNIPROT up-regulates sumoylation Lys816 PLVPVKVkQETVEPM 9606 22555612 t miannu "Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor." SIGNOR-197265 abiraterone chemical CHEBI:68642 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-204810 "Nucleosome_H3.1t variant" complex SIGNOR-C325 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 20498094 f miannu "A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1." SIGNOR-263728 SGK1 protein O00141 UNIPROT SLC1A3 protein P43003 UNIPROT "up-regulates activity" phosphorylation Thr482 LDRLRTTtNVLGDSL -1 12911626 t miannu "Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1." SIGNOR-263075 Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 20479780 f lperfetto "The genetic causes of PD seem to participate in con­ verging pathways to pathogenesis, but it is unclear whether all or only some of these pathways need to be activated for lewy body deposition and neuronal death to occur." SIGNOR-249703 pyruvate smallmolecule CHEBI:15361 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR "up-regulates activity" 9606 18613815 f "Pyruvate carboxylase (PC) is a biotin-containing enzyme that catalyses the HCO3−- and MgATP-dependent carboxylation of pyruvate to form oxaloacetate. This is a very important anaplerotic reaction, replenishing oxaloacetate withdrawn from the Krebs cycle for various pivotal biochemical pathways." SIGNOR-267384 SYVN1 protein Q86TM6 UNIPROT HERPUD1 protein Q15011 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 28827405 t miannu "FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp" SIGNOR-261349 PP1 proteinfamily SIGNOR-PF54 SIGNOR PYGL protein P06737 UNIPROT "down-regulates activity" dephosphorylation Ser15 QEKRRQIsIRGIVGV 9606 22225877 t "GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation" SIGNOR-267403 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 BTO:0000150;BTO:0000938 15695813 t gcesareni "Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth." SIGNOR-133861 CREB1 protein P16220 UNIPROT UXT protein Q9UBK9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 17761951 f lperfetto "The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells." SIGNOR-254092 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." SIGNOR-246244 NPFFR1 protein Q9GZQ6 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256987 SEPTIN2 protein Q15019 UNIPROT SEPT6/SEPT2 complex SIGNOR-C71 SIGNOR "form complex" binding 9606 16914550 t miannu "We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains." SIGNOR-148889 ACSS2 protein Q9NR19 UNIPROT GBA protein P04062 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 28552616 t lperfetto "Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants" SIGNOR-276552 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT "up-regulates activity" phosphorylation Thr262 IVHQRVHtGEKPYKC 9606 BTO:0002552 31399647 t miannu "We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A." SIGNOR-276753 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser123 APPSPAWsEPEPEAG 10090 37029927 t miannu "TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling." SIGNOR-277809 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 19584320 t lperfetto "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-216499 CSNK2A1 protein P68400 UNIPROT KIR3DL1 protein P43629 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser385 AGNRTANsEDSDEQD -1 17911614 t miannu "Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far." SIGNOR-276077 NANOG protein Q9H9S0 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 f flangone "Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. " SIGNOR-242073 "CENP-A nucleosome" complex SIGNOR-C321 SIGNOR Centromere_assembly phenotype SIGNOR-PH154 SIGNOR up-regulates 9606 BTO:0000567 20566683 f miannu "Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity." SIGNOR-263704 APC-c complex SIGNOR-C150 SIGNOR SKIL protein P12757 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 11741538 t miannu " We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC. " SIGNOR-272622 NGLY1 protein Q96IV0 UNIPROT RAD23B protein P54727 UNIPROT "up-regulates activity" binding 9606 16401726 t miannu "The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome." SIGNOR-261061 MAPK3 protein P27361 UNIPROT EPAS1 protein Q99814 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser484 SSCSTPNsPEDYYTS 9606 BTO:0006155 35191554 t miannu "The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells." SIGNOR-277584 EGFR protein P00533 UNIPROT IKBKE protein Q14164 UNIPROT "up-regulates activity" phosphorylation Tyr153 GEEGQSIyKLTDFGA 9606 27287717 t miannu "EGFR phosphorylates IKBKE at tyrosine-153 and -179 residues.|To understand the mechanism by which IKBKE is activated by mutant EGFR, we first investigated if activating mutation of EGFR is able to form a complex with IKBKE." SIGNOR-278223 MTNR1B protein P49286 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257102 MBTPS2 protein O43462 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" cleavage 10029 BTO:0000246 10419520 t "In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted" SIGNOR-267499 NARS2 protein Q96I59 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270466 AKT proteinfamily SIGNOR-PF24 SIGNOR LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr324 GGRSREGtMELRTTP 9606 22044535 t llicata "Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis." SIGNOR-177019 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT "down-regulates activity" phosphorylation Ser711 EEEEESDsSETEKED -1 21296876 t miannu "CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis" SIGNOR-276251 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000567 SIGNOR-C14 SIGNOR-C13 10521409 t lperfetto "Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta." SIGNOR-71270 MAPK10 protein P53779 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 17686459 t gcesareni "Here we demonstrate that jnk3 can phosphorylate smac. Phosphorylation of smac by jnk3 attenuates its interaction with xiap. These results suggest that jnk3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between smac and xiap." SIGNOR-157280 RNF168 protein Q8IYW5 UNIPROT TP53BP1 protein Q12888 UNIPROT "up-regulates quantity" ubiquitination 9606 30953555 t miannu "E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR|We further found that overexpression of RNF168 enhanced 53BP1 ubiquitination inhibited by G0S2 overexpression in U87 and LN229 cells in response to IR (Fig. xref f)." SIGNOR-278777 PRKACA protein P17612 UNIPROT RGS14 protein O43566 UNIPROT "up-regulates activity" phosphorylation Ser260 NAALRREsQGSLNSS -1 12534294 t miannu "RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP" SIGNOR-250045 FOXN1 protein O15353 UNIPROT DSG4 protein Q86SJ6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000552 19683850 f miannu "we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle." SIGNOR-254182 "NAN 190" chemical CHEBI:64131 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258855 PTPN1 protein P18031 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation 9606 18253097 t lperfetto "The protein tyrosine phosphatase, PTP1B, is known to negatively regulate EGF-induced signaling in several cell types by dephosphorylating the epidermal growth factor receptor (EGFR).|Together, these findings provide evidence that PTP1B plays a role in the negative regulation of EGFR signaling in rat corneal endothelial cells, at least at the level of Tyr992 phosphorylation." SIGNOR-276981 "A4/b1 integrin" complex SIGNOR-C162 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257704 FGFR2 protein P21802 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17543283 f lperfetto "Furthermore, in cultures receiving FGF-2 before adipogenic induction, mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a key transcription factor in adipogenesis, was upregulated." SIGNOR-236220 NFIB protein O00712 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268900 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates binding 9606 10490659 t "JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660)" gcesareni "These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins." SIGNOR-70854 AMOT protein Q4VCS5 UNIPROT YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR "down-regulates activity" binding 9606 21205866 t miannu "AMOT inhibits YAP/TAZ by regulating YAP/TAZ localization via physical interaction and promoting YAP/TAZ phosphorylation by the Hippo pathway." SIGNOR-277657 TP53 protein P04637 UNIPROT PMS2 protein P54278 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 15781865 t ".... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron." SIGNOR-257604 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser645 RPASVPPsPSLSRHS 11427888 t "Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II." SIGNOR-251238 AMPK complex SIGNOR-C15 SIGNOR GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser8 MPLNRTLsMSSLPGL -1 22233421 t miannu "Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations)." SIGNOR-263102 KAT2A protein Q92830 UNIPROT H3-4 protein Q16695 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269604 HOXD12 protein P35452 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." SIGNOR-241232 OSBPL3 protein Q9H4L5 UNIPROT RRAS protein P10301 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18270267 t miannu "We show that ORP3 interacts with R-Ras, a small GTPase regulating cell adhesion, spreading and migration. Gene silencing of ORP3 in HEK293 cells results in altered organization of the actin cytoskeleton, impaired cell-cell adhesion, enhanced cell spreading and an increase of beta1 integrin activity--effects similar to those of constitutively active R-Ras(38V)." SIGNOR-277221 DLGAP1 protein O14490 UNIPROT SHANK1 protein Q9Y566 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264586 LNX1 protein Q8TBB1 UNIPROT SUFU protein Q9UMX1 UNIPROT "down-regulates quantity" ubiquitination Lys470 SWPEKKLkVSILPDV 9606 33608498 t miannu "Indeed, they target different lysine residues in the SuFu protein, as LNX1 ubiquitinates SuFu at K59 and K470, and SCF Fbxl17 acts at K257, while Itch ubiquitinates at K321 and K457.|XREF_FIG, ectopic LNX1 expression reduced SuFu protein levels in HEK-293T cells, while shRNA mediated knockdown of LNX1 increased these levels." SIGNOR-278626 TRIM7 protein Q9C029 UNIPROT STING1 protein Q86WV6 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 32126128 t miannu "RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation.|Finally, in vitro ubiquitination assays suggested that RNF90 promoted the ubiquitination of MITA directly (Fig 5E and 5F)." SIGNOR-278678 HTR2B protein P41595 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256743 miR-29b mirna URS0000150A7D_9606 RNAcentral DNMT3B protein Q9UBC3 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 26344767 f Luana "We also found that miR-199a expression and blockade (see below for details) potentiated and attenuated, respectively, the phosphorylation levels in neurons of S6 ribosomal protein, which signify the activation of mTOR signaling, indicating that miR-199a positively regulates mTOR signaling activity" SIGNOR-264544 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB3 protein Q9Y5G1 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265707 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 10581361 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-72724 MDH1 protein P40925 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI "up-regulates quantity" "chemical modification" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266287 SNIP1 protein Q8TAD8 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270671 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser358 WPLSRTRsEPLPPSA -1 15738054 t lperfetto "We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro." SIGNOR-249274 CDC7 protein O00311 UNIPROT PSIP1 protein O75475 UNIPROT up-regulates phosphorylation Ser206 MVKQPCPsESDIITE 9606 BTO:0001271;BTO:0000785 7231784 t llicata "We now report identification of the cdc7-activator of s-phase kinase (ask) heterodimer as a novel interactor of ledgf. the kinase phosphorylated ledgf in vitro, with ser-206 being the major target, and ledgf phosphorylated at this residue could be detected during s phase of the cell cycle. Ledgf potently stimulated the enzymatic activity of cdc7-ask, increasing phosphorylation of mcm2 in vitro by more than 10-fold." SIGNOR-25763 SGK1 protein O00141 UNIPROT SLC9A3 protein P48764 UNIPROT "up-regulates activity" phosphorylation Ser663 TMRKRLEsFKSTKLG 9606 21054167 t miannu "The NHE3 activation by SGK1 is dependent on their combined interaction with NHERF2 and then phosphorylation at S663 of NHE3 by SGK1 ( xref , xref )." SIGNOR-279112 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 9606 11544529 t gcesareni "Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2." SIGNOR-252063 PRKAA2 protein P54646 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000007 11069105 t miannu "AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells.  activation of PFK-2 was due to the phosphorylation of Ser466" SIGNOR-250323 LRRK2 protein Q5S007 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" phosphorylation Thr825 LKISDFGtSKRLAGI 9606 BTO:0000007 28888991 t miannu "LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site. " SIGNOR-277251 TEC protein P42680 UNIPROT BTK protein Q06187 UNIPROT "down-regulates activity" phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 12573241 t lperfetto "Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the SH3 domain via a transphosphorylation mechanism, which for Bruton's tyrosine kinase (Btk) affects tyrosine 223.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role" SIGNOR-246652 TIMP1 protein P01033 UNIPROT MMP9 protein P14780 UNIPROT "down-regulates activity" binding 9606 BTO:0003494 36935521 t "Tissue inhibitor of metalloproteinase (TIMP-1) is an inhibitor of MMP-9 that binds to MMP-9 precursors and to the active form." SIGNOR-278116 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Thr228 HEGAVTHtFCGTIEY -1 11733037 t miannu "In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity." SIGNOR-250294 LARS1 protein Q9P2J5 UNIPROT "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR "form complex" binding 9606 32644155 t miannu "In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes)." SIGNOR-270355 AKT1 protein P31749 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser246 LSRERVFsEDRARFY -1 16549426 t miannu "Autophosphorylation of Akt on Thr-72 and Ser-246 appeared to require prior phosphorylation of Akt on Thr-308 and Ser-473. Compared with wild-type Akt, Akt/T72A/S246A mutant exhibited markedly reduced basal Akt kinase activity and response to cellular stimulation by insulin-like growth factor-1, and also conferred less cellular resistance to doxorubicin-induced apoptosis." SIGNOR-276055 carfilzomib chemical CHEBI:65347 ChEBI PSMB10 protein P40306 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000898 17591945 t miannu "Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM." SIGNOR-259308 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY -1 8413257 t lperfetto "Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1." SIGNOR-39054 CDC25A protein P30304 UNIPROT CDK4 protein P11802 UNIPROT "up-regulates activity" dephosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 BTO:0000007 23429262 t lperfetto "Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs." SIGNOR-267568 KHSRP protein Q92945 UNIPROT SRC protein P12931 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" -1 9858532 t lperfetto "We show here that this component of the DCS complex is hnRNP H and that, like hnRNP F and KSRP, hnRNP H is needed for src N1 splicing in vitro." SIGNOR-261274 SMAD6 protein O43541 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "SMAD6 functions as a negative regulator of the TGFB and BMP signaling pathways by interacting with other SMADs and/or TBRI." SIGNOR-64079 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24024136 t irozzo "In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs)." SIGNOR-256277 AKT proteinfamily SIGNOR-PF24 SIGNOR CLK2 protein P49760 UNIPROT up-regulates phosphorylation Thr127 RRRRRSRtFSRSSSQ 9606 BTO:0000567 20682768 t lperfetto "Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva" SIGNOR-244218 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT "up-regulates activity" phosphorylation Ser204 SGAEGDVsSEREP -1 25258324 t done miannu " Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D)." SIGNOR-273976 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-75633 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB4 protein P16144 UNIPROT "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259003 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIF22 protein Q14807 UNIPROT up-regulates phosphorylation Thr463 QGAPLLStPKRERMV 9606 12727876 t lperfetto "Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes" SIGNOR-216793 RAC1 protein P63000 UNIPROT "Phagocyte NADPH oxidase complex" complex SIGNOR-C557 SIGNOR "form complex" binding 9606 37263099 t miannu "NADPH oxidase is composed of essential protein components in its active state: membranous subunits, including p22-phox and gp91-phox, and cytoplasmic subunits, including p47-phox, p67-phox, p40-phox, and RAC2 (in neutrophils), among which NCF4 encodes the cytoplasmic subunit p40-phox" SIGNOR-277631 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser352 AATNRPNsIDPALRR 9606 BTO:0000150 16551632 t llicata "Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I" SIGNOR-252491 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide chemical CHEBI:91433 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195675 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 13760840 t gcesareni SIGNOR-251700 SEMA3B protein Q13214 UNIPROT PLXNA4 protein Q9HCM2 UNIPROT "up-regulates activity" binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu "We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin. " SIGNOR-261810 DUSP6 protein Q16828 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates dephosphorylation 9606 22521266 t gcesareni "Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase)." SIGNOR-197194 NFE2L2 protein Q16236 UNIPROT TALDO1 protein P37837 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22789539 f miannu "We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C)." SIGNOR-267357 Guanfacine chemical CHEBI:5558 ChEBI ADRA2C protein P18825 UNIPROT "up-regulates activity" "chemical activation" 9606 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258918 Tosedostat chemical CID:15547703 PUBCHEM LAP3 protein P28838 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207417 TEP1 protein Q99973 UNIPROT "Vault ribonucleoprotein complex" complex SIGNOR-C643 SIGNOR "form complex" binding 9606 38612882 t miannu "In the human genome, four vault RNA paralogues can be distinguished. They are associated with vault complexes, considered the largest ribonucleoprotein complexes. The protein part of these complexes consists of a major vault protein (MVP) and two minor vault proteins (vPARP and TEP1). The name of the complex, as well as vault RNA, comes from the hollow barrel-shaped structure that resembles a vault." SIGNOR-281071 PARP4 protein Q9UKK3 UNIPROT "Vault ribonucleoprotein complex" complex SIGNOR-C643 SIGNOR "form complex" binding 9606 38612882 t miannu "In the human genome, four vault RNA paralogues can be distinguished. They are associated with vault complexes, considered the largest ribonucleoprotein complexes. The protein part of these complexes consists of a major vault protein (MVP) and two minor vault proteins (vPARP and TEP1). The name of the complex, as well as vault RNA, comes from the hollow barrel-shaped structure that resembles a vault." SIGNOR-281072 ROGDI protein Q9GZN7 UNIPROT "RAVE complex, DMXL1 variant" complex SIGNOR-C644 SIGNOR "form complex" binding 9606 37812645 t miannu "While RAVE (regulator of H+-ATPase of vacuolar and endosomal membranes) and Raboconnectin-3 complexes assemble V-ATPase subunits in Saccharomyces cerevisiae and humans, respectively, the function of the RAVE complex in fungal pathogens remains largely unknown." SIGNOR-281073 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKACB protein P22694 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258211 CDK1 protein P06493 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0003918 19917720 t lperfetto "Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis." SIGNOR-267987 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT "up-regulates activity" phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0002181 24841198 t miannu "When the CaMKI activity is elevated, it phosphorylates PME-1 at Ser15." SIGNOR-276636 ROCK1 protein Q13464 UNIPROT SLC9A1 protein P19634 UNIPROT "up-regulates activity" phosphorylation 9606 27302366 t miannu "We then engineered the T653A NHE1 mutant (ROCKA mutant), which can not be phosphorylated by p160ROCK.|p160ROCK has also been shown to activate NHE1 at threonine 653 , in close vicinity to the Akt phosphorylation site at serine 648." SIGNOR-279566 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation 9606 19282669 t "inferred from 70% family members" lperfetto "Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway" SIGNOR-270020 AKT proteinfamily SIGNOR-PF24 SIGNOR RAC1 protein P63000 UNIPROT "down-regulates activity" phosphorylation Ser71 YDRLRPLsYPQTDVF 9606 BTO:0003476 10617634 t gcesareni "The results suggest that Akt kinase of the phosphoinositide 3-kinase signal transduction pathway phosphorylates serine 71 of Rac1 as one of its authentic substrates and modulates the Rac1 signal transduction pathway through phosphorylation." SIGNOR-248036 TP53 protein P04637 UNIPROT BID protein P55957 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16151013 t "Nuclear p53" lperfetto "Bid is a p53 primary-response gene." SIGNOR-140248 MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154783 DYRK1A protein Q13627 UNIPROT LIN52 protein Q52LA3 UNIPROT "up-regulates activity" phosphorylation Ser28 FEKLDRAsPDLWPEQ 9606 BTO:0001583 21498570 t miannu "Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly." SIGNOR-262846 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser528 KPRSSRGsIFTFRRR -1 12242273 t miannu "These results demonstrate that the effect of PKA stimulation to increase cardiac INa requires at least 2 processes: phosphorylation of consensus sites in the I-II interdomain linker, and one or more additional molecular events mediated by the kinase, that could include phosphorylation of other substrates/proteins." SIGNOR-275992 S1PR3 protein Q99500 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256933 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 16403219 t lperfetto "All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death." SIGNOR-249607 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP9 protein P55211 UNIPROT "up-regulates activity" -1 10988287 f lperfetto "One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway." SIGNOR-256479 "Sumanirole maleate" chemical CID:9818478 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-207594 HCRTR1 protein O43613 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257220 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT "up-regulates activity" phosphorylation Ser130 GPKVNRPsLLEIHEQ 9606 BTO:0000007 21321328 t miannu " We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A)." SIGNOR-276305 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 BTO:0000142 16401070 t lperfetto "Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence." SIGNOR-143481 SIRT7 protein Q9NRC8 UNIPROT H3C15 protein Q71DI3 UNIPROT "up-regulates activity" deacetylation Lys37 APATGGVkKPHRYRP 30653310 t lperfetto "Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37." SIGNOR-275881 CDK5 protein Q00535 UNIPROT KIF13B protein Q9NQT8 UNIPROT "down-regulates activity" phosphorylation Thr506 SEGQVMLtPQKNTRT 10029 BTO:0000246 27512725 t miannu "Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport." SIGNOR-262737 Loratadine chemical CHEBI:6538 ChEBI SLC6A15 protein Q9H2J7 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 25318072 t "Simone Vumbaca" "Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B0AT2. Our studies provide thefirst chemical tool for B0AT2." SIGNOR-261092 AMFR protein Q9UKV5 UNIPROT INSIG1 protein O15503 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 25003069 t miannu "The ubiquitination of Insig-1 is mediated by gp78 and regulated by sterols.|gp78 mediates the degradation of Insig-1 and Insig-2." SIGNOR-278567 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001103 15829723 t apalma "IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt." SIGNOR-255106 NOX1 protein Q9Y5S8 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" "chemical modification" 9606 17237347 t lperfetto "Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS)." SIGNOR-264721 SS18 protein Q15532 UNIPROT GBAF complex SIGNOR-C467 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269782 GRIK3 protein Q13003 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264344 FAM20C protein Q8IXL6 UNIPROT P4HB protein P07237 UNIPROT "up-regulates activity" phosphorylation Ser357 KIKPHLMsQELPEDW 32149426 t lperfetto "The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a ""foldase"" into a ""holdase"", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity." SIGNOR-275574 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636-4 UNIPROT "down-regulates activity" phosphorylation Ser352 PRHLSNVsSTGSIDM -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273929 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser446 SGIKSHNsALYSQVQ 9606 15574499 t amattioni "Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility." SIGNOR-131455 bexarotene chemical CHEBI:50859 ChEBI RXRB protein P28702 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002058 17483357 t miannu "Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification." SIGNOR-259231 AMPK complex SIGNOR-C15 SIGNOR HNF4A protein P41235 UNIPROT "down-regulates activity" phosphorylation Ser303 DPDAKGLsDPGKIKR -1 12740371 t miannu "Here we demonstrate that AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo." SIGNOR-263106 "LINC complex" complex SIGNOR-C303 SIGNOR NXF1 protein Q9UBU9 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 28831067 t lperfetto "SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1." SIGNOR-263297 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr249 APGPQDIyDVPPVRG 9606 12972425 t lperfetto "We tested synthetic peptides modeled on cas phosphorylation sites, and found that the sequence containing tyrosine 253 was phosphorylated by src most efficiently. Using cells derived from cas-deficient mice, we confirmed that cas greatly enhanced the ability of src to transform cells." SIGNOR-100363 MTSS1 protein O43312 UNIPROT GLI1 protein P08151 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 t gcesareni "Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex" SIGNOR-130542 SMURF2 protein Q9HAU4 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0001538 11163210 t miannu "Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. " SIGNOR-272939 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 15735019 t miannu "Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates" SIGNOR-150484 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser111 SPPSPAPsSFSSTSV 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129410 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-70473 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-251593 PRKCE protein Q02156 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata "Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm." SIGNOR-97291 RPA3 protein P35244 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto "The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275707 SMO protein Q99835 UNIPROT GNG3 protein P63215 UNIPROT up-regulates binding 9606 16885213 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-148598 GDP smallmolecule CHEBI:17552 ChEBI GNAQ protein P50148 UNIPROT down-regulates "chemical inhibition" 9606 12040175 t gcesareni "Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of gdp from the alfa subunit followed by gtp-binding to galfa and the dissociation of galfa from gbetagamma subunits1." SIGNOR-88229 SYCE1 protein Q8N0S2 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR "form complex" binding 9606 22394509 t miannu "The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region." SIGNOR-264201 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT "up-regulates activity" phosphorylation Ser661 QNEFAGFsYTNPEFV 9606 17115692 t lperfetto "The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif" SIGNOR-150861 YEATS4 protein O95619 UNIPROT "NuA4 complex" complex SIGNOR-C459 SIGNOR "form complex" binding 9606 14966270 t miannu "NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails." SIGNOR-269302 fexofenadine chemical CHEBI:5050 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257785 TYMS protein P04818 UNIPROT Purine_biosynthesis phenotype SIGNOR-PH186 SIGNOR up-regulates 9606 21876188 t lperfetto "In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS." SIGNOR-253139 CDK5 protein Q00535 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation 9606 15471880 t miannu "In addition, we demonstrate that co-expression of cdk5 and its regulatory activator p35 with TH increases the stability of TH.|We show that cdk5 phosphorylates TH at serine 31 and that this phosphorylation is associated with an increase in total TH activity." SIGNOR-279022 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT "down-regulates activity" dephosphorylation Ser227 DHEKKAYsFCGTVEY 10090 15206906 t "RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity" SIGNOR-248320 PTPRZ1 protein P23471 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" dephosphorylation 9606 23100427 t miannu "PTPRZ1 constitutively promotes the tyrosine dephosphorylation of \u03b2-catenin, and thus \u03b2-catenin participation in TCF-mediated transcription." SIGNOR-277044 FBXO7 protein Q9Y3I1 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 15145941 t miannu "We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP).Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner." SIGNOR-271507 DISP1 protein Q96F81 UNIPROT SHH protein Q15465 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 22902404 t lperfetto "We show that the vertebrate homologue, dispatched-a (dispa) interacts with human sonic hedgehog (hshh) via its cholesterol anchor, and that this interaction is necessary for hshh secretion. binding to dispa is necessary but not sufficient for hshh secretion" SIGNOR-191888 ERCC5 protein P28715 UNIPROT ERCC2 protein P18074 UNIPROT "up-regulates quantity by stabilization" binding 9606 20840796 t "Regulation of binding" "The NER protein XPG was also found to associate with the TFIIH complex by interacting directly with XPD stabilizing the interaction between TFIIH and the CAK-XPD complex" SIGNOR-251974 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DRA protein P01903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253998 oxandrolone chemical CHEBI:7820 ChEBI AR protein P10275 UNIPROT "up-regulates activity" "chemical activation" 9606 10077001 t miannu "The anabolic steroids, oxandrolone and fluoxymesterone, have high inhibition constants for binding, yet induce the N/C interaction and stabilize AR at relatively low ligand concentrations and are AR agonists in vivo." SIGNOR-259265 MAPK11 protein Q15759 UNIPROT MAPK11 protein Q15759 UNIPROT "down-regulates activity" phosphorylation Ser261 HARTYIQsLPPMPQK -1 26976637 t miannu "P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261" SIGNOR-277214 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E2 complex SIGNOR-C497 SIGNOR "form complex" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270839 PRKCA protein P17252 UNIPROT PRKD2 protein Q9BZL6 UNIPROT "up-regulates activity" phosphorylation Ser876 QGLAERIsVL 12058027 t lperfetto "Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead." SIGNOR-275953 DUOX1 protein Q9NRD9 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" "chemical modification" 9606 17237347 t lperfetto "Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS)." SIGNOR-264726 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 12163482 t "inferred from 70% family members" lperfetto "Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein" SIGNOR-270099 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR ATP2A1 protein O14983 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136300 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000050 2139411 t lperfetto "The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione." SIGNOR-268639 PMAIP1 protein Q13794 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" phosphorylation 9606 9988720 t "Ga16 is phosphorylated in vivo by PMA and by TRH receptor stimulation" SIGNOR-278131 MYOG protein P15173 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25211658 t "P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells" SIGNOR-251575 RAB5C protein P51148 UNIPROT EEA1 protein Q15075 UNIPROT "up-regulates activity" binding -1 12493736 t Federica "The Rab5 effector early endosome antigen 1 (EEA1) is a parallel coiled coil homodimer with an N-terminal C(2)H(2) Zn(2+) finger and a C-terminal FYVE domain. Rab5 binds to independent sites at the N and C terminus of EEA1.|The results demonstrate that the C(2)H(2) Zn(2+) finger is both essential and sufficient for the N-terminal interaction with Rab5." SIGNOR-261266 LYN protein P07948 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249384 alvimopan chemical CHEBI:135686 ChEBI OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" -1 18313920 t Luana "A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors." SIGNOR-257773 ATM protein Q13315 UNIPROT HNF1A protein P20823 UNIPROT up-regulates phosphorylation Ser249 IQRGVSPsQAQGLGS 9606 24821553 t lperfetto "Serine 249 phosphorylation by atm protein kinase regulates hepatocyte nuclear factor-1_ transactivation" SIGNOR-205087 WDR7 protein Q9Y4E6 UNIPROT "RAVE complex, DMXL1 variant" complex SIGNOR-C644 SIGNOR "form complex" binding 9606 37812645 t miannu "While RAVE (regulator of H+-ATPase of vacuolar and endosomal membranes) and Raboconnectin-3 complexes assemble V-ATPase subunits in Saccharomyces cerevisiae and humans, respectively, the function of the RAVE complex in fungal pathogens remains largely unknown." SIGNOR-281075 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser68 LRDAIRQsNQILRER 9606 SIGNOR-C14 17977820 t lperfetto "In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I" SIGNOR-209788 BTRC protein Q9Y297 UNIPROT RAP1GAP protein P47736 UNIPROT down-regulates ubiquitination 9606 25329897 t lperfetto "Here, we demonstrated that rap1gap is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of rap1gap requires the plk1 kinase and _-trcp ubiquitin ligase complex." SIGNOR-203548 EGLN3 protein Q9H6Z9 UNIPROT ADRB2 protein P07550 UNIPROT "up-regulates quantity by stabilization" hydroxylation Pro382 KLLCEDLpGTEDFVG 9606 BTO:0000007 19584355 t lperfetto "We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation." SIGNOR-262006 EGFR protein P00533 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 25164010 t miannu "One possible explanation is that activation of \u03b2-catenin by EGFR mutants may \u201cprime\u201d pulmonary cells to be susceptible to other downstream signaling aberrations and subsequent transformation into tumor cells.|beta-catenin is phosphorylated at Y86 by Src and oncogenic Bcr-Abl and at Y654 by activated wild type EGFR and oncogenic FLT3-ITD." SIGNOR-278308 hsa-miR-320a-5p mirna URS000042A57E_9606 RNAcentral GNAI1 protein P63096 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003227 23691483 t Parnian "GNAI1 was a target of miR-320a/c/d in HCC cells.| Western blot assays revealed that miR-320a/c/d dramatically down-regulated the endogenous GNAI1 protein level, which indicates that these miRNAs may directly target GNAI1 in HCC cells." SIGNOR-278026 PLK1 protein P53350 UNIPROT SNCB protein Q16143 UNIPROT "down-regulates activity" phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 19889641 t lperfetto "Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation." SIGNOR-176079 CS protein O75390 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI "down-regulates quantity" "chemical modification" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266238 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 9606 23898330 t lperfetto "In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation" SIGNOR-249505 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Ser332 LSRSRTAsLTSAASV 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 t llicata "Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344" SIGNOR-129672 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR hsa-mir-223 mirna URS000037EC34_9606 RNAcentral "down-regulates quantity by repression" "transcriptional regulation" 10090 25477897 t miannu "The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC" SIGNOR-255797 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT "down-regulates activity" phosphorylation Ser311 DALDLEEsSSSDHAE 10029 BTO:0000246 7876239 t "The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization." SIGNOR-251440 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258279 ERBB4 protein Q15303 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16829981 t gcesareni "Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength." SIGNOR-147847 MPC2 protein O95563 UNIPROT "Mitochondrial pyruvate carrier complex, testis variant" complex SIGNOR-C645 SIGNOR "form complex" binding 9606 35278701 t miannu "We determined that the functional unit of human MPC is a hetero-dimer. In this study, we established in vitro systems relying on recombinant, heterologously expressed human MPC proteins to investigate the key features of inhibitor binding. First, we showed that the human MPC is a hetero-dimeric complex mediating pyruvate transport in proteoliposomes." SIGNOR-281076 "perfluorooctanoic acid" chemical CHEBI:35549 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -1 23764977 t miannu "Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. " SIGNOR-268768 STAG1 protein Q8WVM7 UNIPROT "Cohesin complex" complex SIGNOR-C304 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1‚ÄìInt14 (Integrator subunits)¬†" SIGNOR-267729 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr332 ILAIHDSyKPEFHSD 10029 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248418 NFIB protein O00712 UNIPROT NEUROD4 protein Q9HD90 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268898 CDK1 protein P06493 UNIPROT EP300 protein Q09472 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2039 GLGQVGIsPLKPGTV 9606 BTO:0000551 24530506 t miannu "In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels. " SIGNOR-276456 SUPT6H protein Q7KZ85 UNIPROT "Iws1:Spt6:CTD complex" complex SIGNOR-C548 SIGNOR "form complex" binding 9606 19141475 t miannu "We showed recently that Spt6, a transcription elongation factor and histone H3 chaperone, binds to the Ser2P CTD and recruits Iws1 and the REF1/Aly mRNA export adaptor to facilitate mRNA export.In vitro, recombinant Spt6 binds selectively to a stretch of uninterrupted consensus repeats located in the N-terminal half of the CTD and recruits Iws1. Thus Iws1 connects two distinct CTD-binding proteins, Spt6 and HYPB/Setd2, in a megacomplex that affects mRNA export as well as the histone modification state of active genes." SIGNOR-273498 GNB5 protein O14775 UNIPROT ADCY5 protein O95622 UNIPROT "down-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC" SIGNOR-264998 Corticotropin protein P01189-PRO_0000024969 UNIPROT CYP11A1 protein P05108 UNIPROT "up-regulates quantity" 9606 24631756 f lperfetto "CTH signaling promotes the single steroidogenic rate limiting step, which is the conversion of cholesterol to pregnenolone by Cholesterol Side-Chain Cleavage Enzyme (P450scc), encoded in the CYP11A1 gene. This is conferred by a direct stimulating effect of ACTH on the promoter of CYP11A1 (Chung et al., 1997, Liu and Simpson, 1997, Hu et al., 2001). Further, it stimulates conversion of pregnenolone to 17-hydroxypregnenolone by upregulating the expression of 3β hydroxysteroid dehydrogenase enzyme (3β-HSD)" SIGNOR-268719 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 10660534 t lperfetto "Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function" SIGNOR-74848 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2A protein P29274 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257447 SMN1 protein Q16637 UNIPROT "SMN complex" complex SIGNOR-C158 SIGNOR "form complex" binding 12065586 t lperfetto "SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry." SIGNOR-253115 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT "up-regulates activity" phosphorylation Thr357 FELRKTQtSMSLGTT -1 24012422 t gianni "MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays" SIGNOR-266438 AKT proteinfamily SIGNOR-PF24 SIGNOR AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 t gcesareni "Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40" SIGNOR-236929 TUBA1C protein Q9BQE3 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu "We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching." SIGNOR-269728 DEF6 protein Q9H4E7 UNIPROT RAP1A protein P62834 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 26483383 t lperfetto "Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion." SIGNOR-253365 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR ENO3 protein P13929 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136550 NR2F1 protein P10589 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 t lperfetto "Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site" SIGNOR-79440 HNF1A protein P20823 UNIPROT SLC22A9 protein Q8IVM8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 20829431 t lperfetto "Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1 in HepG2 cells." SIGNOR-268982 AURKB protein Q96GD4 UNIPROT HDAC9 protein Q9UKV0 UNIPROT down-regulates phosphorylation Ser239 QKVAERRsSPLLRRK 9606 22865920 t lperfetto "We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions" SIGNOR-198654 HCRTR2 protein O43614 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256729 CAMK2G protein Q13555 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 11114197 t gcesareni "Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation." SIGNOR-85098 CLN8 protein Q9UBY8 UNIPROT PPP2CA protein P67775 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 30453012 t miannu "CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8." SIGNOR-265583 PRKD3 protein O94806 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "up-regulates activity" phosphorylation Ser259 FPLRKTAsEPNLKVR 18692497 t lperfetto "Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]." SIGNOR-275926 TRAF6 protein Q9Y4K3 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002181 30806153 t miannu "TRAF6 catalyzes K63-linked polyubiquitination of LC3B and promotes the formation of the LC3B-ATG7 and LC3B-CTNNB1 complexes." SIGNOR-277439 MPC1L protein P0DKB6 UNIPROT "Mitochondrial pyruvate carrier complex, testis variant" complex SIGNOR-C645 SIGNOR "form complex" binding 9606 35278701 t miannu "We determined that the functional unit of human MPC is a hetero-dimer. In this study, we established in vitro systems relying on recombinant, heterologously expressed human MPC proteins to investigate the key features of inhibitor binding. First, we showed that the human MPC is a hetero-dimeric complex mediating pyruvate transport in proteoliposomes." SIGNOR-281077 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 20562916 t "Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis" SIGNOR-248766 GLI3 protein P10071 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 12435361 t Gianni "Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH" SIGNOR-268949 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr198 PGLRRRQt 9606 12042314 t miannu "Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation." SIGNOR-88294 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 1310899 t lperfetto "A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2." SIGNOR-236080 ESR1 protein P03372 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000093;BTO:0000567 16144913 t lperfetto "Our data show for the first time that eralpha binds to ppar response element and represses its transactivation" SIGNOR-140233 RNF144B protein Q7Z419 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000772 20864535 t miannu "NPMc degradation was mediated by the ubiquitin-proteasome pathway involving the IBR-type RING-finger E3 ubiquitin ligase IBRDC2, and genetic correction of FA-A or FA-C lymphoblasts prevented NPMc ubiquitination. As shown in Fig. 4C, knockdown of IBRDC2, an IBR-type RING-finger E3 ubiquitin ligase (21), significantly reduced NPMc ubiquitination and restored NPMc stability in FA-A cells" SIGNOR-271490 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation 9606 21440011 t lperfetto "Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs" SIGNOR-252833 ABCA1 protein O95477 UNIPROT MEGF10 protein Q96KG7 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17205124 t miannu "ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level." SIGNOR-265164 STT3B protein Q8TCJ2 UNIPROT "OST-B complex" complex SIGNOR-C536 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272070 corticosterone smallmolecule CHEBI:16827 ChEBI 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000048 33117906 t lperfetto "The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone" SIGNOR-268674 IKK-complex complex SIGNOR-C14 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t lperfetto "Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation." SIGNOR-252950 TRIM59 protein Q8IWR1 UNIPROT ECSIT protein Q9BQ95 UNIPROT "down-regulates activity" binding 9606 "BTO:0000567; BTO:0002181" 22588174 t Giorgia "In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. The B-box and RING domains of TRIM59 are important for interaction with ECSIT.|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation.|Luciferase reporter assays using reporter plasmids including NF-kappaB responsive element, interferon beta (IFN-beta) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities." SIGNOR-260369 PRKN protein O60260 UNIPROT RHOT2 protein Q8IXI1 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 22078885 t miannu "PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. " SIGNOR-272726 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18997792 t gcesareni "A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution." SIGNOR-182124 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR CRY2 protein Q49AN0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20817722 t miannu "The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements." SIGNOR-267968 CREB5 protein Q02930 UNIPROT ATF2 protein P15336 UNIPROT "up-regulates activity" binding 9534 BTO:0000318 8378084 t miannu "CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription" SIGNOR-219655 CDR2 protein Q01850 UNIPROT CENPE protein Q02224 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 20383333 f lperfetto "Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology" SIGNOR-252020 ALPL protein P05186 UNIPROT Bone_mineralization phenotype SIGNOR-PH69 SIGNOR up-regulates 9606 19049325 f miannu "PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate." SIGNOR-252196 LRRFIP2 protein Q9Y608 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 15677333 t gcesareni "In particular, a previously unrecognized activator, lrrfip2 (leucine-rich repeat in flightless interaction protein 2), was found that interacts with dvl to increase the cellular levels of _-catenin and activate _-catenin/lef/tcf-dependent transcriptional activity" SIGNOR-133429 CXCL3 protein P19876 UNIPROT CXCR2 protein P25025 UNIPROT "up-regulates activity" binding 9606 38309677 t miannu "CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively" SIGNOR-277719 AV412 chemical CID:11700696 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190053 SIRT3 protein Q9NTG7 UNIPROT IDH2 protein P48735 UNIPROT up-regulates deacetylation Lys413 VESGAMTkDLAGCIH 9606 22416140 t miannu "Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity." SIGNOR-196617 CAMK2G protein Q13555 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Ser727 TDNLLPMsPEEFDEV BTO:0000944 11972023 t llicata "For maximal gene activation, S727 in the transcription activation domain of Stat1 also is inducibly phosphorylated by IFN-gamma. We previously purified a group of nuclear proteins that interact specifically with the Stat1 transcription activation domain. In this report, we identified one of them as the multifunctional Ca(2+)/calmodulin-dependent kinase (CaMK) II. We demonstrate that IFN-gamma mobilizes a Ca(2+) flux in cells and activates CaMKII. CaMKII can interact directly with Stat1 and phosphorylate Stat1 on S727 in vitro. Inhibition of Ca(2+) flux or CaMKII results in a lack of S727 phosphorylation and Stat1-dependent gene activation, suggesting in vivo phosphorylation of Stat1 S727 by CaMKII. " SIGNOR-250706 FOXO1 protein Q12778 UNIPROT TCF4 protein P15884 UNIPROT "down-regulates activity" binding 9606 BTO:0000797 18250171 t Gianni "Here we show that the beta-catenin binding to FOXO serves a dual effect. beta-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with beta-catenin, thereby inhibiting TCF transcriptional activity." SIGNOR-262529 PFK proteinfamily SIGNOR-PF79 SIGNOR "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266474 17beta-estradiol smallmolecule CHEBI:16469 ChEBI MAPK3 protein P27361 UNIPROT up-regulates 9606 BTO:0000150 11043579 f gcesareni "Estrogen rapidly activates the mitogen-activated protein kinases, erk-1 and erk-2, via an as yet unknown mechanism." SIGNOR-83280 CUL7 protein Q14999 UNIPROT "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR "form complex" binding 9606 BTO:0001109 phosphorylation:Thr286 17205132 t miannu "FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1 " SIGNOR-271625 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 30017632 t miannu "The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression" SIGNOR-260437 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto "In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity." SIGNOR-118023 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile chemical CHEBI:95341 ChEBI JAK1 protein P23458 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20363976 t Luana "INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM)." SIGNOR-257833 SREBF2 protein Q12772 UNIPROT ABCG5 protein Q9H222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21123766 f miannu "these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α." SIGNOR-254455 PRKACA protein P17612 UNIPROT USP20 protein Q9Y2K6 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser333 RMKDRKFsWGQQRTN 9534 BTO:0000298 25666616 t done miannu "Upon β2AR activation, a specific isoform of the second messenger cAMP-dependent protein kinase A (PKAα) rapidly phosphorylates USP20 on serine 333 located in its unique insertion domain. This phosphorylation of USP20 correlates with a characteristic SDS-PAGE mobility shift of the protein, blocks its deubiquitinase activity, promotes its dissociation from the activated β2AR complex, and facilitates trafficking of the ubiquitinated β2AR to autophagosomes, which fuse with lysosomes to form autolysosomes where receptors are degraded." SIGNOR-273795 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 9606 BTO:0000567 9687510 t lperfetto "Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3)" SIGNOR-59363 "Mitochondrial pyruvate carrier complex, testis variant" complex SIGNOR-C645 SIGNOR pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" relocalization 9606 35278701 t miannu "We determined that the functional unit of human MPC is a hetero-dimer. In this study, we established in vitro systems relying on recombinant, heterologously expressed human MPC proteins to investigate the key features of inhibitor binding. First, we showed that the human MPC is a hetero-dimeric complex mediating pyruvate transport in proteoliposomes." SIGNOR-281078 SMARCD2 protein Q92925 UNIPROT "SWI/SNF ACTL6A-ARID1A-SMARCA2 variant" complex SIGNOR-C470 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269821 SREBF2 protein Q12772 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17921436 t miannu "Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9." SIGNOR-255223 SGK1 protein O00141 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation 9606 11410590 t miannu "Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf.|We observed that SGK inhibits B-Raf activity." SIGNOR-279110 "monoisononyl phthalate" chemical CHEBI:132593 ChEBI PPARD protein Q03181 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 27551952 t miannu "MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs." SIGNOR-268781 PTEN protein P60484 UNIPROT KIF11 protein P52732 UNIPROT "up-regulates activity" dephosphorylation Thr926 LDIPTGTtPQRKSYL 9606 27492783 t lperfetto "PTEN significantly reduces EG5 phosphorylation at Thr926 (XREF_FIG), suggesting PTEN may target this EG5 site for dephosphorylation." SIGNOR-277000 MAPK1 protein P28482 UNIPROT RSPH3 protein Q86UC2 UNIPROT "up-regulates activity" phosphorylation Thr286 AFLDRPPtPLFIPAK 9606 19684019 t miannu "ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D)." SIGNOR-262838 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr395 AKHHQDAyIRIVLEN 9606 15952790 t llicata "We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts." SIGNOR-138150 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269376 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 11432829 t gcesareni "This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway." SIGNOR-109035 CCDC47 protein Q96A33 UNIPROT "PAT intramembrane chaperone complex" complex SIGNOR-C647 SIGNOR "form complex" binding 9606 32814900 t miannu " Here we identify the PAT complex, an abundant obligate heterodimer of the widely conserved ER-resident membrane proteins CCDC47 and Asterix. The PAT complex engages nascent TMDs that contain unshielded hydrophilic side chains within the lipid bilayer, and it disengages concomitant with substrate folding. " SIGNOR-281079 Sin3B_complex complex SIGNOR-C409 SIGNOR "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" binding 9606 BTO:0000007 21041486 t "inferred from 70% of family members" miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-269844 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 t lperfetto "We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1" SIGNOR-176891 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t "Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases." SIGNOR-248411 GHR protein P10912 UNIPROT MAP2K5 protein Q13163 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0005787 BTO:0001103 23612709 t miannu "The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion" SIGNOR-255452 PRKCB protein P05771 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 t lperfetto "A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis." SIGNOR-249237 PTPN2 protein P17706 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" dephosphorylation 9606 21984578 f miannu "Moreover, it indicates that PTPN2 modulates the apoptotic activity of Bim via regulation of the protein kinase JNK1.|PTPN2 inhibition increased Bim phosphorylation at residue 65 in untreated INS-1E cells, and this effect was prolonged until 4 h of treatment with IFNalpha or 8 h after treatment with IFNgamma (XREF_FIG)." SIGNOR-277055 NUMB protein P49757 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates binding 9606 20818436 t gcesareni "Numb activates the catalytic activity of itch, releasing it from an inhibitory intramolecular interaction between its homologous to e6-ap c-terminus and ww domains." SIGNOR-167844 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR EIF3F protein O00303 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0000165 18354498 t miannu "Mediation of eIF3-f polyubiquitination by the SCFMAFbx. The association of MAFbx with the essential Skp1, Roc 1 and Cul1 proteins, specific components of an E3 ubiquitin–protein ligase (SCFMAFbx), was previously described. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome." SIGNOR-271767 ITGB7 protein P26010 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257726 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2N protein P61088 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271320 ATM protein Q13315 UNIPROT MECOM protein Q03112 UNIPROT "up-regulates activity" phosphorylation Ser1037 IGNSNHGsQSPRNVE 29939287 t "phosphorylation site remapping based on Fig 1" lperfetto "To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif." SIGNOR-273433 ATM protein Q13315 UNIPROT UCHL3 protein P15374 UNIPROT "up-regulates activity" phosphorylation 9606 27941124 t lperfetto "Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM." SIGNOR-279794 "Elongator complex" complex SIGNOR-C466 SIGNOR RAB3IL1 protein Q8TBN0 UNIPROT "up-regulates activity" binding -1 15780940 t miannu "Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. We show that elp1Δ suppression of sec2ts is not a result of reduced transcriptional elongation and that Elp1p physically associates with Sec2p. The Sec2p interaction domain of Elp1p is necessary for both Elp1p function and for the polarized localization of Sec2p. Mutations in human Elp1p (IKAP) are a known cause of familial dysautonomia (FD)." SIGNOR-269714 hsa-mir-494-3p mirna URS0000535FDD_9606 RNAcentral CXCR4 protein P61073 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000815 25955111 t "MiR-494 suppresses the progression of breast cancer through the Wnt/β-catenin signaling pathway, which is mediated by CXCR4." SIGNOR-277943 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT "down-regulates activity" phosphorylation Ser792 LTQSAPAsPTNKGVH 10090 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto "These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK" SIGNOR-163463 IL5RA protein Q01344 UNIPROT SOX4 protein Q06945 UNIPROT "up-regulates activity" binding 10090 BTO:0003104 11498591 t miannu "Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation." SIGNOR-223010 MEF2D protein Q14814 UNIPROT MYH2 protein Q9UKX2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 15728583 t lperfetto "Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation" SIGNOR-238712 ELOVL proteinfamily SIGNOR-PF93 SIGNOR 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI "up-regulates quantity" "chemical modification" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267902 GSK3B protein P49841 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" phosphorylation Ser1490 AILNPPPsPATERSH 9606 SIGNOR-C110 16341017 t gcesareni "Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin." SIGNOR-143041 "PAT intramembrane chaperone complex" complex SIGNOR-C647 SIGNOR Protein_insertion_into_membrane phenotype SIGNOR-PH236 SIGNOR up-regulates 9606 32814900 f miannu " Here we identify the PAT complex, an abundant obligate heterodimer of the widely conserved ER-resident membrane proteins CCDC47 and Asterix. The PAT complex engages nascent TMDs that contain unshielded hydrophilic side chains within the lipid bilayer, and it disengages concomitant with substrate folding. " SIGNOR-281082 CDA protein P32320 UNIPROT water smallmolecule CHEBI:15377 ChEBI "down-regulates quantity" "chemical modification" 9606 24183806 t miannu "Cytidine deaminase (CDA, cytidine/2′-deoxycytidine aminohydrolase; EC 3.5.4.5, gene map locus 1p36.2-p35) is an enzyme of the pyrimidine salvage pathways, which catalyzes the formation of uridine and 2′-deoxyuridine by hydrolytic deamination of cytidine and 2′deoxycytidine, respectively. " SIGNOR-280618 CDA protein P32320 UNIPROT uridine smallmolecule CHEBI:16704 ChEBI "up-regulates quantity" "chemical modification" 9606 24183806 t miannu "Cytidine deaminase (CDA, cytidine/2′-deoxycytidine aminohydrolase; EC 3.5.4.5, gene map locus 1p36.2-p35) is an enzyme of the pyrimidine salvage pathways, which catalyzes the formation of uridine and 2′-deoxyuridine by hydrolytic deamination of cytidine and 2′deoxycytidine, respectively. " SIGNOR-280619 DGUOK protein Q16854 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 17073823 t miannu "DGUOK [dG (deoxyguanosine) kinase] is one of the two mitochondrial deoxynucleoside salvage pathway enzymes involved in precursor synthesis for mtDNA (mitochondrial DNA) replication. DGUOK is responsible for the initial rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside triphosphate as phosphate donor." SIGNOR-280569 SNAPC4 protein Q5SXM2 UNIPROT SNAPC complex SIGNOR-C565 SIGNOR "form complex" binding CPX-8637 11056176 t miannu "In the case of the human RNA polymerase II and III small nuclear RNA (snRNA) genes, whose core promoters consist of a proximal sequence element (PSE) and a PSE combined with a TATA box, respectively, the same multisubunit complex is involved in the establishment of RNA polymerase II and III initiation complexes. This factor, the snRNA-activating protein complex or SNAP(c), binds to the PSE of both types of promoters and contains five types of subunits, SNAP190, SNAP50, SNAP45, SNAP43, and SNAP19. SNAP(c) binds cooperatively with both Oct-1, an activator of snRNA promoters, and in the RNA polymerase III snRNA promoters, with TATA-binding protein, which binds to the TATA box located downstream of the PSE. " SIGNOR-280628 GSK3B protein P49841 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation 9606 33081032 t miannu "GSK3β regulates S6K1 activity positively through modulating phosphorylation of S6K1 at p.Ser371." SIGNOR-263513 WDR48 protein Q8TAF3 UNIPROT USP1 protein O94782 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 18082604 t lperfetto "In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM)." SIGNOR-263274 DAB2IP protein Q5VWQ8 UNIPROT NRAS protein P01111 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 27858941 t miannu "The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP." SIGNOR-254747 AKT1 protein P31749 UNIPROT TSC complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t lperfetto " In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis" SIGNOR-235340 SNAPC2 protein Q13487 UNIPROT SNAPC complex SIGNOR-C565 SIGNOR "form complex" binding 11056176 t miannu "In the case of the human RNA polymerase II and III small nuclear RNA (snRNA) genes, whose core promoters consist of a proximal sequence element (PSE) and a PSE combined with a TATA box, respectively, the same multisubunit complex is involved in the establishment of RNA polymerase II and III initiation complexes. This factor, the snRNA-activating protein complex or SNAP(c), binds to the PSE of both types of promoters and contains five types of subunits, SNAP190, SNAP50, SNAP45, SNAP43, and SNAP19. SNAP(c) binds cooperatively with both Oct-1, an activator of snRNA promoters, and in the RNA polymerase III snRNA promoters, with TATA-binding protein, which binds to the TATA box located downstream of the PSE. " SIGNOR-280630 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser243 TDSEVDSsCSGQPIH 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273128 PDGFA protein P04085 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763 11803579 t gcesareni "Platelet-derived growth factors (pdgf) constitute a family of four gene products (pdgf-a-d) acting by means of two receptor tyrosine kinases, pdgfr alpha and beta. Three of the ligands (pdgf-a, -b, and -c) bind to pdgfr alpha with high affinity." SIGNOR-114268 EEF1A1P5 protein Q5VTE0 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269555 DPYSL2 protein Q16555 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 25040932 f lperfetto "In the non-phosphorylated state, CRMP2 binding to tubulin induces the promotion of tubulin polymerisation leading to dendrite outgrowth while" SIGNOR-264842 HMOX2 protein P30519 UNIPROT heme smallmolecule CHEBI:30413 ChEBI "down-regulates quantity" "chemical modification" 9606 10490932 t Regulation miannu "Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme" SIGNOR-251912 EEF1A2 protein Q05639 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269535 6-propyl-2-thiouracil smallmolecule CHEBI:8502 ChEBI DIO proteinfamily SIGNOR-PF83 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0001379 27347897 t "inferred from family member" scontino "The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU)." SIGNOR-270240 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HSPA5 protein P11021 UNIPROT down-regulates 9606 31226023 f miannu "In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation." SIGNOR-260163 TBK1 protein Q9UHD2 UNIPROT TNIP1 protein Q15025 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser123 PPSSGTSsEFEVVTP 36574265 t lperfetto "TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1" SIGNOR-275734 AKT1 protein P31749 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 t gcesareni "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-187006 JUND protein P17535 UNIPROT FOSL1 protein P15407 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 13679379 t Luana "Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. " SIGNOR-261603 GSK3A protein P49840 UNIPROT CD274 protein Q9NZQ7 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser279 CGIQDTNsKKQSDTH 9606 BTO:0002181 33879767 t miannu "We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation." SIGNOR-277552 PRKACA protein P17612 UNIPROT SEC14L2 protein O76054 UNIPROT "up-regulates activity" phosphorylation Ser289 VQISRGSsHQVEYEI -1 15680919 t miannu "These results suggest that phosphorylation of SPF by PKA is a dynamic process and that, in the absence of PKA activity, SPF is rapidly inactivated.Thus, phosphorylation of SPF at Ser-289 appears necessary for maximal stimulation of squalene monooxygenase activity in vitro and absolutely required for the stimulation of cholesterol synthesis in cell culture." SIGNOR-276027 CDK20 protein Q8IZL9 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 14597612 t gcesareni "P42 is essential for the phosphorylation of thr-160 and activation of cdk2." SIGNOR-118986 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation 9606 14967450 t gcesareni "Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1." SIGNOR-121944 PPARG protein P37231 UNIPROT ACADM protein P11310 UNIPROT "down-regulates activity" binding 9606 BTO:0001370 28974683 t Federica "This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation" SIGNOR-261264 RAPGEF3 protein O95398 UNIPROT RAP1B protein P61224 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9534 BTO:0000298 10777494 t miannu "Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well." SIGNOR-263957 NOTCH1 protein P46531 UNIPROT IL2RA protein P01589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001454 10933396 f gcesareni "Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression." SIGNOR-80336 pentazocine chemical CHEBI:7982 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258935 EP300 protein Q09472 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 SIGNOR-C6 22298955 t gcesareni "Ski and snon also prevent smads from binding to the transcriptional coactivator p300/cbp" SIGNOR-195582 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser205 LATPPTLsSTVLIVR 9606 BTO:0001938 12815053 t lperfetto "Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation." SIGNOR-249218 IMPDH2 protein P12268 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI "down-regulates quantity" "chemical modification" 9606 19480389 t miannu "IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS)." SIGNOR-267334 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT "down-regulates activity" phosphorylation Ser495 STSTESSsQDVESTF 31938050 t lperfetto "Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization." SIGNOR-275854 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr225 LGETKQEtLTNISAV 9606 15611134 t gcesareni "Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates." SIGNOR-132463 CNR2 protein P34972 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256843 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DNM1L protein O00429 UNIPROT "up-regulates activity" phosphorylation Ser585 WRGMLKTSKAEELLA 9606 BTO:0000007 17301055 t Barakat "Drp1 was specifically phosphorylated at Ser-585 by Cdk1/cyclin B, which stimulated the mitochondrial fission in mitosis. From these results, we concluded that mitochondrial morphology is regulated by Drp1-dependent mitochondrial fission in mitotic cells" SIGNOR-274131 ORF4b protein K9N643 UNIPROT IKBKE protein Q14164 UNIPROT "down-regulates activity" binding 9606 26631542 t miannu "Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm" SIGNOR-260592 PXDN protein Q92626 UNIPROT COL4A4 protein P53420 UNIPROT "up-regulates quantity by stabilization" "catalytic activity" 9606 BTO:0000567 29305973 t miannu "Peroxidasin (PXDN), an ECM protein with peroxidase activity, is integral to basement membrane consolidation through catalysis of sulfilimine bonds in collagen IV. PXDN has been shown to form dityrosine crosslinks and also catalyses sulfilimine bonds, in the presence of hypohalous acids, to connect collagen IV protomers, which are an integral component of the basement membrane" SIGNOR-265250 PMS2 protein P54278 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 9500552 f "Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer" SIGNOR-257596 CTNNB1 protein P35222 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 22298955 f gcesareni "In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs." SIGNOR-195570 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT "down-regulates activity" phosphorylation Thr107 PKKERRRtESINSAF 10116 BTO:0001556 14636580 t miannu "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function." SIGNOR-249991 "A2/b1 integrin" complex SIGNOR-C160 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu "Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing." SIGNOR-269009 SUFU protein Q9UMX1 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates relocalization 9606 BTO:0001130 16316410 t gcesareni "Negative regulation of gli1 and gli2 activator function by suppressor of fused through multiple mechanisms.Together, these observations reveal that su(fu) regulates the activity of gli1 and gli2 through distinct cytoplasmic and nuclear mechanisms." SIGNOR-142608 NRXN2 protein P58401 UNIPROT DAG1 protein Q14118 UNIPROT "up-regulates activity" binding 9606 22626542 t miannu "The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM." SIGNOR-265461 STK3 protein Q13188 UNIPROT RCC1 protein P18754 UNIPROT up-regulates phosphorylation Ser2 sPKRIAKR 9606 BTO:0000007 19559616 t miannu "MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets." SIGNOR-263146 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Thr23 ESPPVSDtPDEGDEP 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-174856 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258176 STK26 protein Q9P289 UNIPROT ASAP3 protein Q8TDY4 UNIPROT "up-regulates activity" phosphorylation Thr545 HRFARRCtPEPQRLW 9606 BTO:0000007 28808054 t lperfetto "Here we show that MST4 phosphorylates ACAP4, an ARF6 GTPase-activating protein, at Thr545|Significantly, phosphorylation of Thr545 enables ACAP4 to interact with ezrin. Given the location of Thr545 between the GTPase-activating protein domain and the first ankyrin repeat, we reason that MST4 phosphorylation elicits a conformational change that enables ezrin-ACAP4 interaction." SIGNOR-272238 KIF18A protein Q8NI77 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272526 BMI1 protein P35226 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 23239878 t gcesareni "Here, we report that BMI1 autoactivates its own promoter via an E-box present in its promoter." SIGNOR-245344 HTR7 protein P34969 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257323 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates "chemical activation" 9606 16794003 t gcesareni "The evidence suggests that s1p acting on s1p receptors coupled to gq." SIGNOR-147230 GABRD protein O14764 UNIPROT "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263773 RELN protein P78509 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni "The hypothesis that the vldl receptor signals in response to reelin binding was recently supported by studies (37) showing direct binding of reelin to the vldl receptor and changes in tyrosine phosphorylation in response to reelin-vldl receptor association." SIGNOR-106295 ICOSLG protein O75144 UNIPROT ICOS protein Q9Y6W8 UNIPROT "up-regulates activity" binding 9606 27559335 t "ICOSL expression is largely restricted to professional antigen-presenting cells (APCs), including B cells [in which ICOSL is regulated by BAFFR and non-canonical NFκB signaling (20)], macrophages, and dendritic cells (DCs) (12, 17, 21, 22), but is also expressed by certain endothelial cells (23) and lung epithelium" SIGNOR-272497 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257932 GADL1 protein Q6ZQY3 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "down-regulates quantity" "chemical modification" 9606 22718265 t miannu "Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms." SIGNOR-267545 CDK5 protein Q00535 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Thr354 HLGPHRStPESRAAV 9606 12056836 t lperfetto "Cyclin-dependent kinase-5/p35 phosphorylates presenilin 1 to regulate carboxy-terminal fragment stabilityhere we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates ps1 on threonine(354) within c-ps1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize c-ps1." SIGNOR-89145 CREBBP protein Q92793 UNIPROT DDX21 protein Q9NR30 UNIPROT "down-regulates activity" acetylation Lys600 HFKQSAEkLIEEKGA 28790157 t lperfetto "Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21." SIGNOR-275906 DYRK1A protein Q13627 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates activity" phosphorylation Ser10 NVRVSNGsPSLERMD 9606 24806449 t miannu "DYRK1A phosphorylates p27 Kip1 at Ser10 in primary neurons and in vivo.|Thus, our results identify DYRK1A as the predominant kinase that phosphorylates and stabilizes p27Kip1 during neuronal differentiation." SIGNOR-278250 TRIM28 protein Q13263 UNIPROT FBP1 protein P09467 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000594 28394358 t lperfetto "In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28." SIGNOR-267591 IL18 protein Q14116 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 10653850 f miannu "IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement." SIGNOR-260965 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002428 31908417 t miannu "The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs." SIGNOR-262253 MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000527 16740698 t miannu "Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor" SIGNOR-146915 PLK1 protein P53350 UNIPROT RAN protein P62826 UNIPROT up-regulates phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 16930555 t lperfetto "Plk1 is capable of phosphorylating co-immunoprecipitated ran in vitro on serine-135 and ran is phosphorylated in vivo at the same site during mitosis when plk1 is normally activated. Deregulation of ran phosphorylation disrupts normal spindle structure and segregation of chromosomes." SIGNOR-149073 OXTR protein P30559 UNIPROT DRD2 protein P14416 UNIPROT "up-regulates activity" binding 10116 27425032 t miannu "Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling." SIGNOR-270333 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248400 FBXW7 protein Q969H0 UNIPROT EGLN2 protein Q96KS0 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 28036276 t lperfetto "Mechanistically, we further show that FBW7, an E3 ligase complex component that is frequently downregulated in TNBC, negatively regulates EglN2 protein stability." SIGNOR-261997 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 20626350 t lperfetto "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2." SIGNOR-166619 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273092 PRKACA protein P17612 UNIPROT PIN1 protein Q13526 UNIPROT "down-regulates activity" phosphorylation Ser16 PGWEKRMsRSSGRVY 9606 11723108 t llicata "Pka and pkc readily phosphorylated pin1 and its ww domain in summary, we have demonstrated that phosphorylation of the pin1 ww domain on ser16 regulates its ability to function as a pser/thr-binding module. |To examine the importance of Ser16 of Pin1, it was mutated to Glu to mimic pSer, and the mutant Pin1S16E failed to bind mitotic phosphoproteins" SIGNOR-112164 MYCT1 protein Q8N699 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates activity" 9606 30283340 f miannu "Herein, we observed that overexpression of MYCT1 induced apoptosis in HL-60 and KG-1a cells, and upregulated Bax, downregulated Bcl-2, and enhanced cleavage of caspase-3 and -9. Similar proapoptotic role of MYCT1 was also found in the AML cell xenografts. These results suggest that MYCT1 affects AML cell apoptosis by modulating the endogenous apoptotic pathways." SIGNOR-261942 lidocaine chemical CHEBI:6456 ChEBI SCN2A protein Q99250 UNIPROT "down-regulates activity" "chemical inhibition" 10116 1658608 t miannu "This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner." SIGNOR-258354 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto "TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-236366 KIF21B protein O75037 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 f "In this study, we showed that KIF21B is a highly processive MT plus-end directed motor, which can potently induce pausing of MT plus ends. This activity depends on several regions of this large motor protein." SIGNOR-272515 SIM1 protein P81133 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR "down-regulates activity" binding -1 9020169 t 2 miannu "SIM1 can inhibit AHR·ARNT binding to the XRE and can inhibit expression from an XRE-driven reporter gene indicates that SIM1 may act as negative regulator of transcription as well as a positive regulator. The above inhibitory effects may result from SIM1 competing with AHR for binding to ARNT, although we cannot exclude the possibility that SIM1 may also have other inhibitory effects of AHR·ARNT activity. In a similar fashion, SIM1 may act as a negative regulator of all ARNT-dependent genes." SIGNOR-240811 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto "The transcription factor, forkhead in rhabdomyosarcoma (FKHR), is phosphorylated at three amino acid residues (Thr-24, Ser-256 and Ser-319) by protein kinase b (PKB)alpha. FKHR (forkhead in rhabdomyosarcoma), AFX (all1 fused gene from chromosome x) and FKHRL1 (FKHR-like 1) are phosphorylated directly by PKB in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus." SIGNOR-105459 E2F1 protein Q01094 UNIPROT HSPA5 protein P11021 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18840615 f miannu "we show that E2F1 represses GRP78/BIP at the transcriptional level, and this requires its DNA binding domain." SIGNOR-253845 NDUFV3 protein P56181 UNIPROT "NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262185 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258846 CDC16 protein Q13042 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252006 MAPK3 protein P27361 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser225 ARLGSQHsPGRTASL 9606 21419341 t gcesareni "We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1." SIGNOR-172881 NR1H3 protein Q13133 UNIPROT BHLHE40 protein O14503 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19032342 f lperfetto "LXRα and LXRβ are potent positive regulators for hepatic Dec1" SIGNOR-253691 SMO protein Q99835 UNIPROT GNAT2 protein P19087 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-199171 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 19667122 t lperfetto "Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta." SIGNOR-187578 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 BTO:0000567 19789335 t lperfetto "we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1." SIGNOR-109684 EP300 protein Q09472 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11796223 t lperfetto "Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription." SIGNOR-232159 NFIA protein Q12857 UNIPROT FOXO6 protein A8MYZ6 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268875 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni "Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity." SIGNOR-252824 KAT2B protein Q92831 UNIPROT H3-2 protein Q5TEC6 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269624 GSK3B protein P49841 UNIPROT XIAP protein P98170 UNIPROT "up-regulates activity" phosphorylation Thr180 WPDYAHLtPRELASA 9606 BTO:0002181 29678905 t miannu " We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAPT180A) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos. " SIGNOR-277390 NFX1 protein Q12986 UNIPROT TERT protein O14746 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17267499 t miannu "NFX1-123 positively regulated hTERT expression, as its knockdown decreased hTERT mRNA levels and telomerase activity and its overexpression increased telomerase activity. NFX1-123 was found to interact with cytoplasmic poly(A) binding proteins (PABPCs), and together they synergistically augmented expression from the hTERT promoter when activated by HPV16 E6." SIGNOR-261050 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF11 protein A6NNE9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271244 AURKB protein Q96GD4 UNIPROT KIF20A protein O95235 UNIPROT "down-regulates activity" phosphorylation Ser878 RILRSRRsPLLKSGP 9606 BTO:0000567 27939310 t miannu "We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878." SIGNOR-262659 MAPK14 protein Q16539 UNIPROT COL1A1 protein P02452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f gcesareni "(tak1) and tak1 binding protein 1 (tab1) play a pivotal role as upstream sig-nal transducers by activating the mkk3-p38 mapk signaling cascade that leads to the induction of type i collagen expression by tgf-beta1." SIGNOR-192796 "URI1 prefoldin co-chaperone" complex SIGNOR-C514 SIGNOR "PAQosome co-chaperone complex" complex SIGNOR-C516 SIGNOR "form complex" binding 9606 30484152 t miannu "The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92. " SIGNOR-270924 CHRM5 protein P08912 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256873 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 t lperfetto "Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor." SIGNOR-26586 CABIN1 protein Q9Y6J0 UNIPROT "HIRA complex 1" complex SIGNOR-C461 SIGNOR "form complex" binding 9606 30285846 t miannu "H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex." SIGNOR-269435 ERBB3 protein P21860 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16729043 t gcesareni "All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3." SIGNOR-146858 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates activity" phosphorylation Ser171 SALNRTSsDSALHTS 9606 BTO:0000567 16306228 t lperfetto "We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression" SIGNOR-249172 SNAPC complex SIGNOR-C565 SIGNOR POU2F1 protein P14859 UNIPROT "up-regulates activity" binding 11056176 t miannu "In the case of the human RNA polymerase II and III small nuclear RNA (snRNA) genes, whose core promoters consist of a proximal sequence element (PSE) and a PSE combined with a TATA box, respectively, the same multisubunit complex is involved in the establishment of RNA polymerase II and III initiation complexes. This factor, the snRNA-activating protein complex or SNAP(c), binds to the PSE of both types of promoters and contains five types of subunits, SNAP190, SNAP50, SNAP45, SNAP43, and SNAP19. SNAP(c) binds cooperatively with both Oct-1, an activator of snRNA promoters, and in the RNA polymerase III snRNA promoters, with TATA-binding protein, which binds to the TATA box located downstream of the PSE. " SIGNOR-280634 SNAPC complex SIGNOR-C565 SIGNOR "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "up-regulates activity" binding 36369505 t miannu "In eukaryotes, small nuclear RNAs (snRNAs) function in many fundamental cellular events such as precursor messenger RNA splicing, gene expression regulation, and ribosomal RNA processing. The snRNA activating protein complex (SNAPc) exclusively recognizes the proximal sequence element (PSE) at snRNA promoters and recruits RNA polymerase II or III to initiate transcription. " SIGNOR-280635 SNAPC complex SIGNOR-C565 SIGNOR "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "up-regulates activity" binding 36369505 t miannu "In eukaryotes, small nuclear RNAs (snRNAs) function in many fundamental cellular events such as precursor messenger RNA splicing, gene expression regulation, and ribosomal RNA processing. The snRNA activating protein complex (SNAPc) exclusively recognizes the proximal sequence element (PSE) at snRNA promoters and recruits RNA polymerase II or III to initiate transcription. " SIGNOR-280636 TK1 protein P04183 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI "up-regulates quantity" "chemical modification" 9606 17407781 t miannu "The two dTTP biosynthetic routes are the de novo and the salvage pathways. Human thymidine kinase 1 (hTK1) catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate." SIGNOR-280519 CBLB protein Q13191 UNIPROT TYRO3 protein Q06418 UNIPROT "up-regulates activity" ubiquitination 9606 31531847 t miannu "Consistent with these data, we also found that Tyro3 is ubiquitinated by Cbl-b.|These data suggest that not only was Tyro3 a ubiquitination target of Cbl-b, but also that Cbl-b was a phosphorylation target of Tyro3." SIGNOR-278807 "Trifunctional enzyme" complex SIGNOR-C564 SIGNOR (E)-hexadec-2-enoyl-CoA(4-) smallmolecule CHEBI:61526 ChEBI "down-regulates quantity" "chemical modification" 9606 30850536 t miannu "Membrane-bound mitochondrial trifunctional protein (TFP) catalyzes β-oxidation of long chain fatty acyl-CoAs, employing 2-enoyl-CoA hydratase (ECH), 3- hydroxyl-CoA dehydrogenase (HAD), and 3-ketothiolase (KT) activities consecutively. " SIGNOR-280310 GMPR protein P36959 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI "up-regulates quantity" "chemical modification" 9606 33369428 t miannu "The human GMPR enzyme maintains the intracellular balance between the adenine and guanine nucleotide pools. The chemical reaction of this enzyme proceeds by deamination and hydride transfer steps. In deamination, the thiol group of Cys186 reacts on C2 of 5GP to form an intermediate E-XMP. In the second step, nicotinamide moves adjacent to C2 of E-XMP to allow hydride ion transfer, resulting in the production of inosine-5′-monophosphate (IMP) (Figure S4). " SIGNOR-280514 PJA2 protein O43164 UNIPROT PRKAR2B protein P31323 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21423175 t miannu "Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits" SIGNOR-271858 "Endoplasmic reticulum membrane complex- EMC9 variant" complex SIGNOR-C566 SIGNOR Protein_insertion_into_membrane phenotype SIGNOR-PH236 SIGNOR up-regulates 9606 32439656 f miannu "The nine-subunit ER membrane protein complex (EMC) is a conserved co- and post-translational insertase at the endoplasmic reticulum. We determined the structure of the human EMC in a lipid nanodisc to an overall resolution of 3.4 Å by cryo-electron microscopy, permitting building of a nearly complete atomic model. " SIGNOR-280646 LARP4B protein Q92615 UNIPROT PABPC1 protein P11940 UNIPROT "up-regulates activity" binding 9606 20573744 t miannu "Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex." SIGNOR-260940 PRKAA1 protein Q13131 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser385 RRRKKRTsIETNIRV 9606 1684878 t lperfetto "Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites." SIGNOR-20971 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 ChEBI ADRA2C protein P18825 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258923 Ub:E2 complex SIGNOR-C497 SIGNOR RFPL4B protein Q6ZWI9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271178 EDNRB protein P24530 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256924 CDK1 protein P06493 UNIPROT CLN3 protein Q13286 UNIPROT "down-regulates activity" phosphorylation 9606 23217712 t miannu "(D) Phosphorylation of Cln3 by Cdk1 is independent of Ssa1 T36.|Thereby, both Cdk1 and Pho85can promote Cln3 degradation, though under distinct circumstances." SIGNOR-279013 NEK7 protein Q8TDX7 UNIPROT EML4 protein Q9HC35 UNIPROT "up-regulates activity" phosphorylation Ser146 PQIRASPsPQPSSQP -1 31409757 t done miannu "The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression." SIGNOR-273884 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 21035469 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-169154 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Ser293 FNTLAFPsMKRKDVV -1 19264966 t miannu "The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites." SIGNOR-276130 LIMK2 protein P53671 UNIPROT SPOP protein O43791 UNIPROT "down-regulates activity" phosphorylation Ser171 VQDSVNIsGQNTMNM 9606 33311589 t miannu "LIMK2 phosphorylates SPOP at S59, S171 and S226.|Together, these results depict that LIMK2-mediated SPOP degradation is a key mechanism that regulates AR stability." SIGNOR-278339 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120184 "Papain-like proteinase" protein P0C6X7-PRO_0000037311 UNIPROT STING1 protein Q86WV6 UNIPROT "down-regulates activity" binding 9606 22312431 t miannu "Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING" SIGNOR-260247 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser371 AHSSHLKsKKGQSTS 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-51280 PPARG protein P37231 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 17681149 f lperfetto "This mechanism is mainly operative in native monocytes that, in the presence of an appropriate M2 stimulus such as IL-4, can be primed by PPARg ligands to an enhanced M2 phenotype." SIGNOR-249542 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 t gcesareni "In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site." SIGNOR-83217 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 t lperfetto "Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities" SIGNOR-137635 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 14563837 t gcesareni "Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc" SIGNOR-118844 STK38 protein Q15208 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser76 SNLQRMGsSESTDSG 9606 25936524 t miannu "Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation." SIGNOR-279488 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Sec) smallmolecule CHEBI:29264 ChEBI "up-regulates quantity" "chemical modification" 9606 27911719 t lperfetto "RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)" SIGNOR-269495 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 22898666 t gcesareni "Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity." SIGNOR-191851 PLK1 protein P53350 UNIPROT RAP1GAP protein P47736 UNIPROT down-regulates phosphorylation Ser525 AGQKTPDsGHVSQEP 9606 25329897 t lperfetto "Plk1 phosphorylates ser525 in conserved 524dsghvs529 degron of rap1gap and promotes its interaction with _-trcp. Together, these results further support a model in which plk1, but not cdk1 or gsk-3_-mediated phosphorylation of rap1gap is a prerequisite for mitotic degradation." SIGNOR-205577 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "down-regulates activity" relocalization 9606 27871158 t lperfetto "Integrin αIIbβ3 is retained by the actin cytoskeleton in resting platelets but is released to the cell surface during platelet activation. " SIGNOR-261864 clozapine chemical CHEBI:3766 ChEBI HTR1B protein P28222 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0001311 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258519 ANK3 protein Q12955 UNIPROT DAG1 protein Q14118 UNIPROT "up-regulates quantity" relocalization 10090 BTO:0001103 19109891 t miannu "We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4." SIGNOR-266714 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT3 protein Q9NTG7 UNIPROT "up-regulates activity" phosphorylation Ser159 SGIPDFRsPGSGLYS 9606 BTO:0001109 26141949 t miannu " Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. " SIGNOR-276921 CSNK2B protein P67870 UNIPROT HOXB6 protein P17509 UNIPROT unknown phosphorylation Ser214 LLSASQLsAEEEEEK -1 10327653 t llicata "Using two-dimensional tryptic phosphopeptide mapping and purified protein kinases, we demonstrate that Hoxb-6 is phosphorylated in vitro by casein kinase II and cAMP-dependent protein kinase. The casein kinase II phosphorylation site was mapped to serine-214. " SIGNOR-251071 SIAH2 protein O43255 UNIPROT AKAP1 protein Q92667 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 18323779 t miannu "Seven In-Absentia Homolog 2 (Siah2), an E3-ubiquitin ligase whose expression is induced in hypoxic conditions, formed a complex and degraded AKAP121." SIGNOR-272641 IL10RB protein Q08334 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t milica "Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor ? Chain) and tyk2 (associated with the il-10 receptor ? Chain) and induces the activation of stat1, stat3, and, in some cells, stat5." SIGNOR-68013 PKC proteinfamily SIGNOR-PF53 SIGNOR NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0001853 24379783 t "inferred from 70% family members" lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-269971 MAPK3 protein P27361 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 t gcesareni "Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms" SIGNOR-44949 LNPEP protein Q9UIQ6 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 25767437 t miannu "It has been shown that the steady state of the mature OT form can be controlled by an oxytocinase (P-LAP) that is produced in periphery and centrally by the OT-magnocellular neurons. Noticeably, P-LAP is also expressed in parvocellular OT neurons and in other brain structures| The OT intermediate forms are produced from E16.5 (see above) but the mature amidated OT form is detected only from birth. The released mature form is then degraded by an oxytocinase (PLAP)" SIGNOR-268552 NEFL protein P07196 UNIPROT "Neurofilament L/M" complex SIGNOR-C207 SIGNOR "form complex" binding 9606 19468066 t miannu "Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H" SIGNOR-255270 DUX4 protein Q9UBX2 UNIPROT PITX1 protein P78337 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 17984056 t Luana "DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1" SIGNOR-261590 hydromorphone chemical CHEBI:5790 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258038 NFYB protein P25208 UNIPROT SOX18 protein P35713 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 18496767 f miannu "co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells" SIGNOR-254819 MC5R protein P33032 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257271 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 17567956 t gcesareni "In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)" SIGNOR-155987 "tacrolimus (anhydrous)" chemical CHEBI:61049 ChEBI PPP3CC protein P48454 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127245 CUDC-907 chemical CID:54575456 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252661 ATM protein Q13315 UNIPROT ABRAXAS1 protein Q6UWZ7 UNIPROT "up-regulates activity" phosphorylation Ser404 MKGFGEYsRSPTF 9606 BTO:0000007 26778126 t "In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer." SIGNOR-255587 MEF2C protein Q06413 UNIPROT JUN protein P05412 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9069290 f gcesareni "One consequence of mef2c activation is increased c-jun gene transcription. Our results show that p38 may influence host defence and inflammation by maintaining the balance of c-jun protein consumed during infection" SIGNOR-47139 CDKN2A protein P42771 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f "Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation." SIGNOR-259406 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT "down-regulates activity" phosphorylation Ser164 TSTPGRRsCFGFEGL -1 23901111 t miannu "Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. " SIGNOR-276113 DLGAP2 protein Q9P1A6 UNIPROT SHANK3 protein Q9BYB0 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264591 SLC38A2 protein Q96QD8 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "up-regulates quantity" relocalization 9606 26724577 t "Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine." SIGNOR-266913 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR TSC2 protein P49815 UNIPROT "up-regulates activity" phosphorylation Ser1217 MSLENPLsPFSSDIN 9606 BTO:0000007 32294430 t done miannu "We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. " SIGNOR-274101 PRKCD protein Q05655 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates phosphorylation Thr312 TNGEFKMtDPDEVAR 9606 21321929 t lperfetto "We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter." SIGNOR-172113 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" phosphorylation Ser821 ARDIKNDsNYVVKGN 9823 7539802 t lperfetto "We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling." SIGNOR-248897 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270376 TANC2 protein Q9HCD6 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10116 21068316 t miannu "In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses." SIGNOR-266897 STAT6 protein P42226 UNIPROT SLC26A4 protein O43511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24429829 f miannu "We then examined the ability of STAT6 to bind each of the N4 GAS motifs in vivo with a site-specific ChIP assay, the results of which showed that STAT6 interacted with only the N4 GAS motif that was functionally implicated in increasing the activity of the pendrin promoter following IL-4 treatment." SIGNOR-255250 AMFR protein Q9UKV5 UNIPROT MFN2 protein O95140 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 23427266 t miannu "Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2." SIGNOR-272887 MDM2 protein Q00987 UNIPROT OVOL2 protein Q9BRP0 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 35896951 t miannu "In breast cancer cells, MDM2 overexpression or p53 KD reduced OVOL2 protein expression, and the proteasome inhibitor MG132 blocked the MDM2 overexpression\u2010 or p53 KD\u2010mediated reduction in OVOL2 expression (Figure\u00a06B,C).|The E3 ubiquitin ligase MDM2 ubiquitinates and degrades the OVOL2 protein." SIGNOR-278826 TBK1 protein Q9UHD2 UNIPROT SLC6A4 protein P31645 UNIPROT "up-regulates activity" phosphorylation Ser13 LNSQKQLsACEDGED 9606 32757223 t miannu "Taken together, our data suggest that TBK1 expression promotes the general cellular clearance mechanism of soluble HTT and prevents its accumulation and aggregation by enhancing autophagy.|This confirmed that TBK1 phosphorylated endogenous HTT at S13 (Fig XREF_FIG G and H)." SIGNOR-278384 TNIK protein Q9UKE5 UNIPROT NF2 protein P35240 UNIPROT "up-regulates activity" phosphorylation Thr576 GGSSKHNtIKKLTLQ 9606 33495197 t miannu "Consistently with TNIK modulating Merlin, we also observed reduced YAP levels following TNIK knockdown in LK2 and NCI-H520 cells (Supplementary Fig. S7B).|Using in vitro kinase assays followed by phosphopeptide mapping, and mass spectrometry analysis on Merlin isolated from cells co-expressing TNIK and Merlin, we determined that TNIK could phosphorylate Merlin at S13, T272, S315, and T576 (Fig. 4B, Supplementary Fig. S4D, and Supplementary Table S3)." SIGNOR-278385 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273056 MRPL30 protein Q8TCC3 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262365 IL1RL1 protein Q01638 UNIPROT IL1RAP protein Q9NPH3 UNIPROT "up-regulates activity" binding 9606 35238669 t miannu "The initial step in IL-33 signal transduction is ligand-induced conformational changes in IL-33R, which facilitate recruitment of interleukin-1 receptor accessory protein (IL-1RAP)." SIGNOR-277715 RNASEK protein Q6P5S7 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR "form complex" binding 9606 33065002 t miannu "Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes." SIGNOR-277753 MIS18BP1 protein Q6P0N0 UNIPROT "CENP-A recruiting complex" complex SIGNOR-C632 SIGNOR "form complex" binding 9606 38951710 t miannu "A central player mediating this process is the Mis18 complex (Mis18α, Mis18β and Mis18BP1), which recruits the CENP-A-specific chaperone HJURP to centromeres for CENP-A deposition. Here, using a multi-pronged approach, we characterise the structure of the Mis18 complex and show that multiple hetero- and homo-oligomeric interfaces facilitate the hetero-octameric Mis18 complex assembly composed of 4 Mis18α, 2 Mis18β and 2 Mis18BP1. " SIGNOR-281033 GRK5 protein P34947 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 2787365 t gcesareni "we found that g protein-coupled receptor kinases 5 and 6 (grk5/6), traditionally known to phosphorylate and desensitize 7tm g protein-coupled receptors, directly phosphorylate the pppsp motifs on single transmembrane lrp6 and regulate wnt/lrp6 signaling" SIGNOR-23330 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270406 MYCT1 protein Q8N699 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30283340 f miannu "MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2." SIGNOR-261734 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT "down-regulates quantity by destabilization" cleavage Tyr27 LSSTCVAyVATRDNC -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263616 CREB1 protein P16220 UNIPROT MUC4 protein Q99102 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001861 19757157 f lperfetto "Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level." SIGNOR-254091 FLI1 protein Q01543 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR "up-regulates activity" 10090 BTO:0000725 23320737 f "The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice" SIGNOR-259972 AP1 complex SIGNOR-C154 SIGNOR GLIS1 protein Q8NBF1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 24383088 t miannu "Co-transfection experiments revealed that HIF-2α had greater potency on the GLIS1 promoter activation than HIF-1α. Subsequent studies using wild-type and mutant HIF-2α demonstrated that DNA binding activity was not necessary but TADs were critical for GLIS1 induction. Finally, co-transfection experiments indicated that HIF-2α cooperated with AP-1 family members in upregulating GLIS1 transcription. These results suggest that the hypoxic signaling pathway may play a pivotal role in regulating the reprogramming factor GLIS1, via non-canonical mechanisms involving partner transcription factor rather than by direct HIF transactivation." SIGNOR-269041 RPS6KA5 protein O75582 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 BTO:0000975 11145955 t gcesareni "Phosphorylation on ser383 and ser389 of elk-1 by mapk enhances this basal binding but, most importantly, elk-1 exhibits new interactions with p300." SIGNOR-85514 EP300 protein Q09472 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" acetylation Lys28 LATKAARkSAPSTGG 9606 SIGNOR-C6 21131905 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" fspada "These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription." SIGNOR-170266 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120104 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser641 GKVYGKTsHLRAHLR 9606 16943418 t gcesareni "The hdac inhibitor tsa-induced cell-specific phosphatase release from the promoter, which serves as an 'on' mechanism for sp1 phosphorylation by phosphatidylinositol 3-kinase/protein kinase czeta (pi3k/pkczeta) at ser641, leading to p107 repressor derecruitment and lhr transcriptional activation." SIGNOR-149287 BRLF1 protein P03209 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 20381110 t scontino "EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs." SIGNOR-266644 "Phenylalanyl-tRNA synthetase" complex SIGNOR-C473 SIGNOR phenylalanine smallmolecule CHEBI:28044 ChEBI "down-regulates quantity" "chemical modification" 9606 20223217 t miannu "Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers." SIGNOR-270439 BGLF4 protein P13288 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" phosphorylation Ser123 DFSQPDTsPDTNGGG 9606 BTO:0002181 19052084 t scontino "BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity." SIGNOR-266647 BGLF4 protein P13288 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 BTO:0002181 19052084 t scontino "BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity." SIGNOR-266648 BGLF4 protein P13288 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" phosphorylation Thr180 SPSLDNPtPFPNLGP 9606 BTO:0002181 19052084 t scontino "BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity." SIGNOR-266649 F2RL3 protein Q96RI0 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257370 NODAL protein Q96S42 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0004094 15531507 f Regulation miannu "Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7." SIGNOR-251934 MAPK7 protein Q13164 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser78 ANPSPPPsPSQQINL 9606 11254654 t lperfetto "Bmk1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinasebmk1 activates sgk by phosphorylation at serine 78." SIGNOR-105728 DEPTOR protein Q8TB45 UNIPROT MTOR protein P42345 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 19446321 t "DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival" SIGNOR-251657 MEF2C protein Q06413 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002320 21598020 t miannu "GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter" SIGNOR-265816 N protein P59595 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" 9606 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites." SIGNOR-260337 3b protein P59633 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" 9606 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites." SIGNOR-260338 6 protein P59634 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" 9606 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites." SIGNOR-260339 FAM20C protein Q8IXL6 UNIPROT HRC protein P23327 UNIPROT "up-regulates activity" phosphorylation Ser96 EKEDEDVsKEYGHLL 10116 BTO:0001879 28784772 t miannu "Here, we demonstrate that family with sequence similarity 20C (Fam20C), a recently characterized protein kinase in the secretory pathway, phosphorylates HRC on Ser96. HRC Ser96 phosphorylation was confirmed in cells and human hearts.The pSer96-HRC binds tighter to triadin than S96A-HRC, which cannot be phosphorylated. Conversely, S96A-HRC or unphosphorylated Ser96-HRC binds tighter to SERCA2a. This suggests that Ser96-HRC phosphorylation (P) regulates HRC’s interactions with the major SR Ca-cycling proteins." SIGNOR-273639 EZH2 protein Q15910 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 23239736 t miannu "This study demonstrates that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a Polycomb repressor to a transcriptional coactivator of AR (and potentially other factors)." SIGNOR-251542 YY1 protein P25490 UNIPROT GDAP1 protein Q8TB36 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19720140 f miannu "Overexpression of YY1 activated the GDAP1 promoter in a reporter gene system as well as increased the level of endogenous mRNA." SIGNOR-255618 TTI1 protein O43156 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates quantity by stabilization" binding 9606 BTO:0000007 20427287 t miannu "MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2." SIGNOR-272002 ENMD-2076 chemical CID:16041424 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191466 CPT1A protein P50416 UNIPROT O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI "up-regulates quantity" "chemical modification" 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267129 IL10 protein P22301 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 23357618 f miannu "Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α." SIGNOR-253499 8a protein Q7TFA0 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" binding 9606 29294448 t miannu "Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. Overexpression of 8b and 8ab resulted in the reduction of poly (I:C)-induced IRF3 dimerization and inhibition of the IFN-β signaling pathway." SIGNOR-260239 8b protein Q80H93 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" binding 9606 29294448 t miannu "Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. This counteracting effect was partially mediated by protein 8b/8ab-induced degradation of IRF3 in a ubiquitin-proteasome-dependent manner. Taken together, we propose that SARS-CoV may exploit the unique functions of proteins 8b and 8ab as novel mechanisms to overcome the effect of IFN response during virus infection.." SIGNOR-260240 F12 protein P00748 UNIPROT F11 protein P03951 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000131 8427954 t lperfetto "Activation of factor XI in plasma is dependent on factor XII | Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided." SIGNOR-263519 ANAPC2 protein Q9UJX6 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 19805045 t gcesareni "We now report that the anaphase-promoting complex (apc/c) recognizes a d-box motif of dvl and ubiquitylates dvl on a highly conserved lysine residue.We now report that expression of the apc/c subunit anapc2 activates the apc/c-dependent degradation of dvl by disrupting canonical wnt signaling." SIGNOR-188393 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT "up-regulates activity" phosphorylation Ser389 LKEAEEEsSGGEEED 9606 BTO:0001938 11861906 t llicata "Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis." SIGNOR-251069 MICU1 protein Q9BPX6 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270859 ZBTB14 protein O43829 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 10080939 f miannu "ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter" SIGNOR-220537 CREB1 protein P16220 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity" "transcriptional regulation" 9606 26652733 t "inferred from family member" miannu "Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB" SIGNOR-267786 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates activity" dephosphorylation Tyr594 TYVDPHTyEDPNQAV -1 21538645 t gcesareni "The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates" SIGNOR-246039 CDK2 protein P24941 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Ser76 VQDTSGTsPVHDAAR 9606 22558186 t lperfetto "Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation." SIGNOR-197270 BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7791754 t fspada "Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor." SIGNOR-33425 FZD2 protein Q14332 UNIPROT LRP5 protein O75197 UNIPROT "up-regulates activity" binding 9606 25902418 t areggio "Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain." SIGNOR-258968 CARS1 protein P49589 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI "up-regulates quantity" "chemical modification" 9606 11347887 t miannu "Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine." SIGNOR-270474 ZDHHC2 protein Q9UIJ5 UNIPROT AKAP5 protein P24588 UNIPROT "up-regulates activity" palmitoylation Cys129 KSRLKIPcIKFPRGP 10116 25589740 t "Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms" SIGNOR-261289 ORC6 protein Q9Y5N6 UNIPROT ORC complex SIGNOR-C419 SIGNOR "form complex" binding 9606 32808929 t lperfetto "The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA" SIGNOR-267562 PRKCD protein Q05655 UNIPROT IL6ST protein P40189 UNIPROT "up-regulates activity" phosphorylation Thr909 PKSYLPQtVRQGGYM -1 12361954 t lperfetto "Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling." SIGNOR-249177 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t lperfetto "Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells" SIGNOR-264658 "Elongator complex" complex SIGNOR-C466 SIGNOR TUBA4A protein P68366 UNIPROT "up-regulates activity" acetylation 9606 BTO:0000007 19185337 t miannu "Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin." SIGNOR-269722 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser77 PGPFATRsPLFIFMR 12818176 t miannu "JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity." SIGNOR-250135 CDK1 protein P06493 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT "up-regulates activity" phosphorylation Ser1252 QPTLPSSsPVPIPVS 9606 BTO:0000567 37584777 t "phosphorylation site remapping based on mass spec table" lperfetto "CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects." SIGNOR-272968 NCKIPSD protein Q9NZQ3 UNIPROT NCK1 protein P16333 UNIPROT unknown binding 9606 14559906 t gcesareni "Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck" SIGNOR-118750 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT "down-regulates activity" phosphorylation Ser486 SSWGRTYsFTSAMSR 10090 SIGNOR-C469 21148297 t miannu "RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase. kt2 directly phosphorylated all three sites on RGC2 (Figure 5A)." SIGNOR-269797 RPS6K proteinfamily SIGNOR-PF26 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 15342917 t lperfetto "The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1" SIGNOR-252796 AMP smallmolecule CHEBI:456215 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI "up-regulates quantity" "precursor of" -1 31461341 t Luana "Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine." SIGNOR-269741 CCNE1 protein P24864 UNIPROT CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR "form complex" binding 37104883 t lperfetto "Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively." SIGNOR-273186 NRXN3 protein Q9HDB5 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626546 t miannu "The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites" SIGNOR-265456 CDK4 protein P11802 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates 9606 21902831 t gcesareni "Not much is known about how this occurs, but inhibition of mef2c by cdk4 prevents the association of mef2 with its transcriptional coactivator, glucocorticoid receptor-interacting protein 1 (grip1)." SIGNOR-176521 PTPN13 protein Q12923 UNIPROT PDCD10 protein Q9BUL8 UNIPROT "down-regulates activity" dephosphorylation 9606 17657516 t "In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling." SIGNOR-248714 HTRA2 protein O43464 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates binding 9606 15328349 t gcesareni "Htra2 promotes cell death by binding and degrading the anti-apoptotic protein pea15" SIGNOR-126966 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT "down-regulates activity" phosphorylation Thr204 NEAAARFtLGSPLTS 9606 9630228 t lperfetto "Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4." SIGNOR-109768 LRIG1 protein Q96JA1 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates ubiquitination 9606 16123311 t gcesareni "We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation." SIGNOR-139948 ARX protein Q96QS3 UNIPROT EBF3 protein Q9H4W6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19627984 f "Regulation of expression" miannu "Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissues partially rescues tangential cell movement." SIGNOR-251971 BAP1 protein Q92560 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 26470845 t lperfetto "Since we found that ASXL1 and BAP1 both are enriched at the INK4B locus, our results suggest that activation of the INK4B locus requires ASXL1/BAP1-mediated deubiquitinylation of H2AK119ub1." SIGNOR-241656 "BRCA1-B complex" complex SIGNOR-C298 SIGNOR ATR protein Q13535 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 16530042 t lperfetto "These results establish that TopBP1 can activate both Xenopus and human ATR. Furthermore, these experiments provide conclusive evidence that the kinase activity that is induced by TopBP1 is intrinsic to the ATR protein itself and is not due to a kinase that associates with ATR." SIGNOR-263231 ARHGEF1 protein Q92888 UNIPROT RHOA protein P61586 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 BTO:0000887;BTO:0001260 10836144 t gcesareni "Rhogefs catalyze the exchange of gdp for gtp and thereby activate rho." SIGNOR-77914 GADD45G protein O95257 UNIPROT CDK11A protein Q9UQ88 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 26885618 t lperfetto "Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58." SIGNOR-273025 PAN3 protein Q58A45 UNIPROT "PAN2-PAN3 deadenylation complex" complex SIGNOR-C553 SIGNOR "form complex" binding 9606 34280615 t miannu "There are two major deadenylase complexes, Ccr4-Not and Pan2-Pan3, which shorten the 3′ poly(A) tail of mRNA and are conserved from yeast to human.The Ccr4-Not complex has two catalytic subunits including the Ccr4 (Carbon catabolite repressor 4) and Pop2 (PGK promoter directed overproduction). The Pan2-Pan3 complex comprises the catalytic subunit Pan2, a member of the RNase D family, and the regulatory subunit Pan3. Degradation of mRNA begins with either shortening of the poly(A) tail by deadenylases or removal of 5′ cap structure by the decapping enzyme Dcp1-Dcp2." SIGNOR-273871 PRKCD protein Q05655 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 16377624 t llicata "Here, we show that the pro-apoptotic kinase, protein kinase c delta (pkcdelta), is involved in phosphorylation of p53 on ser(46). pkcdelta potentiates p53-dependent apoptosis by ser(46) phosphorylation in response to genotoxic stress." SIGNOR-143382 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser316 VEEEPLNsEDDVSDE -1 11278496 t llicata "We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function." SIGNOR-250876 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 10669763 t gcesareni "Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association." SIGNOR-74935 AURKA protein O14965 UNIPROT SGO1 protein Q5FBB7 UNIPROT "up-regulates activity" phosphorylation -1 16824953 t lperfetto "Loss of INCENP/Aurora B in Mitosis Correlates with Delocalization of MEI-S332|MEI-S332 Is Phosphorylated by Aurora B In Vitro|Of these, MEI-S332S124,125,126A was a poor substrate for Aurora B kinase in vitro" SIGNOR-252046 ATM protein Q13315 UNIPROT SNAI1 protein O95863 UNIPROT "up-regulates activity" phosphorylation Ser100 DEDSGKGsQPPSPPS 9606 23891091 t miannu "ATM-mediated Snail Serine 100 phosphorylation regulates cellular radiosensitivity." SIGNOR-279587 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273052 SOSTDC1 protein Q6X4U4 UNIPROT WNT7B protein P56706 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242733 ATM protein Q13315 UNIPROT FANCA protein O15360 UNIPROT up-regulates phosphorylation Ser1449 AAPDADLsQEPHLF 9606 19109555 t lperfetto "The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site" SIGNOR-182949 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR RUNX1 protein Q01196 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17442773 f miannu "Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. Runx1 is also upregulated in the NUP98‐HOXA9 transcriptosome and is a critical regulator of hematopoietic development and a frequent target for chromosomal translocation in leukemia" SIGNOR-261499 AKT1 protein P31749 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 t lperfetto "These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf" SIGNOR-252478 CDK2 protein P24941 UNIPROT ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 SIGNOR-C16 9029153 t lperfetto "Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_" SIGNOR-46397 CDK1 protein P06493 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates phosphorylation Thr292 ETPPRPRtPGRPLSS 9606 8114697 t gcesareni "P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well" SIGNOR-36116 HIPK2 protein Q9H2X6 UNIPROT PAX6 protein P26367 UNIPROT "up-regulates activity" phosphorylation Thr304 QPIPQPTtPVSSFTS 9606 BTO:0001938 16407227 t "HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373." SIGNOR-251270 MAPK7 protein Q13164 UNIPROT PML protein P29590 UNIPROT "down-regulates activity" phosphorylation Ser403 AAVSKKAsPEAASTP 9606 23730625 t miannu "Big MAP kinase 1 (BMK1) also phosphorylates PML at two sites : S403 and T409.|Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation." SIGNOR-279075 valine smallmolecule CHEBI:27266 ChEBI Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI "up-regulates quantity" "precursor of" 9606 30755602 t miannu "Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase." SIGNOR-270532 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275773 TCF3 protein P15923 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r." SIGNOR-197523 CYBA protein P13498 UNIPROT "Phagocyte NADPH oxidase complex" complex SIGNOR-C557 SIGNOR "form complex" binding 9606 37263099 t miannu "NADPH oxidase is composed of essential protein components in its active state: membranous subunits, including p22-phox and gp91-phox, and cytoplasmic subunits, including p47-phox, p67-phox, p40-phox, and RAC2 (in neutrophils), among which NCF4 encodes the cytoplasmic subunit p40-phox" SIGNOR-277634 ARIH1 protein Q9Y4X5 UNIPROT CD274 protein Q9NZQ7 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 33879767 t miannu "E3 ubiquitin ligase ARIH1 directly ubiquitinates PD-L1 and targets it for proteasomal degradation, following EGFR inhibition." SIGNOR-278582 HDAC11 protein Q96DB2 UNIPROT BRD2 protein P25440 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 30089714 t lperfetto "Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein." SIGNOR-262058 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser299 SSPTLSSsPPVLCNP 9606 22017875 t llicata "Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome." SIGNOR-176853 EDNRA protein P25101 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257165 AMPK complex SIGNOR-C15 SIGNOR CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser158 REGTRVQsVEQIREV 9606 23291169 t lperfetto "We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1" SIGNOR-216604 quetiapine chemical CHEBI:8707 ChEBI HTR1E protein P28566 UNIPROT "up-regulates activity" "chemical activation" 9534 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258531 KDM6A protein O15550 UNIPROT ETS2 protein P15036 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29736013 t miannu "Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase" SIGNOR-260035 FLT3 protein P36888 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14981546 f "FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression" SIGNOR-261524 GATA3 protein P23771 UNIPROT T-lymphocyte_diff phenotype SIGNOR-PH112 SIGNOR "up-regulates activity" 10090 22267605 f "Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs" SIGNOR-259953 FOXE1 protein O00358 UNIPROT TPO protein P07202 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001073 27347897 t scontino "TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8" SIGNOR-267279 MTOR protein P42345 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" phosphorylation 9606 26522726 t miannu "Thus our results indicate that the interaction between ER\u03b1 and raptor is necessary to recruit raptor to the nucleus, where mTOR phosphorylates and activates ER\u03b1." SIGNOR-278295 PRKDC protein P78527 UNIPROT MITF protein O75030 UNIPROT "up-regulates activity" phosphorylation Ser431 S-->C 9606 BTO:0000848 38316520 t miannu "These results suggest that DNA-PK can target MITF-S325 for phosphorylation. In melanocytes and melanoma cells, MITF is rapidly phosphorylated by DNA-PK and interacts with NBS1–RAD50 but not MRE11, destabilizing the MRN complex." SIGNOR-277899 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation 9606 17900900 t lperfetto "We have recently found that AMPK phosphorylates human FOXO3 in mammalian cells at novel regulatory sites that are distinct from the AKT sites" SIGNOR-216481 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser401 VPSDNIDsQGRNCST -1 8662852 t "we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411)." SIGNOR-251196 PRKACA protein P17612 UNIPROT ARHGEF6 protein Q15052 UNIPROT "down-regulates activity" phosphorylation Ser640 RKTERKPsEEEYVIR 9606 BTO:0000132 26507661 t lperfetto "ARHGEF6 is a Rho guanine nucleotide exchange factor for Rac1 and constitutively bound to GIT1. NO and PGI2 activate PKG and PKA, respectively and both kinases phosphorylate ARHGEF6 on Ser-684 and possibly on Ser-640. Phosphorylation of ARHGEF6 results in the assembly of a GIT1-ARHGEF6–14-3-3 complex. These changes might contribute to PGI2- and NO-mediated Rac1 inhibition." SIGNOR-272162 WWP2 protein O00308 UNIPROT GSC protein P56915 UNIPROT "up-regulates activity" ubiquitination 9606 21170031 t miannu "These results indicated that Wwp2 augments the transcription activity of Gsc.|We confirmed that Gsc was being mono-ubiquitinated by Wwp2 via in vitro ubiquitination assays that utilized purified Gsc, recombinant Wwp2 and ubiquitin-K0 proteins that resulted in a pattern of Gsc ubiquitination similar to WT ubiquitin (XREF_FIG)." SIGNOR-278797 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser672 TLYDRYSsPPASTTR 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus)" SIGNOR-104715 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRC1 protein O43663 UNIPROT unknown phosphorylation Thr481 RRGLAPNtPGKARKL 9885575 t llicata "We have shown that PRC1 is a good in vitro substrate for several CDKs, and that it is also phosphorylated in a cell cycle–dependent manner in vivo at Thr-481 (major mitosis. and Thr-470 (minor site), which are the in vitro phosphorylation sites." SIGNOR-250746 "sorafenib tosylate" chemical CHEBI:50928 ChEBI PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I." SIGNOR-259227 TAK-960 chemical CID:53357478 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207200 GRIN1 protein Q05586 UNIPROT "NMDA receptor_2A" complex SIGNOR-C347 SIGNOR "form complex" binding 9606 BTO:0000938 12871085 t miannu "The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits" SIGNOR-264120 PAK5 protein Q9P286 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9534 BTO:0000298 12897128 t miannu "P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112" SIGNOR-250247 AURKB protein Q96GD4 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser180 KKGGGKKsGKKSYLS 9606 23226345 t lperfetto "Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1" SIGNOR-200075 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129268 ATXN7 protein O15265 UNIPROT CRX protein O43186 UNIPROT "down-regulates activity" binding 10090 11580893 t miannu "We found that ataxin-7 and CRX colocalize and coimmunoprecipitate. We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation." SIGNOR-223226 "GABA-A (a6-b2-d) receptor" complex SIGNOR-C328 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268597 SOS2 protein Q07890 UNIPROT HRAS protein P01112 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." SIGNOR-175262 LARP7 protein Q4G0J3 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "down-regulates activity" binding 9606 BTO:0000567 30824372 t Monia "To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system." SIGNOR-261184 BAG1 protein Q99933 UNIPROT HSPA8 protein P11142 UNIPROT "up-regulates activity" binding -1 27474739 t lperfetto "Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70." SIGNOR-254115 SIRT5 protein Q9NXA8 UNIPROT SHMT2 protein P34897 UNIPROT "down-regulates activity" "post translational modification" Lys280 IVTTTTHkTLRGARS 34929314 t desuccinylation lperfetto "Mitochondrial serine hydroxymethyl transferase (SHMT2) is a rate-limiting enzyme that catalyzes the catabolism of serine and drives the proliferation of osteosarcoma cells and colon cancer cells. SIRT5 directly mediates the desuccinylation of Lysine 280 on SHMT2. Therefore, SIRT5 is a candidate target to inhibit serine catabolism" SIGNOR-267644 ACTB protein P60709 UNIPROT "Neural progenitor-specific SWI/SNF" complex SIGNOR-C477 SIGNOR "form complex" binding 9606 25195934 t miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270619 POLD2 protein P49005 UNIPROT "DNA polymerase delta" complex SIGNOR-C376 SIGNOR "form complex" binding -1 12403614 t lperfetto "Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme." SIGNOR-265516 PIK-93 chemical CID:6852167 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206241 TRAPPC11 protein Q7Z392 UNIPROT "TRAPP III complex, TRAPPC2 variant" complex SIGNOR-C568 SIGNOR "form complex" binding 9606 27066478 t miannu "Transport protein particle (TRAPP; also known as trafficking protein particle), a multimeric guanine nucleotide-exchange factor for the yeast GTPase Ypt1 and its mammalian homologue, RAB1, regulates multiple membrane trafficking pathways. TRAPP complexes exist in three forms, each of which activates Ypt1 or RAB1 through a common core of subunits and regulates complex localization through distinct subunits. Whereas TRAPPI and TRAPPII tether coated vesicles during endoplasmic reticulum to Golgi and intra-Golgi traffic, respectively, TRAPPIII has recently been shown to be required for autophagy." SIGNOR-280660 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000007 25081058 t lperfetto "PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop." SIGNOR-262595 RPS27L protein Q71UM5 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262445 LHX4 protein Q969G2 UNIPROT POU1F1 protein P28069 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15998782 f miannu "We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression." SIGNOR-254558 AKT proteinfamily SIGNOR-PF24 SIGNOR EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15531580 t lperfetto "Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression" SIGNOR-244263 SH3BP4 protein Q9P0V3 UNIPROT TFRC protein P02786 UNIPROT down-regulates binding 9606 16325581 t miannu "Here, we report that ttp (sh3bp4), a sh3-containing protein, specifically regulates the internalization of the transferrin receptor (tfr). / overexpression of ttp specifically inhibits tfr internalization" SIGNOR-142840 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT "down-regulates activity" phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000007 16023596 t lperfetto "The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance" SIGNOR-235892 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 19797085 t llicata "In addition, we show that the beta-trcp-mediated degradation requires phosphorylation of phlpp1 by casein kinase i and glycogen synthase kinase 3beta (gsk-3beta), and activation of the phosphatidylinositol 3-kinase/akt pathway suppresses the degradation of phlpp1 by inhibiting the gsk-3beta activity." SIGNOR-188330 NCOA3 protein Q9Y6Q9 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 15808510 f gcesareni "Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1." SIGNOR-135056 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu46 TRANSFLeEMKKGHL -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263664 TWIST1 protein Q15672 UNIPROT ILK protein Q13418 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255528 MRPL19 protein P49406 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262375 TLN1 protein Q9Y490 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257610 "CFI complex" complex SIGNOR-C388 SIGNOR "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity" cleavage 9606 8626397 t lperfetto "Purification and characterization of human cleavage factor Im involved in the 3' end processing of messenger RNA precursors|Gel retardation experiments confirmed the results obtained by UV cross-linking. In addition, we could show that CF Im stabilizes the binding of the cleavage and polyadenylation specificity factor (CPSF) to pre-mRNA and that CPSF and CF Im together form a slower migrating complex with pre-mRNA than the single protein factors." SIGNOR-266125 pentazocine chemical CHEBI:7982 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9262330 t miannu "We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine." SIGNOR-258659 CASP6 protein P55212 UNIPROT "Caspase 6 complex" complex SIGNOR-C228 SIGNOR "form complex" binding cleavage:Asp23 EENMTETdAFYKREM 21621544 t lperfetto "It is generally recognized that effector caspases undergo proteolytic cleavage of the inactive zymogen at a specific aspartate residue, resulting in a large N-terminal p20 polypeptide chain and a small C-terminal p10 polypeptide chain, leading to a p202/p102 tetramer." SIGNOR-256391 PRKDC protein P78527 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 9363941 t gcesareni "We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage." SIGNOR-53030 Ruboxistaurin chemical CID:153999 PUBCHEM PRKACB protein P22694 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258275 WWP1 protein Q9H0M0 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" ubiquitination 9606 16924229 t miannu "Unlike other E3 ligases, WWP1 increases p53 stability; inhibition of WWP1 expression or expression of a ligase-mutant form results in decreased p53 expression.|WWP1 associates with p53 and induces p53 ubiquitylation." SIGNOR-278649 FANCL protein Q9NW38 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" ubiquitination 9606 22653977 t miannu "Here we provide evidence that FANCL increases the activity and expression of beta-catenin, a key pluripotency factor in hematopoietic stem cells.|We show that FANCL ubiquitinates \u03b2-catenin with atypical ubiquitin chain extension known to have nonproteolytic functions." SIGNOR-278651 HUWE1 protein Q7Z6Z7 UNIPROT KAT7 protein O95251 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 32555450 t miannu "Moreover, we determined that Huwe1 is a novel E3 ligase for Myst2 degradation in mESCs, and Brpf3 disturbs Huwe1 mediated ubiquitination of Myst2 via interaction with Huwe1 and Myst2." SIGNOR-278652 CREB3L1 protein Q96BA8 UNIPROT CREB3L1 protein Q96BA8 UNIPROT "up-regulates activity" binding -1 12805554 t miannu "E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins" SIGNOR-224205 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 21798082 f lperfetto "Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome." SIGNOR-235715 PAX6 protein P26367 UNIPROT CTNND2 protein Q9UQB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16973151 f "Indirect:regulation of expression" miannu "In Pax6 mutant embryos, delta-catenin expression was severely reduced in the optic vesicle neural ectoderm, in the ventricular zone of the neocortex and in the external granule layer of the cerebellum. We identified a Pax6 binding site in delta-catenin promoter that is conserved between mice and humans and which is effectively bound by Pax6 in vitro. Our results suggest that Pax6 regulates delta-catenin expression during CNS development in mice." SIGNOR-251878 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation 6239 SIGNOR-C15 17900900 t lperfetto "The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt." SIGNOR-252983 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni "These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase" SIGNOR-76076 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 SIGNOR-C17 19709076 t lperfetto "Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane." SIGNOR-187766 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" SIGNOR-183616 ACLY protein P53396 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "chemical modification" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-267102 PRKCA protein P17252 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 7523419 t lperfetto "Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site." SIGNOR-248894 CDK1 protein P06493 UNIPROT UBE2I protein P63279 UNIPROT "up-regulates activity" phosphorylation 9606 22509284 t miannu "Overall, these results suggest that Cdk1 and cyclin B mediates the phosphorylation of Ubc9 at serine 71." SIGNOR-278174 Aflibercept chemical SID:134445687 ChEBI VEGFB protein P49765 UNIPROT "down-regulates activity" "chemical inhibition" 9606 22813448 t miannu "Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor." SIGNOR-259387 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT "down-regulates activity" phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 11333986 t lperfetto "P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-107412 CDC73 protein Q6P1J9 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR "form complex" binding 9606 BTO:0000567 20178742 t miannu "Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). " SIGNOR-269836 RPS6KA1 protein Q15418 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 BTO:0000848 15024089 t gcesareni "We show that the n-terminal kinase domain of rsk phosphorylates flna on ser(2152) in response to mitogens" SIGNOR-123458 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" SIGNOR-252524 FBXO33 protein Q7Z6M2 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 16797541 t miannu "Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1" SIGNOR-271605 LGALS3 protein P17931 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "up-regulates activity" binding 9606 BTO:0000584 32745890 t miannu "Oncogenic RAS requires a protein scaffold to induce downstream signaling and macropinocytosis, three separate studies have identified upstream and downstream regulators that help drive this process in cancer cells. Anchorage-independent growth of cancer cells is supported by avb3 integrins which can be clustered by the extracellular lectin, galectin-3 to drive mutant RAS-mediated macropinocytosis for nutrient supplementation and growth of anchorage-independent cells. Secreted galectin-3 was found to bind to the N-glycans on surface avb3 integrins, clustering the integrins on the surface of the nonadherent cells for the recruit- ment of mutant KRAS as a signaling platform for inducing macropinocytosis" SIGNOR-277741 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" lperfetto "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-244703 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr696 ARQSRRStQGVTLTD 9606 12030846 t lperfetto "Mypt1 was phosphorylated by ilk and phosphorylation sites in the n- and c-terminal fragments of mypt1 were detected. From sequence analyses, three sites were identified: a primary site at thr(709), and two other sites at thr(695) and thr(495)" SIGNOR-87924 LPAR3 protein Q9UBY5 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22863277 t gcesareni "Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2." SIGNOR-198547 DYRK1A protein Q13627 UNIPROT MEF2D protein Q14814 UNIPROT "down-regulates activity" phosphorylation Ser251 NKVIPAKsPPPPTHS -1 34109727 t miannu "Here, we uncovered that dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a kinase critical in Down's syndrome pathogenesis, directly bound to and phosphorylated MEF2D at Ser251 in vitro. Phosphorylation of MEF2D by DYRK1A significantly increased MEF2D protein level but attenuated its transcriptional activity, which resulted in decreased transcriptions of MEF2D target genes." SIGNOR-277565 IFNG protein P01579 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu "Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection" SIGNOR-261033 halothane chemical CHEBI:5615 ChEBI KCNK3 protein O14649 UNIPROT "up-regulates activity" "chemical activation" 10090 20519544 t Luana "We further demonstrate that TASK channels are required for normal sensitivity to immobilizing effects of halothane and isoflurane and to sedative/hypnotic effects of halothane." SIGNOR-257846 MVD protein P53602 UNIPROT HRAS protein P01112 UNIPROT "up-regulates quantity by stabilization" 9534 12646231 f miannu "An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B)" SIGNOR-265888 PTH1R protein Q03431 UNIPROT CYP27B1 protein O15528 UNIPROT "up-regulates quantity" 28363951 f lperfetto "These PTH actions are mainly mediated by Gsalpha signaling, which induces the expression of the gene encoding 25-hydroxyvitamin D 1alpha-hydroxylase (Cyp27b1) and destabilizes the transcript encoding vitamin D 24-hydroxylase (Cyp24a1)" SIGNOR-270554 CHEK2 protein O96017 UNIPROT ELAVL1 protein Q15717 UNIPROT "down-regulates activity" phosphorylation Thr118 SGLPRTMtQKDVEDM 9606 21745814 t miannu "Given the fact that Chk2 phosphorylates HuR at residues S88, S100 and T118 and that each individual phosphorylation site by Chk2 plays a distinct role in regulating HuR- binding to different target mRNAs, we further tested HuR mutants with alanine substitutions at each of the Chk2 phosphorylation sites." SIGNOR-278162 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 9312068 t gcesareni "Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues." SIGNOR-51199 CSNK2A1 protein P68400 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates phosphorylation Ser463 CNQDERIsKLEQQMA 9606 22355754 t lperfetto "We demonstrate that crn2 is a binding partner and substrate of protein kinase ck2, which phosphorylates crn2 at s463 in its c-terminal coiled coil domain" SIGNOR-196193 STK4 protein Q13043 UNIPROT AR protein P10275 UNIPROT down-regulates 21512132 f lperfetto "Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter." SIGNOR-151712 PF-3845 chemical CID:25154867 PUBCHEM FAAH protein O00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206049 UNC80 protein Q8N2C7 UNIPROT NALCN protein Q8IZF0 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 19535918 t miannu "UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex. " SIGNOR-265180 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f irozzo "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins." SIGNOR-255855 M protein P59596 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" 9606 25271362 f Luana "Taken together, our results demonstrated that expression of M-protein causes activation of both caspases 8 and 9 via the PKB/Akt signalling cascades. " SIGNOR-260201 RBP4 protein P02753 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "up-regulates quantity" relocalization 9606 31963453 t lperfetto "In the blood, serum retinol travels in association with Retinol-binding protein 4 (RBP4)" SIGNOR-265106 TRAPPC6A protein O75865 UNIPROT "TRAPP III complex, TRAPPC2B variant" complex SIGNOR-C569 SIGNOR "form complex" binding 9606 27066478 t miannu "Transport protein particle (TRAPP; also known as trafficking protein particle), a multimeric guanine nucleotide-exchange factor for the yeast GTPase Ypt1 and its mammalian homologue, RAB1, regulates multiple membrane trafficking pathways. TRAPP complexes exist in three forms, each of which activates Ypt1 or RAB1 through a common core of subunits and regulates complex localization through distinct subunits. Whereas TRAPPI and TRAPPII tether coated vesicles during endoplasmic reticulum to Golgi and intra-Golgi traffic, respectively, TRAPPIII has recently been shown to be required for autophagy." SIGNOR-280669 "TRAPP III complex, TRAPPC2B variant" complex SIGNOR-C569 SIGNOR RAB1A protein P62820 UNIPROT "up-regulates activity" "gtpase-activating protein" 9606 27066478 t miannu "Transport protein particle (TRAPP; also known as trafficking protein particle), a multimeric guanine nucleotide-exchange factor for the yeast GTPase Ypt1 and its mammalian homologue, RAB1, regulates multiple membrane trafficking pathways. TRAPP complexes exist in three forms, each of which activates Ypt1 or RAB1 through a common core of subunits and regulates complex localization through distinct subunits. Whereas TRAPPI and TRAPPII tether coated vesicles during endoplasmic reticulum to Golgi and intra-Golgi traffic, respectively, TRAPPIII has recently been shown to be required for autophagy." SIGNOR-280678 HTR1A protein P08908 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257197 CDK1 protein P06493 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Thr345 LTAERIKtPPKRPGG 9606 21659531 t lperfetto "Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome" SIGNOR-174054 POU4F1 protein Q01851 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000931 24493753 f miannu "In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression." SIGNOR-253465 PPP2CB protein P62714 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 t miannu "Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37." SIGNOR-248584 MAPK1 protein P28482 UNIPROT DDHD1 protein Q8NEL9 UNIPROT unknown phosphorylation Ser727 TIPSPVTsPVLSRRH -1 11328814 t miannu "Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity" SIGNOR-262972 CNR1 protein P21554 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257119 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" dephosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 t gcesareni "Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a." SIGNOR-163688 "diisononyl phthalate" chemical CHEBI:35459 ChEBI OXER1 protein Q8TDS5 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 27551952 t miannu "We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR)." SIGNOR-268773 (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin chemical CHEBI:272 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258784 UBE3A protein Q05086 UNIPROT UBE3A protein Q05086 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001968 10864652 t miannu "We show here that HPV16 E6 promotes the ubiquitination and degradation of E6AP itself. " SIGNOR-271398 mTORC2 complex SIGNOR-C2 SIGNOR SLC7A11 protein Q9UPY5 UNIPROT "down-regulates activity" phosphorylation Ser26 NVNGRLPsLGNKEPP 9606 BTO:0002036 28648777 t miannu "MTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. " SIGNOR-273682 MT-ATP8 protein P03928 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261406 DTNBP1 protein Q96EV8 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265933 SLC4A10 protein Q6U841 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "down-regulates quantity" relocalization 9606 23056253 t miannu "The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons. " SIGNOR-264686 "CAK complex" complex SIGNOR-C456 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR "form complex" binding 9606 30860024 t lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits" SIGNOR-269318 RPA2 protein P15927 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 19586055 t fstefani "The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex." SIGNOR-186648 SRC protein P12931 UNIPROT TNK2 protein Q07912 UNIPROT "up-regulates activity" phosphorylation Tyr859 KKVSSTHyYLLPERP -1 36178070 t miannu "We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity. " SIGNOR-276342 NMBR protein P28336 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257373 PIAS1 protein O75925 UNIPROT RPA2 protein P15927 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair" SIGNOR-162153 ponatinib chemical CHEBI:78543 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206277 DPF2 protein Q92785 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 20460684 t miannu "Our current findings indicate that REQ is a novel adaptor protein that links the Brm-type SWI/SNF complex and RelB/p52 and operates at the most downstream stages of the noncanonical NF-κB pathway." SIGNOR-261963 PRKCD protein Q05655 UNIPROT TAGLN protein Q01995 UNIPROT "down-regulates activity" phosphorylation Ser181 VIGLQMGsNRGASQA -1 11053353 t lperfetto "Of the three consensus protein kinase C or casein kinase II phosphorylation sites in SM22, only Ser-181 was readily phosphorylated by protein kinase C in vitro, and such phosphorylation greatly decreased actin binding." SIGNOR-249061 USP10 protein Q14694 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0002181 SIGNOR-C242 21962518 t lperfetto "Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)" SIGNOR-260299 MAPKAPK2 protein P49137 UNIPROT CEP131 protein Q9UPN4 UNIPROT "down-regulates quantity" phosphorylation Ser78 NNLRRSNsTTQVSQP 9606 26616734 t miannu "MK2 directly phosphorylates two residues on CEP131, S47 and S78, to create dual binding sites for 14-3-3 proteins.|We identify CEP131 as a major Centriolar satellites-associated substrate of p38-dependent, MK2-mediated phosphorylation on two defined residues and show that these modifications promote binding to 14-3-3 proteins, in turn leading to cytoplasmic sequestration of CEP131 and associated Centriolar satellites factors." SIGNOR-278182 RICTOR protein Q6R327 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR "form complex" binding 9606 25628925 t lperfetto "Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)" SIGNOR-205624 TBK1 protein Q9UHD2 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser293 VELFGPIsLEQVRFP 9606 22412986 t lperfetto "Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated" SIGNOR-196532 GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 t "Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells" SIGNOR-254300 PCDHA7 protein Q9UN72 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-265667 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 t gcesareni "Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity." SIGNOR-252588 ELAVL3 protein Q14576 UNIPROT ANK3 protein Q12955 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 BTO:0000938 29614249 t miannu "NElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Here, we found that the alternative splicing of AnkyrinG exon 34 was misregulated in the cerebella of Elavl3-/- mice. AnkyrinG is an essential factor for the formation of neuronal polarity and is required for normal neuronal functions." SIGNOR-266861 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" phosphorylation Ser959 DHSVRINsVGSTASS 9823 BTO:0004007 7539802 t lperfetto "We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling." SIGNOR-248900 CDK2 protein P24941 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 SIGNOR-C83 24173284 t lperfetto "The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A" SIGNOR-119379 S1PR5 protein Q9H228 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256819 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM43B protein A6NCK2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271266 "Cap-binding complex" complex SIGNOR-C440 SIGNOR "messenger RNA" smallmolecule CHEBI:33699 ChEBI up-regulates relocalization 9606 32873578 t lperfetto "The largely nuclear cap-binding complex (CBC) binds to the 5′ caps of RNA polymerase II (RNAPII)-synthesized transcripts and serves as a dynamic interaction platform for a myriad of RNA processing factors that regulate gene expression." SIGNOR-268360 SYVN1 protein Q86TM6 UNIPROT GPR37 protein O15354 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 15572843 t miannu "HRD1 ubiquitinated and degraded Pael-R through its ubiqutin ligase activity." SIGNOR-278672 MECP2 protein P51608 UNIPROT GAMT protein Q14353 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 10090 BTO:0000614 18511691 t Luana "MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1." SIGNOR-264678 MAPK1 protein P28482 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000671 19261619 t gcesareni "Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation." SIGNOR-184469 ORF6 protein Q19QW5 UNIPROT KPNB1 protein Q14974 UNIPROT "down-regulates activity" relocalization 9534 17596301 t lperfetto "ORF6 also retained KPNB1 at the ER/Golgi membrane in complex with KPNA2. Deletion of the N terminus of KPNA2, which binds KPNB1, no longer retained KPNB1 at the ER/Golgi membrane in the presence of ORF6 and did not antagonize STAT1 nuclear import in response to IFN-beta" SIGNOR-260275 mTORC1 complex SIGNOR-C3 SIGNOR NRBF2 protein Q96F24 UNIPROT "up-regulates activity" phosphorylation Ser113 AEDAEGQsPLSQKYS 9606 28059666 t miannu "Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association." SIGNOR-265876 FANCL protein Q9NW38 UNIPROT UBE2T protein Q9NPD8 UNIPROT "down-regulates quantity" ubiquitination 9606 16916645 t miannu "Monoubiquitination of UBE2T was enhanced by FANCL introduction, suggesting that FANCL feeds back to UBE2T and can downregulate its activity.Although the FA pathway has been extensively studied, the E2 enzyme cooperating with the FA core complex for monoubiquitination of FANCD2 has not been discovered.|This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T." SIGNOR-278809 HUWE1 protein Q7Z6Z7 UNIPROT PPARA protein Q07869 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 29331071 t miannu "Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARalpha polyubiquitination.|This notion is also supported by our finding that Huwe1 knockdown up-regulated the expression of PPARalpha target genes at the cellular level." SIGNOR-278814 PJA2 protein O43164 UNIPROT MFHAS1 protein Q9Y4C4 UNIPROT "up-regulates activity" ubiquitination 9606 28471450 t miannu "These results suggest that the ubiquitylation of MFHAS1 by praja2 has a vital role in M1 macrophage polarization and promotes the transformation of M2 macrophages to M1 macrophages through both the JNK and p38 pathways." SIGNOR-278559 MECP2 protein P51608 UNIPROT CRH protein P06850 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000142 17108082 t Luana "Collectively, these results point to a specific association between WT MeCP2 and the methylated promoter region of Crh in vivo. In contrast, the MeCP2308 protein was not detected at the Crh promoter. | Thus, the results of seqChIP indicate that MeCP2 preferentially associates with a transcriptionally inactive, dimethyl-histone H3 Lys-9-rich form of the Crh promoter in mice." SIGNOR-264548 NPAS2 protein Q99743 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR "form complex" binding 9606 20817722 t miannu "The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements." SIGNOR-267966 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity" phosphorylation Ser61 LGALEQGsPPDISPY 10090 BTO:0000783;BTO:0002284 16407209 t "Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity." SIGNOR-255543 TRPM7 protein Q96QT4 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Ser1164 AVKSGFRsVPLKNGY 9606 22759789 t miannu "We present data indicating that TRPM7 phosphorylates phospholipase C\u03b32 at position Ser1164 in the C2-domain, and at position Thr1045 in the linker between the catalytic region and the C2 domain." SIGNOR-278460 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser344 QAVALPRsEEPASCN 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 17213202 t lperfetto "The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo." SIGNOR-235652 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR KHSRP protein Q92945 UNIPROT down-regulates binding 9606 17177604 t gcesareni "Akt phosphorylates ksrp at a unique serine residue, creating a functional binding site for the molecular chaperone 14-3-3. As a consequence, akt activation impairs ksrp ability to interact with the exoribonucleolytic complex exosome and, in turn, to promote rapid mrna decay." SIGNOR-151212 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr809 LIVEYAKyGSLRGFL 9606 14711813 t llicata "Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation." SIGNOR-121157 SYNJ1 protein O43426 UNIPROT MYO1E protein Q12965 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 17257598 t miannu "We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta." SIGNOR-265423 NFX1 protein Q12986 UNIPROT PABPC1 protein P11940 UNIPROT "up-regulates activity" binding 9606 BTO:0004117 17267499 t miannu "NFX1-123 augments the activation of hTERT expression through interactions with PABPCs" SIGNOR-226011 HTR1D protein P28221 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256864 FOXP2 protein O15409 UNIPROT AUTS2 protein Q8WXX7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 25232744 t miannu "By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets." SIGNOR-266832 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto "The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1" SIGNOR-252599 CHEK1 protein O14757 UNIPROT WEE1 protein P30291 UNIPROT "up-regulates activity" phosphorylation Ser642 KKMNRSVsLTIY 9606 28396830 t miannu "CHK1 phosphorylates Wee1 on Ser642, preventing it from being targeted for extranuclear translocation and activating its CDK1\u2010directed kinase activity xref , xref ." SIGNOR-279027 ENO3 protein P13929 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "chemical modification" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266526 ZFPM1 protein Q8IX07 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR "up-regulates activity" 10090 BTO:0000725 22068055 f "We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment." SIGNOR-259964 "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "up-regulates quantity" "precursor of" 9606 30616754 t lperfetto "FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle" SIGNOR-267589 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17126298 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-150879 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates activity" phosphorylation Ser161 SSLPVPNsAYGGPDF 9606 BTO:0000150 25726523 t lperfetto "GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells." SIGNOR-275655 DLG4 protein P78352 UNIPROT NOS1 protein P29475 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11052931 t miannu "Neuronal NOS, a Ca2+-activated form of NOS, can bind to PSD-95 through a class III PDZ domain interaction in which its own amino-terminal PDZ domain binds to a PDZ domain of PSD-95. PSD-95 may concentrate nNOS near the NMDA receptor at postsynaptic sites in these neurons." SIGNOR-264227 nilotinib chemical CHEBI:52172 ChEBI PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258258 NR2F2 protein P24468 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 t lperfetto "Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site" SIGNOR-79446 MTCP1 protein P56278 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu "Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation" SIGNOR-81674 BTK protein Q06187 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr224 DSNSKKIyGSQPNFN 9606 12573241 t lperfetto "Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180" SIGNOR-98032 "Translation release factor ERF1-ERF3" complex SIGNOR-C494 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR "down-regulates activity" binding 9606 28368393 t miannu "The essential ATP-binding cassette protein ABCE1 splits 80S ribosomes into 60S and 40S subunits after canonical termination or quality-control-based mRNA surveillance processes. Compared to the pre-splitting state, we observe repositioning of ABCE1's iron-sulfur cluster domain, which rotates 150° into a binding pocket on the 40S subunit. This repositioning explains a newly observed anti-association activity of ABCE1. Notably, the movement implies a collision with A-site factors, thus explaining the splitting mechanism." SIGNOR-270817 SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni "the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4" SIGNOR-235183 histamine smallmolecule CHEBI:18295 ChEBI HRH4 protein Q9H3N8 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257515 TOR1A protein O14656 UNIPROT SNAPIN protein O95295 UNIPROT "up-regulates activity" binding 9606 BTO:0000793 18167355 t Monia "In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA." SIGNOR-261170 RPS6KA1 protein Q15418 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 t llicata "Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2." SIGNOR-203298 RAD51AP1 protein Q96B01 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 17996711 f miannu "Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand-pairing step in HR. RAD51 associated protein 1 (RAD51AP1) is a RAD51-interacting protein whose function has remained elusive. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Purified RAD51AP1 binds both dsDNA and a D loop structure and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D loop reaction." SIGNOR-261961 CAD protein P27708 UNIPROT N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI "up-regulates quantity" "chemical modification" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267425 IL10 protein P22301 UNIPROT SCN4A protein P35499 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 23357618 f miannu "Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α." SIGNOR-253500 NFIL3 protein Q16649 UNIPROT CYP3A4 protein P08684 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 18004209 f miannu "The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock." SIGNOR-253836 PRKAB1 protein Q9Y478 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 SIGNOR-C15 11729179 t gcesareni "Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no." SIGNOR-112367 PRKCD protein Q05655 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249280 STK4 protein Q13043 UNIPROT STK38 protein Q15208 UNIPROT "up-regulates activity" phosphorylation Thr444 DWVFINYtYKRFEGL 9606 19062280 t miannu "Although MST1, MST2, and MST3 potently activated NDR1 in vitro, MST4 had only a minor effect.|Indeed, NDR1 phosphorylated at Thr444 by MST1 displayed greatly (7-fold) enhanced protein kinase activity." SIGNOR-279641 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation 9606 15356145 t "inferred from 70% family members" lperfetto "Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623." SIGNOR-270000 PRKCA protein P17252 UNIPROT GSTP1 protein P09211 UNIPROT "up-regulates activity" phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu "Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently" SIGNOR-276024 RFX1 protein P22670 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9583676 t gcesareni "We show that rfxi and c-abl are in direct interaction, in vitro and in cell extracts, through the rfxi proline rich (pxxp) motif and the c-abl sh3 domain. Remarkably, this interaction significantly potentiates c-abl but not v-abl auto-kinase activity" SIGNOR-57516 MAPK14 protein Q16539 UNIPROT ZNHIT1 protein O43257 UNIPROT up-regulates phosphorylation Thr103 AEGPNYLtACAGPPS 9606 17380123 t llicata "Our results indicate that p38 mapk plays an important role in the regulation of p18hamlet half?life. In particular, p38 mapk activation is required for the accumulation of p18hamlet induced by dna damage?inducing Agents such as uv. We also showed that several sites that are phosphorylated by p38? In vitro are also important for p18hamlet protein stability in cells. the high conservation of thr103 as a phosphorylation site in p18hamlet proteins from different species (figure 1a), together with the in vitro phosphorylation experiments, suggested that this residue could be an important target for p38 mapk" SIGNOR-153899 GPR84 protein Q9NQS5 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256704 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser291 PVSSLQAsVPGSVPG 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-250729 KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates binding 9606 24997453 t miannu "Keap1 is an oxidative stress-sensing protein and is a negative regulator of nuclear factor-erythroid-2-related factor 2 (nrf2)." SIGNOR-205229 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000567 20736164 t irozzo "USP8 is known to deubiquitinate EGFR in response to ligand stimulation. USP8 depletion accelerates receptor turnover, whereas loss of hepatocyte growth factor-regulated substrate (Hrs) rescues this phenotype, indicating that USP8 protects EGFR from degradation via an Hrs-dependent pathway. [..]As EGFR stabilization against lysosomal turnover requires deubiquitination by USP8." SIGNOR-259102 RYK protein P34925 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 15454084 t gcesareni "Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled" SIGNOR-129574 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257453 PRKACA protein P17612 UNIPROT GRIA1 protein P42261 UNIPROT "up-regulates activity" phosphorylation Ser863 TSTLPRNsGAGASSG 9606 8663994 t miannu "Phosphorylation of Ser-845 on GluR1 by PKA potentiates its response to glutamate." SIGNOR-249987 FIZ1 protein Q96SL8 UNIPROT NRL protein P54845 UNIPROT "up-regulates activity" binding 9913 12566383 t miannu "Interaction of Fiz1 and NRL-leucine zipper was validated by GST pulldown assays and co-immunoprecipitation from bovine retinal nuclear extracts. Fiz1 suppressed NRL- but not CRX-mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells." SIGNOR-223796 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 21423276 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-172926 IL4 protein P05112 UNIPROT IL13RA1 protein P78552 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1." SIGNOR-100759 TXK protein P42681 UNIPROT CTLA4 protein P16410 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9813138 t lperfetto "We demonstrate that rlk (resting lymphocyte kinase) is capable of phosphorylating ctla-4 at the yvkm motif. Consistent with this finding, rlk is capable of providing conditions for the binding of the sh2 domains of pi 3-kinase to the receptor. Ctla-4 is therefore the first known substrate for rlk suggesting the possibility that this kinase may participate in ctla-4 function" SIGNOR-61624 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM34 protein Q9BYJ4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270966 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 BTO:0000298 8385099 t "The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor." SIGNOR-251320 ARHGAP8 protein P85298 UNIPROT LAMTOR3 protein Q9UHA4 UNIPROT "up-regulates activity" binding 28092672 t lperfetto "Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation." SIGNOR-275551 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM FGFR3 protein P22607 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259705 C3AR1 protein Q16581 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0001669 9108406 f lperfetto " In summary, these findings indicate that C3a and C5a serve as chemotaxins for human mast cells. Anaphylatoxin-mediated recruitment of mast cells might play an important role in hypersensitivity and inflammatory processes." SIGNOR-263472 NLGN1 protein Q8N2Q7 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264144 "5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid" chemical CHEBI:76223 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" -1 22091869 t Luana " Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. " SIGNOR-258323 URI1 protein O94763 UNIPROT "URI1 prefoldin co-chaperone" complex SIGNOR-C514 SIGNOR "form complex" binding 9606 30484151 t miannu "In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR94" SIGNOR-270917 FH protein P07954 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI "up-regulates quantity" "chemical modification" 9606 30761759 t miannu "Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors." SIGNOR-266280 HOXB6 protein P17509 UNIPROT HBG1 protein P69891 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15269212 t Luana "HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion." SIGNOR-261638 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254705 TRIM26 protein Q12899 UNIPROT NEIL1 protein Q96FI4 UNIPROT "down-regulates quantity" ubiquitination 9606 27924031 t miannu "Mule and TRIM26 ubiquitylate NEIL1 in vitro within C-terminal lysine residues.|Similar to these previous results, we again demonstrate that a knockdown of Mule or TRIM26 causes an elevation in the protein stability of NEIL1 in comparison to non-targeting siRNA, unirradiated control (Figure and ; compare lanes 1 and 2)." SIGNOR-278647 NHLRC1 protein Q6VVB1 UNIPROT DVL2 protein O14641 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 22223637 t miannu "We have also found that malin enhances K48- and K63-linked ubiquitination of dishevelled2 that could lead to its degradation through both proteasome and autophagy. Altogether, our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease." SIGNOR-272005 entacapone chemical CHEBI:4798 ChEBI COMT protein P21964 UNIPROT "down-regulates activity" "chemical inhibition" -1 7703232 t miannu "Human soluble (S) and membrane-bound (MB) catechol O-methyltransferase (COMT, EC 2.1.1.6) enzymes have been expressed at sufficiently high levels in Escherichia coli and in baculovirus-infected insect cells to allow kinetic characterization of the enzyme forms. The use of tight-binding inhibitors such as entacapone enabled the estimation of actual enzyme concentrations and, thereby, comparison of velocity parameters, substrate selectivity, and regioselectivity of the methylation of both enzyme forms." SIGNOR-258476 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser502 FSTDNSGsQPKQKSD 9606 22123827 t lperfetto "Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication." SIGNOR-177805 AP1M1 protein Q9BXS5 UNIPROT "AP-1 complex" complex SIGNOR-C248 SIGNOR "form complex" binding 9606 21097499 t lperfetto "Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)" SIGNOR-260686 PPP2CA protein P67775 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates dephosphorylation Thr255 ITTPELTtPCGSAEY 9606 20927323 t gcesareni "Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e." SIGNOR-168314 CD47 protein Q08722 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266016 ITCH protein Q96J02 UNIPROT JUNB protein P17275 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0001045 11828324 t miannu "Itch promotes Ub conjugation to JunB Molecularly, Itch associated with and induced ubiquitination of JunB, a transcription factor that is involved in TH2 differentiation. However, in Itch−/− T cells under the same conditions, degradation of JunB was markedly delayed." SIGNOR-272619 INPPL1 protein O15357 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 BTO:0000776 10942391 f lperfetto "Taken together, the data presented here demonstrate that ship inhibits akt primarily through regulation of akt membrane localization." SIGNOR-244406 PPP2CA protein P67775 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates dephosphorylation 9606 BTO:0000848 11591705 t lperfetto "Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela." SIGNOR-217421 FGF14 protein Q92915 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253429 NFE2L2 protein Q16236 UNIPROT MTHFD2 protein P13995 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22789539 f miannu "We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C)." SIGNOR-267359 RAD51B protein O15315 UNIPROT RAD51B/RAD51C complex SIGNOR-C65 SIGNOR "form complex" binding 9606 11751636 t miannu "We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities." SIGNOR-111383 AKT1 protein P31749 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni "Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt." SIGNOR-252537 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18570872 t amattioni "In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein." SIGNOR-179104 DLGAP1 protein O14490 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 9115257 t miannu "SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area." SIGNOR-264209 TP53 protein P04637 UNIPROT TIGAR protein Q9NQ88 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001248 27803158 t miannu "TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR is the only known phosphatase glycolytic modulator regulated by TP53. The current study delineates the role of TIGAR in OXPHOS and glycolytic metabolic reprogramming in breast cancer." SIGNOR-267365 RIMBP2 protein O15034 UNIPROT RIMS2 protein Q9UQ26 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264366 TIGAR protein Q9NQ88 UNIPROT "beta-D-fructofuranose 2,6-bisphosphate(4-)" smallmolecule CHEBI:58579 ChEBI "down-regulates quantity" "chemical modification" 9606 27803158 t miannu "TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR decreases glycolysis by functioning as a bisphosphatase that reduces levels of intracellular fructose-2,6-bisphosphate (Fru-2,6-P2) and 2,3-bisphosphoglycerate (7, 9), which are regulators of glycolysis." SIGNOR-267364 SFN protein P31947 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates relocalization 9606 20940406 t lperfetto "Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding" SIGNOR-168540 MAP3K8 protein P41279 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000007 15466476 t lperfetto "Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases." SIGNOR-129694 MCM10 protein Q7L590 UNIPROT RECQL4 protein O94761 UNIPROT down-regulates binding 9606 19696745 t miannu "Mcm10 inhibits recq4 helicase activity." SIGNOR-187701 FOXJ1 protein Q92949 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000939 23822649 t miannu "FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1)." SIGNOR-266939 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT "down-regulates activity" phosphorylation Ser928 SRLATNTsAPDLKNV -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250170 ARID2 protein Q68CP9 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270597 HTR1B protein P28222 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256720 NR3C1 protein P04150 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity" "transcriptional regulation" 9606 26652733 t "inferred from family member" "Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB" SIGNOR-267792 "Exon junction complex" complex SIGNOR-C369 SIGNOR mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11532962 f lperfetto "The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay" SIGNOR-268313 CTSD protein P07339 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Ala92 DHIGFQEaYRRFYGP -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256319 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10480933 t gcesareni "We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks." SIGNOR-70612 IRAK3 protein Q9Y616 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT down-regulates binding 9606 25290089 t flangone "Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation" SIGNOR-205434 TLR4 protein O00206 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." SIGNOR-261930 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser801 VPLLREAsARDRQSA 9534 14523239 t lperfetto "We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA." SIGNOR-249232 IL18 protein Q14116 UNIPROT IFNG protein P01579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10653850 f miannu "IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement." SIGNOR-260860 PTPRR protein Q15256 UNIPROT PXN protein P49023 UNIPROT "down-regulates activity" dephosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 20133777 t "Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth," SIGNOR-248720 SP1 protein P08047 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 15708372 t "We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA." SIGNOR-253664 JAK1 protein P23458 UNIPROT IL10RA protein Q13651 UNIPROT "up-regulates activity" phosphorylation Tyr496 PPALAKGyLKQDPLE 10433356 t "Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3)." SIGNOR-251339 TSLP protein Q969D9 UNIPROT CRLF2 protein Q9HC73 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11418668 t gcesareni "Human tslp is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human tslp receptor and the il-7r alpha-chain." SIGNOR-108920 EBNA1 protein P03211 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates quantity" destabilization 9606 BTO:0000192 17486072 f scontino "The studies described above show that SMAD2 protein levels are reduced by EBNA1 with consequent attenuation of SMAD2 activation in response to TGFβ1. This analysis confirmed the stability of the EBNA1 protein and revealed that the SMAD2 protein is more rapidly degraded in Ad/AH cells expressing EBNA1 as compared to the control cells." SIGNOR-267615 PPP1CA protein P62136 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 t "inferred from 70% of family members" fstefani "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases" SIGNOR-269927 MEIS2 protein O14770 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 21746878 t miannu "We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4." SIGNOR-267242 SATB2 protein Q9UPW6 UNIPROT UPF3B protein Q9BZI7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 23925499 f miannu "chromatin immunoprecipitation demonstrates that SATB2 binds to the UPF3B promoter, and a luciferase reporter assay confirmed that SATB2 expression significantly activates gene transcription using the UPF3B promoter." SIGNOR-255137 NPNT protein Q6UXI9 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 f miannu "The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion" SIGNOR-255458 ibuprofen chemical CHEBI:5855 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" -1 9057869 t miannu "Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM)." SIGNOR-258605 IGF1 protein P05019 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 f lperfetto "Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1." SIGNOR-235828 FLT3 protein P36888 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" 10090 BTO:0001516 23246379 f miannu "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells." SIGNOR-260083 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 t lperfetto "In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity" SIGNOR-252765 VDR protein P11473 UNIPROT CYP24A1 protein Q07973 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000067 9687155 f miannu "Repression of basal transcription of a 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) responsive 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter construct as observed in kidney cells in the absence of ligand and this repression was dependent on a functional vitamin D response element (VDRE). Basal repression was also seen with a construct where a consensus DR-3-type VDRE was fused to the thymidine kinase promoter. Expression of a dominant negative vitamin D receptor (VDR) isoform that strongly bound to the VDRE motif in the CYP24 promoter ablated basal repression." SIGNOR-255599 N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide chemical CHEBI:91617 ChEBI AR protein P10275 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190323 MAPK1 protein P28482 UNIPROT DOCK1 protein Q14185 UNIPROT unknown phosphorylation Thr1772 QQTPPPVtPRAKLSF 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262769 DOK1 protein Q99704 UNIPROT "A11/b1 integrin" complex SIGNOR-C168 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257679 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0004419 12840032 t lperfetto "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).Mapk activity is tightly regulated by phosphorylation and dephosphorylation. The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase" SIGNOR-103159 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t "Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway." SIGNOR-248499 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT "down-regulates activity" phosphorylation Ser21 KEEPKRRsARLSAKP 9606 BTO:0000567 11438671 t lperfetto "We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets." SIGNOR-249100 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256321 GNRHR protein P30968 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256935 PRKCD protein Q05655 UNIPROT IL6ST protein P40189 UNIPROT up-regulates phosphorylation Thr890 GQVERFEtVGMEAAT 9606 12361954 t fspada "This interaction, which does not seem to involve a classical phosphotyrosine sh2-mediated binding, however, significantly enhances the interaction of stat3 and the il-6 receptor subunit glycoprotein (gp) 130, which is the initial step for stat3 activation by il-6. Expression of a dominant negative pkcdelta or depletion of the endogenous pkcdelta by phorbol 12-myristate 3-acetate treatment abrogates the association of stat3 with gp130. At the same time, pkcdelta is recruited to gp130 via association with stat3, which may facilitate its phosphorylation on the gp130 receptor. Finally, we identified thr-890, a putative pkc phosphorylation site on gp130, to be critical for the effect of pkcdelta. Our data indicate that pkcdelta plays important regulatory roles in il-6 signaling." SIGNOR-94012 AT9283 chemical CID:11696609 PUBCHEM ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190008 FUBP1 protein Q96AE4 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19637194 f irozzo "In our analysis of FBP1 shRNA-transduced Hep3B cells, we found that p21 mRNA levels increase following FBP1 knockdown, suggesting that FBP1 functions as a repressor of p21. Our results identify the tumor suppressor p21 as the second direct FBP1 target gene in addition to the proto-oncogene c-myc." SIGNOR-259125 ANAPC4 protein Q9UJX5 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252004 PLK1 protein P53350 UNIPROT NPM1 protein P06748 UNIPROT up-regulates phosphorylation Ser4 sMDMDMSP 9606 BTO:0000567 15190079 t gcesareni "Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis." SIGNOR-125666 KAT5 protein Q92993 UNIPROT "NuA4 complex" complex SIGNOR-C459 SIGNOR "form complex" binding 9606 14966270 t miannu "NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails." SIGNOR-269297 PKA proteinfamily SIGNOR-PF17 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu "PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex" SIGNOR-264961 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT "down-regulates activity" phosphorylation Ser688 KRRRSEDsEEEELAS 9606 15659405 t llicata "CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity." SIGNOR-250961 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser295 LSDTPYDsSASYEKE 9606 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo" SIGNOR-174848 USP22 protein Q9UPT9 UNIPROT SIRT1 protein Q96EB6 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 26049753 t "USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells." SIGNOR-261561 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser234 YRLTRFLsRVIKCDP -1 8058338 t miannu "PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234." SIGNOR-250346 CHEK2 protein O96017 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" phosphorylation Ser612 MYLSPVRsPKKKGST 9606 BTO:0000093 17380128 t lperfetto "Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1" SIGNOR-153908 AVPR1B protein P47901 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256791 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 22187936 t gcesareni "Rsk1/2 stabilize c-fos and increases its activity." SIGNOR-191678 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto "Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-217853 FOXC1 protein Q12948 UNIPROT SOX13 protein Q9UN79 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31650548 f lperfetto "Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX14" SIGNOR-275916 DUSP2 protein Q05923 UNIPROT MAPK6 protein Q16659 UNIPROT "down-regulates activity" dephosphorylation 9606 28252035 t miannu "DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5." SIGNOR-277069 PPP1CA protein P62136 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t "inferred from 70% of family members" fstefani "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases" SIGNOR-269906 PTPRB protein P23467 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates dephosphorylation 9606 12840032 t gcesareni "When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well" SIGNOR-103165 CSNK2A1 protein P68400 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 t llicata "Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. " SIGNOR-250953 TAX1BP1 protein Q86VP1 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates activity" binding 21885437 t lperfetto "ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi." SIGNOR-275737 CDC14B protein O60729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates dephosphorylation 9606 18662541 t lperfetto "The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1" SIGNOR-227927 Cortistatin14 smallmolecule CID:16133803 PUBCHEM MRGPRX2 protein Q96LB1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257544 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 14699166 t llicata "Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells." SIGNOR-120488 EGFR protein P00533 UNIPROT SPRED1 protein Q7Z699 UNIPROT "down-regulates activity" phosphorylation Ser105 KFGLTFQsPADARAF 9606 BTO:0000007 32697994 t miannu "We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions." SIGNOR-273638 ANKRD28 protein O15084 UNIPROT PPP1CC protein P36873 UNIPROT "up-regulates activity" binding -1 17023142 t lperfetto "Phosphatase Interactor Targeting K protein (PITK) was previously identified as a novel PP1 targeting subunit implicated in modulating the phosphorylation of the transcriptional regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K)" SIGNOR-264794 FRAT2 protein O75474 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" binding -1 11738041 t gcesareni "The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation." SIGNOR-244030 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 12172553 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-91392 ADAM9 protein Q13443 UNIPROT FGFR2 protein P21802 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0000007 22632802 t Giulio "Truncated FGFR2 was observed in cells transfected with wild-type ADAM9, but not in those with inactive mutant ADAM9 (Figure 5E). In line with this, cells transfected with wild-type ADAM9 showed reduced pErK1/2 in response to FGF2 as compared to controls or cells expressing mutant ADAM9.|Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface." SIGNOR-260300 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" phosphorylation Ser142 TGTESMVsHRRERAR 9606 16965538 t lperfetto "Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development." SIGNOR-217849 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser249 AVIPINGsPRTPRRG 9606 15809340 t gcesareni "Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively." SIGNOR-135181 CSNK2A2 protein P19784 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1067 GDVEGSQsQDEGEGS 9606 18442975 t gcesareni "Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm." SIGNOR-178487 CSNK1A1 protein P48729 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 16341017 t gcesareni "We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin." SIGNOR-143037 AKT1 protein P31749 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto "We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity" SIGNOR-148983 CASP3 protein P42574 UNIPROT RAD51 protein Q06609 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0002882 11684015 t lperfetto "The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin" SIGNOR-271709 Hypoxia stimulus SIGNOR-ST25 SIGNOR hsa-miR-150-3p mirna URS00005EAAAD_9606 RNAcentral "down-regulates quantity by repression" 9606 BTO:0002745 26622579 f "The results show that miR-150, which normally suppresses CXCR4 expression, is downregulated by hypoxia in pancreatic cancer tissues and cells, leading to increased CXCR4 expression and promoting cancer cell migration and invasion." SIGNOR-277941 TAOK2 protein Q9UL54 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10660600 t gcesareni "Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway." SIGNOR-74867 FLT3 protein P36888 UNIPROT SOCS2 protein O14508 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12468433 f "We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling" SIGNOR-261545 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr191 QKQEKPRtPMPSSVE 9606 BTO:0000007 16682949 t done miannu "Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1." SIGNOR-274087 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN3 protein Q9UGI6 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258024 CARM1 protein Q86X55 UNIPROT PAX7 protein P23759 UNIPROT up-regulates methylation 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu "Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5." SIGNOR-198617 GPC4 protein O75487 UNIPROT WNT5A protein P41221 UNIPROT up-regulates binding 9606 22302992 t gcesareni "Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways" SIGNOR-195752 TP53 protein P04637 UNIPROT PMAIP1 protein Q13794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14500851 f gcesareni "P53 has the ability to activate transcription of various proapoptotic genes, including those encoding members of the bcl-2 family, such as the bh-3 only proteins bax, noxa, and puma pmaip1 may thus represent a mediator of tp53-dependent apoptosis." SIGNOR-118048 ziprasidone chemical CHEBI:10119 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10116 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258505 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT "up-regulates activity" dephosphorylation Ser683 QAQDRKLsTKEALDE 9606 BTO:0000007 24333728 t "Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp" SIGNOR-272510 E2F1 protein Q01094 UNIPROT ISYNA1 protein Q9NPH2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 15464731 f lperfetto "Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate.|Here, we have characterized the minimal promoter of ISYNA1 and show that it is upregulated by E2F1." SIGNOR-254130 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation Thr200 EHQVLMKtVCGTPGY 9606 15769749 t gcesareni "Phosphorylation of ca(2+)/cam-bound camkiv on its activation loop threonine (residue thr(200) in human camkiv) by ca(2+)/calmodulin-dependent kinase kinase leads to increased camkiv kinase activity." SIGNOR-134649 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser469 DGEFSDDsGADQEKD 9606 BTO:0000007 11500362 t llicata "The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo." SIGNOR-250788 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120056 ABL1 protein P00519 UNIPROT UBE3A protein Q05086 UNIPROT "down-regulates activity" phosphorylation Tyr659 GDSHPVLyQSLKDLL 9606 23581475 t Manara "Our results suggest that c-Abl protects p53 from HPV-E6-E6AP complex-mediated degradation by phosphorylating E6AP and impairing its E3 ligase activity" SIGNOR-260930 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI "up-regulates quantity" "precursor of" 9606 10720211 t lperfetto "Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine." SIGNOR-268230 GRPEL1 protein Q9HAV7 UNIPROT "TIM23 complex" complex SIGNOR-C423 SIGNOR "form complex" binding 32074073 t lperfetto "The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE." SIGNOR-267691 AURKA protein O14965 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser962 SSRSGREsVSTASDQ 9606 BTO:0000938 19812038 t llicata "Aurora a interacts directly with the atypical protein kinase c binding domain of par3 and phosphorylates it at serine 962. The phosphorylation of par3 at serine 962 contributes to its function in the establishment of neuronal polarity." SIGNOR-188398 GNA13 protein Q14344 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0004605 37392861 f "Marta Tosoni" "Our results demonstrate that GNA13 expression is negatively correlated with GBM and can suppress tumor metastasis by inhibiting the ERKs signaling pathway and upregulating FOXO3 expression." SIGNOR-278050 ALK protein Q9UM73 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Tyr293 RRPGEKTyTQRCRLF 9606 BTO:0000785 17537995 t lperfetto "Furthermore, psf was shown to be a direct substrate of purified alk kinase domain in vitro, and psf tyr293 was identified as the site of phosphorylation. Psf phosphorylation also increased its binding to rna and decreased the psf-mediated suppression of gage6 expression." SIGNOR-155298 POLR2A protein P24928 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266160 PAK1 protein Q13153 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser111 KESLRSRsTRMSTVS 9606 23055517 t lperfetto "Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes" SIGNOR-199080 PLK1 protein P53350 UNIPROT KIF20A protein O95235 UNIPROT "up-regulates activity" phosphorylation 9606 12939256 t miannu "MKlp2 treated with Plk1 did not form the regular microtubule bundles seen with MKlp2 only; many single microtubules were seen instead, and the bundles that were formed were loose parallel arrays rather than the dense bundles seen with untreated MKlp2.|We propose that phosphorylation of MKlp2 by Plk1 is necessary for the spatial restriction of Plk1 to the central spindle during anaphase and telophase, and the complex of these two proteins is required for cytokinesis." SIGNOR-278201 TSC22D3 protein Q99576 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000011 12671681 f "In this study, we showed that GILZ, which is transcriptionally induced by GCs, inhibits the transcription of the PPAR-γ2 gene and blocks adipocyte differentiation" SIGNOR-253296 BMPR1A protein P36894 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR "up-regulates activity" phosphorylation 10090 19620713 t ggiuliani "The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17)." SIGNOR-255786 DZIP3 protein Q86Y13 UNIPROT H2AC4 protein P04908 UNIPROT "up-regulates activity" monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu " 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation." SIGNOR-271747 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT "up-regulates activity" phosphorylation Tyr133 NFLSEDKyPLIMVPD 9606 18976935 t lperfetto "Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation." SIGNOR-253367 CDK1 protein P06493 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates activity" phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 t miannu "Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. Phosphorylation of Ser-277 is also dramatically increased during mitosis, however this is mediated by Cdk1 and not by ERK. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events." SIGNOR-262840 JNK proteinfamily SIGNOR-PF15 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 14699954 t "inferred from 70% family members" amattioni "The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53" SIGNOR-269985 PAX7 protein P23759 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates BTO:0001103 15501225 f svumbaca "We found that ectopic expression of Pax-7 prevented myogenic differentiation and the induction of myogenin protein." SIGNOR-255367 ULK2 protein Q8IYT8 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19225151 t gcesareni "Ulks directly phosphorylates atg13." SIGNOR-184126 ACADVL protein P49748 UNIPROT (E)-hexadec-2-enoyl-CoA(4-) smallmolecule CHEBI:61526 ChEBI "up-regulates quantity" "chemical modification" 9606 20490924 t miannu "VLCAD is a dimer of two identical subunits bound to the inner mitochondrial membrane (Fig. 1) and accepts long chain acyl-CoAs as substrate (Fig. 4a).The different ACADs catalyze the following reaction: acyl-CoA + FAD - trans-2-enoyl-CoA + FADH2" SIGNOR-280306 GSK3B protein P49841 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates activity" phosphorylation Ser363 GRLPNNSsRPSTPTI 9606 27494834 t miannu "GSK3beta phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3beta upregulates Thr367 phosphorylationin vivo." SIGNOR-278176 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser462 GSPHNPIsSVS 9606 9335504 t llicata "The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1." SIGNOR-52662 CDK1 protein P06493 UNIPROT VCPIP1 protein Q96JH7 UNIPROT "down-regulates activity" phosphorylation Thr761 GPSSAPAtPTKAPYS 23500464 t lperfetto "We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. " SIGNOR-265037 SLBP protein Q14493 UNIPROT H2AC7 protein P20671 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265399 PRKCD protein Q05655 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 11085981 t lperfetto "In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism." SIGNOR-249063 mTORC1 complex SIGNOR-C3 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "up-regulates activity" 10090 BTO:0002314 25047835 f "Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program." SIGNOR-256273 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "precursor of" 9606 6698284 t miannu "The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2)." SIGNOR-267339 "NMDA receptor_2C" complex SIGNOR-C349 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 30037851 t miannu "NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). " SIGNOR-264220 RPP40 protein O75818 UNIPROT "Ribonuclease MRP complex" complex SIGNOR-C570 SIGNOR "form complex" binding 9606 40413743 t miannu "Human RNase MRP is a ribonucleoprotein (RNP) enzyme that processes precursor rRNA (pre-rRNA) at ITS1 site 2 and may have additional activities.Using a genome-wide forward genetic screening that leveraged the requirement of RNase MRP and RNase P for reporter translation, we identified two poorly characterized yet highly enriched human genes, c18orf21 and c3orf17, which we named ribonuclease MRP subunit P24 (RMP24) and RMP64, respectively. We demonstrate that these two genes are specifically required for the activity of human RNase MRP but not RNase P. The protein products of RMP24 and RMP64 associate extensively and exclusively with the only known human RNase MRP-specific component, MRP RNA, but not with the RNase P-specific H1 RNA. Our findings establish Rmp24 and Rmp64 as human protein components unique to RNase MRP." SIGNOR-280680 BAZ2B protein Q9UIF8 UNIPROT H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 t miannu "The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation." SIGNOR-266621 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT "up-regulates activity" phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 t miannu "Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK. " SIGNOR-277858 [5-[5-[5-(hydroxymethyl)-2-thiophenyl]-2-furanyl]-2-thiophenyl]methanol chemical CHEBI:94980 ChEBI TP53 protein P04637 UNIPROT up-regulates "chemical activation" 9606 19223463 t gcesareni "Rita has been proposed to stabilize p53 by inhibiting the p53-hdm2 interaction." SIGNOR-184062 PTPN1 protein P18031 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" dephosphorylation Tyr446 GTEPEPVySMEAADY 9534 BTO:0004055 18387954 t "Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr446, |Cortactin exerts its effects on the actin cytoskeleton by interacting directly with the Arp2/3 complex , F-actin |Src phosphorylates murine cortactin predominantly at three key sites in vitro, Tyr421, Tyr466, and Tyr482 (corresponding to Tyr421, Tyr470, and Try486 in human cortactin), resulting in decreased actin cross-linking activity" SIGNOR-248432 hsa-miR-451a mirna URS00002E857A_9606 RNAcentral CXCL16 protein Q9H2A7 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000971 25391425 t Parnian "Our data reveal a downregulated expression of miR-451 in osteosarcoma tissues, which is inversely associated with CXCL16 levels. These observations demonstrated that miR-451 may play an important role in tumor growth and metastasis in osteosarcoma." SIGNOR-278012 NFYA protein P23511 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 12427542 t miannu "Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response." SIGNOR-254816 PROX1 protein Q92786 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0001033 27476001 f miannu "Our present study reveals that DAB2IP prevents EMT and metastasis of prostate cancer through targeting PROX1 gene transcription and destabilizing HIF1α protein, which provides a new insight into mechanism that DAB2IP regulates EMT and PCa metastasis." SIGNOR-254767 NUTF2 protein P61970 UNIPROT NUP62 protein P37198 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 7744965 t Simone "Our data suggest that NTF2 interacts directly with NPC protein 1362 and exerts its effect at a relatively late step in the nuclear protein import pathway. We obtained a cDNA encoding NTF2 and showed that the recombinant protein restores transport activity to p62-pretreated cytosol." SIGNOR-261255 superoxide smallmolecule CHEBI:18421 ChEBI SOD1 protein P00441 UNIPROT "up-regulates activity" "precursor of" 9606 29301787 t lperfetto "Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD)." SIGNOR-272288 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 19584320 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-186633 IGF1R protein P08069 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates binding 9606 phosphorylation:Tyr1346 SFDERQPyAHMNGGR 9415396 t gcesareni "Moreover, we found that the insulin-like growth factor-1 receptor (igf-ir) bound to p55pik;the interaction occurred at the receptor tyrosine 1316 and involved both p55pik sh2 domains." SIGNOR-52683 IL10 protein P22301 UNIPROT SCN3A protein Q9NY46 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 23357618 f miannu "Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α." SIGNOR-253504 PRKACA protein P17612 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser499 PFGSRRSsAIGIENI -1 1406653 t miannu "We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive." SIGNOR-250044 zotepine chemical CHEBI:32316 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258551 IRS2 protein Q9Y4H2 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9606 22810696 t lperfetto "These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients." SIGNOR-251492 PRKACG protein P22612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t gcesareni "Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no." SIGNOR-112375 TGFBR2 protein P37173 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 19114990 t lperfetto "In immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K" SIGNOR-252731 PRKCZ protein Q05513 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR "up-regulates activity" phosphorylation -1 15894802 t "inferred from family member" lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-270274 PRKCA protein P17252 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 t lperfetto "These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels." SIGNOR-249086 LIMK2 protein P53671 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11171090 t lperfetto "We report here that limk1 and limk2 phosphorylate both cofilin and actin-depolymerizing factor (adf) specifically at ser-3 and exhibit partially distinct substrate specificity when tested using site-directed cofilin mutants as substrates" SIGNOR-105098 TRAF2 protein Q12933 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 8069916 t amattioni "Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2." SIGNOR-35881 Ub:E2 complex SIGNOR-C497 SIGNOR ARIH2 protein O95376 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271011 AKT1 protein P31749 UNIPROT HK1 protein P19367 UNIPROT up-regulates binding 9606 16892082 t gcesareni "The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects." SIGNOR-252495 CCZ1B protein P86790 UNIPROT "MON1-CCZ1B guanyl-nucleotide exchange factor complex, MON1B variant" complex SIGNOR-C636 SIGNOR "form complex" binding 33144569 t miannu "We conclude that mammalian Mon1, Ccz1 and C18orf8 form a stable trimeric complex, the MCC complex, of which C18orf8 is a core component. The Mon1-Ccz1-C18orf8 complex is responsible for mammalian Rab7 activation. The trimeric Mon1-Ccz1-C18orf8 (MCC) complex therefore acts as an activating GEF for mammalian Rab7 and its role in late endosomal trafficking and LDL-cholesterol uptake can be specifically by-passed by a constitutively active Rab7 (Q67L) or by Rab7GAP depletion." SIGNOR-281048 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr470 AYATEAVyESAEAPG 9606 12601080 t lperfetto "Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity" SIGNOR-98716 TRIM59 protein Q8IWR1 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" 9606 "BTO:0000567; BTO:0002181" 22588174 f Giorgia "TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal" SIGNOR-260373 CDK5 protein Q00535 UNIPROT ALDH1A1 protein P00352 UNIPROT "up-regulates quantity" phosphorylation Ser274 TLELGGKsPCIVLAD 9606 29948941 t miannu "Cdk5 Phosphorylates ALDH1A1 at S75 and S274.|These results demonstrate that Cdk5 increases ALDH1A1 levels in neurotoxin exposed neuronal cells both at transcriptional level and by direct phosphorylation at S75 and S274 sites." SIGNOR-279399 CIITA protein P33076 UNIPROT HLA-DRB1 protein P01911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002417 10886240 f "These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma." SIGNOR-253976 SMAD5 protein Q99717 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0002729 23993924 f flangone "Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes." SIGNOR-242059 NRAS protein P01111 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-175225 ERBB2 protein P04626 UNIPROT NOTCH3 protein Q9UM47 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 21743488 f gcesareni "We demonstrate that her2 overexpression in this cellular model of dcis drives transcriptional upregulation of multiple components of the notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising notch3, its cleaved intracellular domain and the transcriptional regulator hes1." SIGNOR-174747 MRE11 protein P49959 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR "form complex" binding 17713585 t lperfetto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50." SIGNOR-251504 DUSP5 protein Q16690 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 10224087 t "inferred from 70% of family members" gcesareni "Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway" SIGNOR-269932 MYC protein P01106 UNIPROT SLC2A1 protein P11166 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 10823814 t "C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway." SIGNOR-259987 CNOT3 protein O75175 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003292 24550297 t Luana "Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis." SIGNOR-261572 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000142 20654717 f gcesareni "This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1." SIGNOR-167073 CREB1 protein P16220 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 17584923 f Luana "These findings, together with studies in Aplysia and Drosophila, strongly suggest that CREB is an evolutionary conserved component of the molecular cascade of events leading to memory consolidation." SIGNOR-265773 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CAPN2 protein P17655 UNIPROT up-regulates phosphorylation 9606 14993287 t "inferred from 70% family members" lperfetto "Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo." SIGNOR-270179 TFEB protein P19484 UNIPROT BLOC1S3 protein Q6QNY0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 33176151 f lperfetto "Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4)." SIGNOR-276683 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WEE1 protein P30291 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser123 EEGFGSSsPVKSPAA 23051732 t lperfetto "Cdk1 phosphorylates Wee1 on Ser-123, which primes additional phosphorylation by other kinases, leading to the formation of phosphodegrons responsible for SCF (Skp1/cullin/F-box) ubiquitin-mediated degradation of Wee1" SIGNOR-267471 GSK3B protein P49841 UNIPROT STK38 protein Q15208 UNIPROT "down-regulates activity" phosphorylation Ser6 sTPCSSMS -1 22142472 t miannu "GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress." SIGNOR-276392 PPP1CC protein P36873 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 t "The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation" SIGNOR-248501 SNRPD2 protein P62316 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270661 JAG1 protein P78504 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 7227 18660822 t "Binding Ca-dependent" lperfetto "We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner." SIGNOR-219253 PRKCA protein P17252 UNIPROT NPHS1 protein O60500 UNIPROT "up-regulates activity" phosphorylation Thr1125 QWTGERDtQSSTVST 9606 BTO:0000007 21321125 t llicata "Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_." SIGNOR-172056 RPAP3 protein Q9H6T3 UNIPROT "R2TP core co-chaperone" complex SIGNOR-C515 SIGNOR "form complex" binding 9606 29662061 t miannu " Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. " SIGNOR-270927 IGF1R protein P08069 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 10090 BTO:0000165 11715022 f lperfetto "we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy." SIGNOR-244403 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" 9606 BTO:0000093 8415704 t "PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site" SIGNOR-259940 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 11781339 f gcesareni "In these collagen gel cultures, p38 activation was induced more potently by fgf-2 treatment compared with that in proliferating cultures" SIGNOR-113649 TFEB protein P19484 UNIPROT SACM1L protein Q9NTJ5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 30145926 f lperfetto "Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB" SIGNOR-276801 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f gcesareni "Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck)" SIGNOR-142204 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Thr276 DGIMYYLtPQWDKIL 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262926 BMP7 protein P18075 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR up-regulates binding 10090 BTO:0000165 11282024 t lperfetto "Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2" SIGNOR-235364 TFEB protein P19484 UNIPROT PSAP protein P07602 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 19556463 f "Figure 1" lperfetto "Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells." SIGNOR-276545 SETD5 protein Q9C0A6 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 32299058 f "The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression" SIGNOR-268627 carbachol chemical CHEBI:3385 ChEBI CHRM4 protein P08173 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258621 GPI protein P06744 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "chemical modification" 9606 16051738 t miannu "Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P." SIGNOR-266461 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT "down-regulates activity" phosphorylation Ser712 EEEESDSsETEKEDD 21296876 t lperfetto "Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2." SIGNOR-275500 ASNS protein P08243 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "chemical modification" 9606 29084849 t miannu "Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7." SIGNOR-267535 NHLH2 protein Q02577 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21573214 f miannu "Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter." SIGNOR-254828 CDK5 protein Q00535 UNIPROT SYN1 protein P17600 UNIPROT up-regulates phosphorylation Ser553 ARPPASPsPQRQAGP 9606 10880969 t lperfetto "Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin." SIGNOR-78887 "A4/b1 integrin" complex SIGNOR-C162 SIGNOR DLL1 protein O00548 UNIPROT "up-regulates quantity by expression" 10090 25786978 f lperfetto "First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs." SIGNOR-253285 AURKB protein Q96GD4 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates phosphorylation Thr232 APSLRRKtMCGTLDY 9606 14722118 t lperfetto "We report here that human aurora-b is phosphorylated at thr-232 through interaction with the inner centromere protein (incenp) in vivo. The phosphorylation of thr-232 occurs by means of an autophosphorylation mechanism, which is indispensable for the aurora-b kinase activity." SIGNOR-121340 GPR84 protein Q9NQS5 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257099 hsa-miR-520a-5p mirna URS0000534239_9606 RNAcentral CXCL8 protein P10145 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000093 21343296 t Parnian "Overall, these data strongly suggest that the IL-8 gene is a direct target of miR-520b and is involved in breast cancer cell migration. | We then confirmed that the 3 UTR of IL-8 is a target of miR-520b" SIGNOR-278015 hsa-miR-183-5p mirna URS0000528CBC_9606 RNAcentral DKK3 protein Q9UBP4 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001061 23538390 t Parnian "This is the first report to show that the oncogenic miR-183 activates the Wnt/b-catenin pathway by directly inhibiting tumour suppressors Dkk-3 and SMAD4 in PC.| indicating that Dkk-3 and SMAD4 are direct targets of miR-183." SIGNOR-278016 CDK1 protein P06493 UNIPROT PDCD1 protein Q15116 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser261 PSGMGTSsPARRGSA 9606 BTO:0000007 36104103 t miannu "We demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7." SIGNOR-277605 CAMK2A protein Q9UQM7 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS BTO:0000944 7523419 t llicata "Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site. Expression of K18 ser-52-->ala mutant in mammalian cells showed minimal phosphorylation but no distinguishable difference in filament assembly when compared with wild-type K18. In contrast, the ser-52 mutation played a clear but nonexclusive role in filament reorganization," SIGNOR-250633 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser289 PPQDQESsPIENDSS 9606 7678037 t llicata "These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase erine threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-250916 IL3 protein P08700 UNIPROT IL3RA protein P26951 UNIPROT up-regulates binding 9606 11700046 t gcesareni "The results demonstrate that both the association and dissociation rates for the binding of il-3 to the il-3ralpha are altered by truncation and by amino acid substitution at individual sites. Intracellular signaling studies using k116w and e43n demonstrate that differences in the il-3alpha binding characteristics are reflected in magnitude and kinetics of stat5 phosphorylation." SIGNOR-111404 CYSLTR2 protein Q9NS75 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256889 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 15723037 t gcesareni "Modulation of human nuclear receptor lrh-1 activity by phospholipids and shpthe human nuclear receptor liver receptor homolog 1 (hlrh-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor shp" SIGNOR-134202 ATF4 protein P18848 UNIPROT NARS2 protein Q96I59 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269423 CSNK2A1 protein P68400 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 12588975 t gcesareni "Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites." SIGNOR-98280 PAFAH1B1 protein P43034 UNIPROT Cerebral_cortex_development phenotype SIGNOR-PH66 SIGNOR up-regulates 9606 23973156 f miannu "LIS1, the first gene to be identified as involved in a neuronal migration disease, is a dosage-sensitive gene whose proper levels are required for multiple aspects of cortical development. Deletions in LIS1 result in a severe brain malformation, known as lissencephaly, whereas duplications delay brain development. LIS1 affects the proliferation of progenitors, spindle orientation and interkinetic nuclear movement in the ventricular zone, as well as nucleokinesis and migration of neurons." SIGNOR-252165 HRH1 protein P35367 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257425 E2F1 protein Q01094 UNIPROT DHFR protein P00374 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253853 TESK1 protein Q15569 UNIPROT TESK1 protein Q15569 UNIPROT "up-regulates activity" phosphorylation Ser220 EPLAVVGsPYWMAPE 9606 BTO:0000567 10207045 t lperfetto "Site-directed mutagenesis analyses revealed that Ser-215 within the activation loop of the kinase domain is the site of serine autophosphorylation of TESK1. Replacement of Ser-215 by alanine almost completely abolished serine autophosphorylation and histone H3 kinase activities." SIGNOR-246667 PRKCB protein P05771 UNIPROT CASR protein P41180 UNIPROT "down-regulates activity" phosphorylation Thr888 FKVAARAtLRRSNVS 9606 BTO:0000007 12356761 t lperfetto "Expression of a mutant CaR in which the major PKC phosphorylation site is altered by substitution of alanine for threonine (T888A) eliminated oscillatory behavior, producing [Ca(2+)](i) responses almost identical to those produced by the wild type CaR exposed to PKC inhibitors. These results support a model in which phosphorylation of the CaR at the inhibitory threonine 888 by PKC provides the negative feedback needed to cause [Ca(2+)](i) oscillations mediated by this receptor." SIGNOR-249176 AURKA protein O14965 UNIPROT MAPRE3 protein Q9UPY8 UNIPROT up-regulates phosphorylation Ser176 MQTSGRLsNVAPPCI 9606 19696028 t llicata "Aurora-a and aurora-b phosphorylate eb3 at ser-176 in a spatial and cell cycle-specific manner, respectively during mitosis two kinases, aurora-a and aurora-b, phosphorylate eb3 at ser-176, and the resulting phosphorylation disrupts the eb3-siah-1 complex. Indeed, eb3 is stabilized during mitosis and facilitates cell cycle progression." SIGNOR-187657 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189981 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM3 protein P20309 UNIPROT "up-regulates activity" "chemical activation" 10029 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258648 HIF1AN protein Q9NWT6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates hydroxylation Asn1955 LEASADAnIQDNMGR 9606 18299578 t gcesareni "We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation." SIGNOR-161057 quetiapine chemical CHEBI:8707 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10116 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258533 3a protein P59632 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 BTO:0001950 18632968 f Luana "Severe Acute Respiratory Syndrome Coronavirus 3a Protein Activates the Mitochondrial Death Pathway Through p38 MAP Kinase Activation" SIGNOR-260444 TGFB1 protein P01137 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11331591 f gcesareni "Tgf-beta inhibited the expression of the cbfa1 and_ osteocalcin_ genes." SIGNOR-107248 PD318088 chemical CID:10231331 PUBCHEM MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244927 FZD4 protein Q9ULV1 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 9606 12958364 t amattioni "Endocytosis of frizzled 4 (fz4) in human embryonic kidney 293 cells was dependent on added wnt5a protein and was accomplished by the multifunctional adaptor protein beta-arrestin 2 (betaarr2), which was recruited to fz4 by binding to phosphorylated dvl2." SIGNOR-100274 PICALM protein Q13492 UNIPROT CLTCL1 protein P53675 UNIPROT up-regulates binding 9606 BTO:0001271;BTO:0000785 16491119 t miannu "Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro" SIGNOR-144733 SDC4 protein P31431 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Like other wnt co receptors, syndecan 4 directly interacts with dvl during pcp." SIGNOR-199635 STK11 protein Q15831 UNIPROT STRADA protein Q7RTN6 UNIPROT "up-regulates activity" phosphorylation Thr419 SGIFGLVtNLEELEV 9606 BTO:0000007 12805220 t lperfetto "Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419" SIGNOR-247564 SCRIB protein Q14160 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "down-regulates activity" binding 9606 BTO:0000007 20622900 t miannu "These two KIM sites are found at N- and C-terminal locations on hScrib, and both are essential for directing the interaction between ERK and hScrib, but with the C-terminal site having the strongest affinity for ERK. One of the most likely consequences of this interaction is to inhibit ERK translocation to the nucleus." SIGNOR-263067 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "L-asparagine zwitterion" smallmolecule CHEBI:58048 ChEBI "up-regulates quantity" "precursor of" 9606 29084849 t miannu "Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7." SIGNOR-268069 ARHGEF7 protein Q14155 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates binding 9606 14505571 t gcesareni "Here, we show that activation of cdc42 protects the egf receptor from the negative regulatory activity of the c-cbl ubiquitin ligase. Activated cdc42 binds to p85cool-1 (for cloned-out-of-library)/beta-pix (for pak-interactive exchange factor), a protein that directly associates with c-cbl. This inhibits the binding of cbl by the egf receptor and thus prevents cbl from catalyzing receptor ubiquitination" SIGNOR-118135 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 t gcesareni "Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b." SIGNOR-49367 WNT2B protein Q93097 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors andinitiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131780 "leukotriene A4(1-)" smallmolecule CHEBI:57463 ChEBI "leukotriene C4(2-)" smallmolecule CHEBI:57973 ChEBI "up-regulates quantity" "precursor of" 9606 27365393 t miannu "Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4)." SIGNOR-277260 ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser317 ENVKYSSsQPEPRTG 9606 15775976 t gcesareni "Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase." SIGNOR-134712 "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 17306385 t miannu "Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase" SIGNOR-256168 "Ionizing radiation" stimulus SIGNOR-ST16 SIGNOR TRIM13 protein O60858 UNIPROT up-regulates 9606 BTO:0000007 21333377 f miannu "These data suggest that irradiation causes RFP2 overexpression, which enhances ionizing radiation-induced apoptosis by increasing p53 stability and decreasing AKT kinase activity through MDM2 and AKT degradation." SIGNOR-271854 "DNA polymerase delta" complex SIGNOR-C376 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9534 BTO:0004055 12930972 f lperfetto "Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA)." SIGNOR-265513 ATF6 protein P18850 UNIPROT ATF6 protein P18850 UNIPROT "up-regulates activity" binding -1 12805554 t miannu "E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins" SIGNOR-224202 IL1R1 protein P14778 UNIPROT MAPK10 protein P53779 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 9625767 t lperfetto "Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab" SIGNOR-249515 RNF6 protein Q9Y252 UNIPROT LIMK1 protein P53667 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 16204183 t miannu "Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons. " SIGNOR-271481 KCNQ4 protein P56696 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 9606 19298256 t miannu "KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations." SIGNOR-265985 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9136927 t lperfetto "Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro" SIGNOR-249648 "cyclosporin A" chemical CHEBI:4031 ChEBI PPP3CA protein Q08209 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127225 EGFR protein P00533 UNIPROT "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR up-regulates binding 9606 11279155 t "inferred from 70% of family members" gcesareni "These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity" SIGNOR-269876 DUSP2 protein Q05923 UNIPROT MAPK4 protein P31152 UNIPROT "down-regulates activity" dephosphorylation 9606 28252035 t miannu "DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5." SIGNOR-277068 PTGS2 protein P35354 UNIPROT "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI "up-regulates quantity" binding 9606 BTO:0000553 33275396 t "Marta Tosoni" "Prostaglandin E2 (PGE2) is an end-product of the cyclooxygenase (COX)-2 pathway that has been reported to promote cell survival, cell growth, migration, invasion and angiogenesis" SIGNOR-278094 HMGCS2 protein P54868 UNIPROT (3S)-3-hydroxy-3-methylglutaryl-CoA(5-) smallmolecule CHEBI:43074 ChEBI "up-regulates quantity" "chemical modification" 29597274 t lperfetto "Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis" SIGNOR-267660 TLN1 protein Q9Y490 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 SIGNOR-C167 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257593 MDM2 protein Q00987 UNIPROT EID1 protein Q9Y6B2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001938 11073989 t miannu "Degradation of EID-1 occurs via ubiquitin-dependent proteolysis and correlates with MDM2 binding. These results are consistent with a model wherein destruction of EID-1 is linked to its ability to interact with MDM2 via either p300 or pRB." SIGNOR-272582 SMOC1 protein Q9H4F8 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20359165 f lperfetto "The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells" SIGNOR-260401 PRKCE protein Q02156 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr52 HKHKHEMtLKFGPAR 9606 BTO:0000848;BTO:0001286 22304920 t lperfetto "Pkc_ phosphorylation of atf2 on thr52. Pkc_ promotes oncogenic functions of atf2 in the nucleus while blocking its apoptotic function at mitochondria" SIGNOR-195761 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 17925232 t "PTIP promotes assembly of the ALR complex and H3K4 methylation at a PAX2-binding DNA element. Without PTIP, Pax2 binds to this element but does not assemble the ALR complex" SIGNOR-251711 IL1RAPL1 protein Q9NZN1 UNIPROT NCS1 protein P62166 UNIPROT "up-regulates activity" binding 10116 BTO:0001009 12783849 t miannu "IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction." SIGNOR-263962 "HIF-1 complex" complex SIGNOR-C418 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity" "transcriptional regulation" 9606 BTO:0000889 17785433 t "Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration" SIGNOR-267494 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu57 EVRKGNLeRECVEET -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263677 ARHGAP40 protein Q5TG30 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260496 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT "up-regulates activity" dephosphorylation Ser834 GSHTSGQsNGRDHQA 9606 BTO:0001109 28114302 t miannu "Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression." SIGNOR-276514 ATM protein Q13315 UNIPROT POLL protein Q9UGP5 UNIPROT "up-regulates activity" phosphorylation Thr204 EASDGEEtQVSAADL 9606 BTO:0000007 28109743 t done miannu " We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ. " SIGNOR-273836 SMAD3 protein P84022 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782 22740686 f lperfetto "PD-1 also inhibited phosphorylation of the transcription factor Smad3, which increased its activity. These events induced additional inhibitory checkpoints in the cell cycle by increasing the abundance of the G(1) phase inhibitor p15(INK4) and repressing the Cdk-activating phosphatase Cdc25A" SIGNOR-245445 PTPN9 protein P43378 UNIPROT NSF protein P46459 UNIPROT down-regulates dephosphorylation Tyr83 QEIEVSLyTFDKAKQ 9606 15322554 t gcesareni "Our results suggest that the molecular mechanism by which ptp-meg2 promotes secretory vesicle fusion involves the local release of nsf from a tyrosine-phosphorylated, inactive state." SIGNOR-128348 FUBP1 protein Q96AE4 UNIPROT BIK protein Q13323 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19637194 f irozzo "FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In particular, elevated expression of the Bcl-2 family members Bik and Noxa was detected." SIGNOR-259127 UBQLN2 protein Q9UHD9 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 10090 27477512 f lperfetto "UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins." SIGNOR-262267 LMO3 protein Q8TAP4 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21573214 f miannu "Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter." SIGNOR-254826 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM ERBB2 protein P04626 UNIPROT "down-regulates activity" "chemical inhibition" -1 24556163 t miannu "This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine" SIGNOR-262233 PTK2B protein Q14289 UNIPROT ASAP1 protein Q9ULH1 UNIPROT "down-regulates activity" phosphorylation Tyr767 RDKQRLSyGAFTNQI 9606 BTO:0000007 12771146 t miannu "The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells.Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation." SIGNOR-263187 Calcineurin complex SIGNOR-C155 SIGNOR Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 15363394 f miannu "In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively." SIGNOR-268386 HNF1B protein P35680 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 7549116 f miannu "HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells." SIGNOR-254638 ESR1 protein P03372 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 18247370 t miannu "The primary conclusion of the results reported here is that ERα and c‐jun, c‐fos and ATF‐2, but not Fra‐2 AP‐1 factors interact “in vivo” with specific estrogen‐responsive regulatory sequences and AP‐1 cis‐elements within the F promoter of the human ERα gene in osteoblast‐like SaOS‐2 cells." SIGNOR-263656 SMAD1 protein Q15797 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0002729 23993924 f flangone "Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes." SIGNOR-255259 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates dephosphorylation 9606 16751101 t lpetrilli "Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads." SIGNOR-146919 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR EIF4B protein P23588 UNIPROT "up-regulates activity" phosphorylation Ser422 RERSRTGsESSQTGT 9606 BTO:0001109 36882522 t lperfetto "CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation." SIGNOR-273116 FCGR3A protein P08637 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000801 10728755 f lperfetto "This study suggests a dominant role for FcgammaRIIIA in the induction of both TNFalpha and IL-1alpha production by human macrophages in rheumatoid arthritis following receptor ligation by small immune complexes. The signaling of TNFalpha production may require the ligation of either 3 FcgammaRIIIA receptors or only 2 FcgammaRIIIA receptors, where one interaction must involve binding via an Fc domain." SIGNOR-249526 CTCF protein P49711 UNIPROT MGAT5B protein Q3V5L5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001976 21771782 f miannu "By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression." SIGNOR-253826 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG -1 7493944 t lperfetto "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." SIGNOR-246264 GOT2 protein P00505 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "chemical modification" 9606 31422819 t miannu "This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-267517 ATM protein Q13315 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser677 RVGKQLAsQKILQLL 9606 BTO:0002181 34188037 t miannu " Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs. " SIGNOR-277307 EGR2 protein P11161 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 11494141 f miannu "Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated." SIGNOR-260048 RPE protein Q96AT9 UNIPROT "D-xylulose 5-phosphate(2-)" smallmolecule CHEBI:57737 ChEBI "up-regulates quantity" "chemical modification" 9606 34775382 t miannu "The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux." SIGNOR-267068 NEPRO protein Q6NW34 UNIPROT "Ribonuclease MRP complex" complex SIGNOR-C570 SIGNOR "form complex" binding 9606 40413743 t miannu "Human RNase MRP is a ribonucleoprotein (RNP) enzyme that processes precursor rRNA (pre-rRNA) at ITS1 site 2 and may have additional activities.Using a genome-wide forward genetic screening that leveraged the requirement of RNase MRP and RNase P for reporter translation, we identified two poorly characterized yet highly enriched human genes, c18orf21 and c3orf17, which we named ribonuclease MRP subunit P24 (RMP24) and RMP64, respectively. We demonstrate that these two genes are specifically required for the activity of human RNase MRP but not RNase P. The protein products of RMP24 and RMP64 associate extensively and exclusively with the only known human RNase MRP-specific component, MRP RNA, but not with the RNase P-specific H1 RNA. Our findings establish Rmp24 and Rmp64 as human protein components unique to RNase MRP." SIGNOR-280686 PSME3 protein P61289 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "up-regulates activity" binding 35932807 t lperfetto "While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome." SIGNOR-275869 aripiprazole chemical CHEBI:31236 ChEBI DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258319 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" dephosphorylation Tyr570 VRREVGDyGQLHETE 9606 30108215 t miannu "Consistently, JAK2/STAT3 signaling was enhanced by overexpression of SHP2   with decreased levels of pJAK2   and increased levels of pJAK2   and pSTAT3  , while it was found suppressed by overexpression of SHP2   (Fig.\u00a06b).|We demonstrate that SHP2 can dephosphorylate JAK2 at Y570 to promote TGF\u03b2-dependent activation of JAK2 and its downstream mediator STAT3 (Supplementary Fig.\u00a04a)." SIGNOR-277037 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR MCM3 protein P25205 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 30224758 f lperfetto "By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ." SIGNOR-276580 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 9606 26260587 t "IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes." SIGNOR-253590 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT "up-regulates activity" phosphorylation Ser946 SVSPCPSsPKQIHLD 9606 BTO:0002181 25452387 t miannu "The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. " SIGNOR-276446 RBL2 protein Q08999 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 10090 BTO:0000165 10801445 f gcesareni "Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program." SIGNOR-267287 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248741 CDK1 protein P06493 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 11986303 t lperfetto "Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%." SIGNOR-87097 "Nucleolar ribonuclease P complex" complex SIGNOR-C571 SIGNOR tRNA(Met) smallmolecule CHEBI:29173 ChEBI "up-regulates quantity" "chemical modification" 9606 30454648 t miannu "Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA." SIGNOR-280713 TOLLIP protein Q9H0E2 UNIPROT IRAK1 protein P51617 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 10854325 t lperfetto "Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)" SIGNOR-251980 mTORC1 complex SIGNOR-C3 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR "down-regulates activity" phosphorylation 9606 23863160 t lperfetto "Several studies published simultaneously illustrated that the equivalent mammalian ULK1Atg13FIP200 complex was also negatively regulated by mTORC1 in an analogous manner [17,18,24]. In mammalian cells, amino acid starvation or rapamycin treatment causes dephosphorylation of both Atg13 and ULK1, indicating that an mTORC1 input regulates the ULK1Atg13FIP200 complex mTORC1 modulates the kinase activity of ULK1 directly, with rapamycin treatment of cells leading to enhanced ULK1 kinase activity, whereas Rheb overexpression causes a decrease in ULK1 kinase activity" SIGNOR-209904 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser31 LKLGSGPsIKALDGR 9606 BTO:0000567 24781523 t miannu "CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase" SIGNOR-276379 RAB32 protein Q13637 UNIPROT "Neuronal AP-3" complex SIGNOR-C445 SIGNOR "up-regulates activity" relocalization 9606 23247405 t miannu "Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes." SIGNOR-268524 ADA protein P00813 UNIPROT inosine smallmolecule CHEBI:17596 ChEBI "up-regulates quantity" "chemical modification" -1 15926889 t Luana "Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates" SIGNOR-269737 PRKACA protein P17612 UNIPROT TBXA2R protein P21731 UNIPROT unknown phosphorylation Ser331 STRPRSLsLQPQLTQ 9606 12147288 t llicata "Ser-331 was found to be involved in pka-mediated phosphorylation." SIGNOR-90976 CAMK2G protein Q13555 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Ser862 IRNKARLsITGSVGE 10366608 t llicata "We found that GluR4 is phosphorylated on serine 842 within the C-terminal domain in vitro and in vivo. Serine 842 is phosphorylated by PKA, PKC, and CaMKII in vitro and is phosphorylated in transfected cells by PKA." SIGNOR-250699 DNA_damage stimulus SIGNOR-ST1 SIGNOR RAD23B protein P54727 UNIPROT up-regulates 24086043 f lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein)." SIGNOR-275688 UBE2G2 protein P60604 UNIPROT DIO2 protein Q92813 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys244 KIAYLGGkGPFSYNL 9606 BTO:0001379 29892818 t scontino "ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244." SIGNOR-267484 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Ser199 PKRKRKNsRVTFSED -1 9407077 t miannu "NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A" SIGNOR-250033 GTF2H4 protein Q92759 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR "form complex" binding 9606 30860024 t lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits" SIGNOR-269315 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 17429065 t lperfetto "Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin." SIGNOR-217631 PKN1 protein Q16512 UNIPROT MEFV protein O15553 UNIPROT "down-regulates activity" phosphorylation Ser208 VRLRRNAsSAGRLQG 10090 BTO:0004732 27270401 t no miannu "PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome." SIGNOR-275462 P-TEFb complex SIGNOR-C238 SIGNOR AFF2 protein P51816 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0000007 17135274 t miannu "P-TEFb phosphorylates Af4 and down-regulates its transactivation activity. P-TEFb also phosphorylates AF4 which down-regulates its transactivation activity, providing a negative feedback mechanism for the control of P-TEFb elongation activity" SIGNOR-266798 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT "down-regulates activity" dephosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000007 17603999 t "Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524." SIGNOR-248561 "Nucleolar ribonuclease P complex" complex SIGNOR-C571 SIGNOR tRNA(Phe) smallmolecule CHEBI:29184 ChEBI "up-regulates quantity" "chemical modification" 9606 30454648 t miannu "Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA." SIGNOR-280714 JNK proteinfamily SIGNOR-PF15 SIGNOR STMN1 protein P16949 UNIPROT down-regulates phosphorylation 9606 20630875 t "inferred from 70% family members" gcesareni "Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress." SIGNOR-269982 SRC protein P12931 UNIPROT FBXO5 protein Q9UKT4 UNIPROT up-regulates phosphorylation Tyr142 ALETSRLyEDSGYSS 9606 20717963 t lperfetto "We found that emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 reduced the stability. Our data suggested bcr-abl-induced emi1 phosphorylation might be mediated by src kinase." SIGNOR-167529 CSNK2A1 protein P68400 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser112 GSDDEEEsEEAKRLR -1 8547318 t llicata "EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent." SIGNOR-250855 GFI1 protein Q99684 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 17213822 t miannu "Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1-mediated transcriptional activation and ETS1 repressed GFI1-mediated transcriptional activation, in a dose-dependent manner." SIGNOR-254201 PRKACA protein P17612 UNIPROT TFAM protein Q00059 UNIPROT up-regulates phosphorylation Ser55 SCPKKPVsSYLRFSK 9606 23201127 t llicata "Here, we demonstrate that tfam is phosphorylated within its hmg box 1 (hmg1) by camp-dependent protein kinase in mitochondria. Hmg1 phosphorylation impairs the ability of tfam to bind dna and to activate transcription." SIGNOR-199934 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A2-B3 complex SIGNOR-C138 SIGNOR "up-regulates activity" "chemical activation" 9606 15036565 t gcesareni "One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)" SIGNOR-243964 TTN protein Q8WZ42 UNIPROT OBSCN protein Q5VST9 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0003324 19840192 t miannu "Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins." SIGNOR-266728 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM2 protein P0DP24 UNIPROT up-regulates "chemical activation" 9606 10884684 t miannu "Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations" SIGNOR-266317 RPS6KA1 protein Q15418 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Thr355 NKRRRSVtPPEEQQE 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-202125 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr169 KRSSRANtVTPAVGR 9606 19530738 t lperfetto "First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form." SIGNOR-186143 EIF3_complex complex SIGNOR-C401 SIGNOR EIF5 protein P55010 UNIPROT "up-regulates activity" stabilization 9606 17581632 t lperfetto "EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit" SIGNOR-269153 CDK1 protein P06493 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 18337751 t gcesareni "Phosphorylation at ser359 inhibits eef2k activity even at high calcium concentrations. we demonstrate that cdc2 contributes to controlling eef2 phosphorylation in cells. inactivation of eef2k by cdc2 may serve to keep eef2 active during mitosis" SIGNOR-177982 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248520 SPAG9 protein O60271 UNIPROT CDON/SPAG9 complex SIGNOR-C21 SIGNOR "form complex" binding 9606 BTO:0000222 17074887 t gcesareni "In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway." SIGNOR-149178 ITK protein Q08881 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 t lperfetto "These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling" SIGNOR-112471 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT "down-regulates activity" phosphorylation Ser726 KKKEKVEs -1 8810272 t miannu "Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250333 JAK2 protein O60674 UNIPROT STAM protein Q92783 UNIPROT up-regulates phosphorylation 9606 9133424 t gcesareni "Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2." SIGNOR-47834 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr77 RASRLGTtRTPSSYG 9606 BTO:0000971 10574968 t lperfetto "We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin" SIGNOR-249033 SRC protein P12931 UNIPROT TGFA protein P01135 UNIPROT up-regulates cleavage 9606 17251915 t lperfetto "Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network." SIGNOR-235888 MAPK1 protein P28482 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 16282323 t lperfetto "Erk phosphorylation serves as a signal for bim ubiquitination and proteasomal degradation" SIGNOR-141584 Netrin proteinfamily SIGNOR-PF97 SIGNOR NEO1 protein Q92859 UNIPROT "up-regulates activity" binding 9606 BTO:0001484 21558366 t miannu "In mammals, three secreted netrins, netrin 1, 3 and 4, and two membrane-tethered glycophosphatidylinositol (GPI)-linked (see Glossary, Box 1) netrins, netrin G1 and G2, have been identified. In mammals, receptors for the secreted netrins include deleted in colorectal cancer (DCC), the DCC paralogue neogenin, the UNC-5 homologues UNC5A-D, and Down syndrome cell adhesion molecule (DSCAM)." SIGNOR-268172 DYRK1A protein Q13627 UNIPROT MCL1 protein Q07820 UNIPROT "up-regulates quantity" phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 32587776 t miannu "Furthermore, DYRK1A likely directly bound and phosphorylated Mcl-1, thereby enhancing Mcl-1 protein stability and contributing to the development of acquired resistance to Bcl-2 inhibitors.|DYRK1A upregulates Mcl-1 expression in NSCLC cells.|We demonstrated that DYRK1A suppression by siRNA or harmine decreased the phosphorylation of Mcl-1 at Ser159/Thr163." SIGNOR-279704 MTHFD2 protein P13995 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI "up-regulates quantity" "chemical modification" 9606 16100107 t lperfetto "Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase|One of the enzymes in this pathway, the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC),5 catalyzes the interconversion of 5,10-methylenetetrahydrofolate (methylene-THF) and 10-formyltetrahydrofolate (formyl-THF) in mammalian mitochondria." SIGNOR-268256 MAT2B protein Q9NZL9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001938 30942439 f miannu "MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen" SIGNOR-261243 TBX2 protein Q13207 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25211658 t lperfetto "TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS" SIGNOR-249594 Starvation stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 BTO:0001760 20810907 f lperfetto "L6 myotubes were incubated in serum-containing or serum-free medium for 3 h. Levels of phosphorylated AMPK, Akt, and ATM were greater in serum-starved cells than in control cells." SIGNOR-209894 LRRK2 protein Q5S007 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation 9606 22998870 t miannu "We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association." SIGNOR-192075 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 23630338 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." gcesareni "C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates." SIGNOR-202007 MC4R protein P32245 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257270 PRPF31 protein Q8WWY3 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270643 SNRNP40 protein Q96DI7 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270644 CCL5 protein P13501 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 t "RANTES interacts with specific cell surface receptors, which are coupled to pertussis toxin-sensitive guanine nucleotide regulatory proteins (G protein) to activate effectors such as phospholipase C (PLC), ion channels, phospholipase D, and protein kinase C. In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5" SIGNOR-254367 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 22898603 t lperfetto "In addition, our work further reveals that above a threshold expression level, DEP-1 can also dephosphorylate Src Y418 and attenuate downstream signaling and biologic responses, consistent with the quiescent behavior of confluent endothelial cells that express the highest levels of endogenous DEP-1." SIGNOR-276978 LRIG1 protein Q96JA1 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates binding 9606 BTO:0001253 15282549 t gcesareni "Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation" SIGNOR-127301 STUB1 protein Q9UNE7 UNIPROT ATXN1 protein P54253 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 16831871 t miannu "CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation|Interestingly, CHIP also interacts with and ubiquitinates unexpanded ataxin-1" SIGNOR-278666 LBX1 protein P52954 UNIPROT ZEB1 protein P37275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 19651985 t Luana "Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively " SIGNOR-266054 TWIST1 protein Q15672 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255516 CAMK1G protein Q96NX5 UNIPROT EIF4G3 protein O43432 UNIPROT up-regulates phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 22514323 t lperfetto "Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii)." SIGNOR-197149 CDK1 protein P06493 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 SIGNOR-C17 17389604 t gcesareni "Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1" SIGNOR-154047 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates quantity by destabilization" binding -1 12620238 t lperfetto "This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral iap repeat (bir3) of xiap at 2.4 a resolution. X-linked inhibitor-of-apoptosis protein (xiap) interacts with caspase-9 and inhibits its activity." SIGNOR-98988 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation 9606 10212258 t gcesareni "C-abl phosphorylates rad51 in vitro and in vivo. In assays using purified components, phosphorylation of rad51 by c-abl enhances complex formation between rad51 and rad52, which cooperates with rad51 in recombination and repair" SIGNOR-67069 PIN4 protein Q9Y237 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" isomerization 9606 BTO:0000599 23720771 t lperfetto "In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events" SIGNOR-265756 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT "down-regulates activity" dephosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000007 17603999 t "Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524." SIGNOR-248562 "glutamic acid" smallmolecule CHEBI:18237 ChEBI "NMDA receptor_2C" complex SIGNOR-C349 SIGNOR "up-regulates activity" "chemical activation" 9606 12871085 t miannu "The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate" SIGNOR-264130 oxytocin smallmolecule CHEBI:7872 ChEBI OXTR protein P30559 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257556 GSK3B protein P49841 UNIPROT LGALS3 protein P17931 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21821001 f miannu "Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells." SIGNOR-261903 IKBKB protein O14920 UNIPROT RPS3 protein P23396 UNIPROT "up-regulates activity" phosphorylation Ser209 KPLPDHVsIVEPKDE 9606 21399639 t miannu "IKKbeta overexpression activated NF-kappaB measured by luciferase assays , and also induced the nuclear translocation of wild-type, but not S209A, RPS3 (XREF_FIG).|Therefore, RPS3 S209 phosphorylation by IKK\u03b2 is apparently required for RPS3 in directing NF-\u03baB to a specific subset of target genes." SIGNOR-278360 PABPC3 protein Q9H361 UNIPROT "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity by stabilization" binding 9606 25480299 t lperfetto "As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length." SIGNOR-268321 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT "up-regulates activity" phosphorylation Tyr503 EAHPNDLyVEGLPEN 9534 11373296 t lperfetto "These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation." SIGNOR-108346 LHX1 protein P48742 UNIPROT OTX2 protein P32243 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10623575 t miannu "Here we show that OTX2 directly associates with LIM1 and HNF-3beta. The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3beta represses, OTX2-directed gene expression." SIGNOR-221161 "STX11-SNAP23 SNARE complex" complex SIGNOR-C272 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR up-regulates 9606 BTO:0000782 22767500 f lperfetto "Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release." SIGNOR-261901 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT up-regulates "transcriptional regulation" 9606 19254573 f fspada "Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression." SIGNOR-209968 SMURF1 protein Q9HCE7 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0002181 15817471 t "In the presence of smad6 or smad7 acting as adaptors" lperfetto "Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes." SIGNOR-236096 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" phosphorylation Thr300 TPVVSVAtPTLPGQG 9606 9858528 t "The effect has been demonstrated using Q06413-3" lperfetto "Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain" SIGNOR-62796 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser19 PAPPVRMsSTIFSTG -1 10075701 t miannu "Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites" SIGNOR-250224 ATP5PO protein P48047 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261403 MYOG protein P15173 UNIPROT PAX7 protein P23759 UNIPROT "down-regulates quantity by destabilization" 10090 BTO:0004058 17548510 f "Simone Vumbaca" "Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions" SIGNOR-255638 HSP90AA1 protein P07900 UNIPROT NOS3 protein P29474 UNIPROT up-regulates binding 9606 9580552 t miannu "The binding of hsp90 to enos enhances the activation of enos." SIGNOR-57211 ULK1 protein O75385 UNIPROT ATG14 protein Q6ZNE5 UNIPROT "up-regulates activity" phosphorylation Ser29 LARDLVDsVDDAEGL 9606 27938392 t miannu "ULK1 phosphorylates ATG14 at serine 29." SIGNOR-278433 PARP1 protein P09874 UNIPROT CHD2 protein O14647 UNIPROT "up-regulates quantity" binding 9606 26895424 t miannu "Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage." SIGNOR-264526 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser454 YVPMNPNsPPRQHSS 9606 15379552 t lperfetto "Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)" SIGNOR-129188 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT "up-regulates activity" phosphorylation Tyr417 LVPKENDyESISDLQ 9534 16920712 t miannu "Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn." SIGNOR-262899 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 21084559 t lperfetto "Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal." SIGNOR-232098 GSK3A protein P49840 UNIPROT GPSM3 protein Q9Y4H4 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser35 STTRPWRsAPPSPPP 9606 BTO:0000876 22843681 t lperfetto "Co-immunoprecipitation of endogenous GPSM3 and 14-3-3 proteins from the human monocytic cell line THP-1 suggests basal phosphorylation of GPSM3 at serine 35 as potentially mediated by GSK3alpha. The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins." SIGNOR-264863 TRIM3 protein O75382 UNIPROT GKAP1 protein Q5VSY0 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 20352094 t miannu "Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites." SIGNOR-271959 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75926 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 8548810 t amattioni "The c-iaps associate with traf1 and traf2" SIGNOR-39596 Ubiquitinated-Viral_Protein complex SIGNOR-C427 SIGNOR "26S Proteasome" complex SIGNOR-C307 SIGNOR "up-regulates activity" binding 9606 15571818 t scontino "The proteasome system is the central proteolytic system of the eukaryotic cell [1] and plays an important role in the generation of MHC-class I peptides. The enzyme complex responsible for the selectivity of intracellular protein degradation is the 26S proteasome that degrades poly-ubiquitinated substrates." SIGNOR-267767 GNAI1 protein P63096 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI down-regulates 9606 23994464 f apalma "The G alpha I subunit inhibits adenylyl cyclase activity and therefore reduces cytoplasmic cAMP levels" SIGNOR-255008 BRD3 protein Q15059 UNIPROT EP300 protein Q09472 UNIPROT "up-regulates activity" binding 9606 BTO:0003292 28045112 t lperfetto "Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3" SIGNOR-262044 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 9748228 t fspada "Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2" SIGNOR-210096 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT "down-regulates activity" phosphorylation Thr431 ASTLDEAtPTLTNQS 9606 19393267 t lperfetto "Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1." SIGNOR-185584 PRKCE protein Q02156 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 BTO:0000150;BTO:0001130;BTO:0000551 23542175 t lperfetto "We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation" SIGNOR-201600 FGFR2 protein P21802 UNIPROT GRB2 protein P62993 UNIPROT up-regulates phosphorylation 9606 22726438 t gcesareni "Inhibition of basal fgf receptor signaling by dimeric grb2." SIGNOR-197980 CREB5 protein Q02930 UNIPROT MX1 protein P20591 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002807 21132541 f miannu "Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition)," SIGNOR-253800 GRM5 protein P41594 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264936 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 17634129 t lperfetto "The activity of Cdc2 is regulated by the phosphatase Cdc25C. Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis.|Cdc2 is activated by Cdc25C that removes phosphate groups from tyrosine 15 and threonine 14 .|Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis." SIGNOR-276945 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation 9606 17900900 t lperfetto "The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt." SIGNOR-252889 CSNK1A1L protein Q8N752 UNIPROT GLI3 protein P10071 UNIPROT up-regulates phosphorylation 9606 16481469 t gcesareni "Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed" SIGNOR-144554 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1060 HGHVSDAsIRVGENV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262900 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" cleavage Arg737 LAAALGIrSFRNSSL -1 10026263 t lperfetto "Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545" SIGNOR-263632 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr72 SDDFDSDyENPDEHS 9606 BTO:0000776 12456653 t llicata "The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex." SIGNOR-96044 MITF protein O75030 UNIPROT ACP5 protein P13686 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0003292 11481336 f miannu "The combination of MITF and PU.1 synergistically activated the TRAP promoter in transient assays." SIGNOR-254584 ETFBKMT protein Q8IXQ9 UNIPROT ETFB protein P38117 UNIPROT "down-regulates activity" methylation Lys203 PNIMKAKkKKIEVIK -1 25416781 t miannu "Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases." SIGNOR-269451 ESR1 protein P03372 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253469 NUAK1 protein O60285 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 21317932 t gcesareni "Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo." SIGNOR-172012 ADRA2C protein P18825 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256699 BNIP3 protein Q12983 UNIPROT RHEB protein Q15382 UNIPROT down-regulates binding 9606 17928295 t gcesareni "Bnip3, a hypoxia-inducible bcl-2 homology 3 domain-containing protein, directly binds rheb and inhibits the mtor pathway. Bnip3 decreases rheb gtp levels in a manner depending on the binding to rheb." SIGNOR-158274 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-34661 PRC1 protein O43663 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 15297875 f miannu "These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins" SIGNOR-265987 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273034 PTK2B protein Q14289 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 16760434 t gcesareni "Activated rock phosphorylates fak on ser732, which is essential for phosphorylation of tyr407 and for cell migration. We further show that pyk2 is activated by vegf-induced clustering of integrin v 3 and is responsible for the phosphorylation of tyr407." SIGNOR-147070 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-126236 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT "up-regulates activity" dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 10454565 t "The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2." SIGNOR-248481 MAPK8 protein P45983 UNIPROT AIMP1 protein Q12904 UNIPROT down-regulates phosphorylation Ser140 KKEKKQQsIAGSADS 9606 20510162 t llicata "We further demonstrated that serine-140 residue of aimp1 was phosphorylated by jnk and alanine mutation of serine-140 suppressed lps-induced cell surface altogether, these results suggest that aimp1 is phosphorylated by jnk through tlr-myd88 pathway and lose the regulatory activity for er retention of gp96expression of gp96." SIGNOR-165763 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT "down-regulates activity" phosphorylation Thr514 SVTPKTVtPASSAKT 9606 phosphorylation:Ser522 PASSAKTsPAKQQAP 25040932 t lperfetto "Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition" SIGNOR-264840 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1B protein P35368 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258453 TGFBR1 protein P36897 UNIPROT VPS39 protein Q96JC1 UNIPROT "up-regulates activity" binding 9534 12941698 t miannu "TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling." SIGNOR-261375 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12429016 t gcesareni "Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge." SIGNOR-95524 HARS1 protein P12081 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 10430027 t miannu "Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes." SIGNOR-270488 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "precursor of" 9606 31422819 t miannu "This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-267511 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 15694340 t gcesareni "Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.. Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1" SIGNOR-133823 PINK1 protein Q9BXM7 UNIPROT TRAP1 protein Q12931 UNIPROT "up-regulates activity" phosphorylation 9606 28358377 t miannu "This would mean that PINK1 knockdown should reduce TRAP1 activity, thereby potentiating BAY induced cell death.|PINK1 can phosphorylate TRAP1 to prevent apoptosis induced by oxidative stress." SIGNOR-278186 ROCK2 protein O75116 UNIPROT LPP protein Q93052 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22886954 f miannu "Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression" SIGNOR-191765 PARP1 protein P09874 UNIPROT SERPINF1 protein P36955 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001949 18312852 f miannu "Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs." SIGNOR-254891 GSK3B protein P49841 UNIPROT FOXP3 protein Q9BZS1 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser274 TKASSVAsSDKGSCC 9606 BTO:0002181 27432879 t miannu "Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser275" SIGNOR-277245 CBP/p300 complex SIGNOR-C6 SIGNOR ALOX15 protein P16050 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000018 12517954 f lperfetto "IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300." SIGNOR-254100 pazopanib chemical CHEBI:71219 ChEBI CSF1R protein P07333 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257740 SDC4 protein P31431 UNIPROT FN1/SDC4 complex SIGNOR-C210 SIGNOR "form complex" binding 23290138 t apalma "We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells" SIGNOR-255286 PIK3C3 protein Q8NEB9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates relocalization 9606 10698680 t lperfetto "One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1)." SIGNOR-252632 PABPC1 protein P11940 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR "up-regulates activity" binding 9606 30209168 t miannu "The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling" SIGNOR-260943 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4A protein P27815 UNIPROT "up-regulates activity" phosphorylation Ser145 ATSQRREsFLYRSDS 9534 BTO:0001538 12023945 t miannu "Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms." SIGNOR-275985 "PB28 dihydrochloride" chemical CID:46861545 PUBCHEM SIGMAR1 protein Q99720 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000093 16891467 t Federica "Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer" SIGNOR-261111 CREB1 protein P16220 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10540320 f miannu "Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter" SIGNOR-254522 NEDD4L protein Q96PU5 UNIPROT TTYH3 protein Q9C0H2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 18577513 t miannu "Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein. " SIGNOR-272633 NLGN4Y protein Q8NFZ3 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 18923512 t brain lperfetto "Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions." SIGNOR-264190 AminoAcids stimulus SIGNOR-ST5 SIGNOR RAG2 protein P55895 UNIPROT up-regulates 9606 22790199 f gcesareni "Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated." SIGNOR-198192 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252759 ACADVL protein P49748 UNIPROT FADH2(2-) smallmolecule CHEBI:58307 ChEBI "up-regulates quantity" "chemical modification" 9606 20490924 t miannu "VLCAD is a dimer of two identical subunits bound to the inner mitochondrial membrane (Fig. 1) and accepts long chain acyl-CoAs as substrate (Fig. 4a).The different ACADs catalyze the following reaction: acyl-CoA + FAD - trans-2-enoyl-CoA + FADH2" SIGNOR-280307 Laminin-1 complex SIGNOR-C183 SIGNOR "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 9361014 t lperfetto "Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI." SIGNOR-253254 DOK1 protein Q99704 UNIPROT ITGB4 protein P16144 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257689 TESK1 protein Q15569 UNIPROT CFL2 protein Q9Y281 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVTVNDE 9606 BTO:0001363 11418599 t lperfetto "Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin" SIGNOR-246719 SHH protein Q15465 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0002314 18662193 f gcesareni "Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors myf-5 and myod, decreases the up-regulation of insulin-like growth factor (igf)-1 and reduces the number of myogenic satellite cells at injured site." SIGNOR-179629 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT "up-regulates activity" binding 9606 16977332 t lperfetto "Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP." SIGNOR-149574 PLK1 protein P53350 UNIPROT PRC1 protein O43663 UNIPROT "down-regulates activity" phosphorylation 9606 22621898 t miannu "Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis.|Plk1, but not Cdk1, phosphorylates PRC1 on Thr-602 to prevent premature midzone assembly in metaphase." SIGNOR-279645 PLK1 protein P53350 UNIPROT TEX14 protein Q8IWB6 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 22405274 t miannu "In addition, we demonstrate that phosphorylation of Tex14 by Plk1 during metaphase promotes APC Cdc20 -mediated Tex14 degradation." SIGNOR-279646 entacapone chemical CHEBI:4798 ChEBI COMT protein P21964 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000759 9681662 t "Simone Vumbaca" "Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P=0.008), respectively, in the liver; consistent results were obtained with the other tissues." SIGNOR-261088 "Nucleolar ribonuclease P complex" complex SIGNOR-C571 SIGNOR tRNA(Pro) smallmolecule CHEBI:29177 ChEBI "up-regulates quantity" "chemical modification" 9606 30454648 t miannu "Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA." SIGNOR-280715 GLI3 protein P10071 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni "Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin." SIGNOR-188878 "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 23142081 t miannu " We provide evidence that mTORC2 can stabilize Fbw8, the substrate-targeting subunit of the CUL7 E3 ligase complex that has been shown to mediate degradation of IRS-1 ." SIGNOR-271941 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 15489227 t gcesareni "Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro." SIGNOR-129939 "1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid" chemical CHEBI:93185 ChEBI SLC6A1 protein P30531 UNIPROT "down-regulates activity" "chemical inhibition" -1 7851497 t miannu "Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1." SIGNOR-258480 PRKACA protein P17612 UNIPROT CACNA1H protein O95180 UNIPROT "down-regulates activity" phosphorylation Ser1144 AWSSRRSsWSSLGRA 9606 19131331 t miannu "Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity." SIGNOR-263111 RAB38 protein P57729 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR "up-regulates activity" relocalization 9606 23247405 t lperfetto "Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes." SIGNOR-260697 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT up-regulates phosphorylation Tyr465 VPVDPATyGQFYGGD 9606 10210201 t lperfetto "Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently" SIGNOR-67014 RIT2 protein Q99578 UNIPROT POU4F1 protein Q01851 UNIPROT "up-regulates activity" binding 9606 BTO:0000934 12934100 t miannu "we describe the evidence for a functional interaction between Brn-3a and Rin and demonstrate the role of Rin in modulating the activation of the Brn-3a regulated egr-1 promoter by the N-terminal domain of Brn-3a." SIGNOR-224546 "Nucleolar ribonuclease P complex" complex SIGNOR-C571 SIGNOR tRNA(Ser) smallmolecule CHEBI:29179 ChEBI "up-regulates quantity" "chemical modification" 9606 30454648 t miannu "Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA." SIGNOR-280716 "Nucleolar ribonuclease P complex" complex SIGNOR-C571 SIGNOR tRNA(Thr) smallmolecule CHEBI:29180 ChEBI "up-regulates quantity" "chemical modification" 9606 30454648 t miannu "Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA." SIGNOR-280717 GTF2I protein P78347 UNIPROT USF1 protein P22415 UNIPROT "up-regulates activity" binding 9606 21282467 t lperfetto "TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription" SIGNOR-268538 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Thr233 DDEDDSGtEES 9606 11546811 t lperfetto "The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm." SIGNOR-110407 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates phosphorylation Ser1236 PKPKPRPsITKATWE 9606 BTO:0000887;BTO:0001260 19103606 t acerquone "Here we show that rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser1150 and attenuated p190a rhogap activity in cos7 cells" SIGNOR-182853 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1B protein P35368 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258461 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr978 AEMSIMTtELQSLCS 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159586 CAPN1 protein P07384 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Lys32 RARRPESkATNATLD -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus" SIGNOR-263559 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr1197 LESEEELySSCRQLR 9606 BTO:0000776 11507089 t lperfetto "These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2." SIGNOR-109746 AKT2 protein P31751 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 t lperfetto "Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300." SIGNOR-217673 tRNA(Asp) smallmolecule CHEBI:29186 ChEBI Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270377 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates activity" binding 9606 BTO:0001271 11283671 t apalma "Here we show that AML1–ETO blocks C/EBPα –dependent activation of its own promoter and thereby inhibits autoregulation." SIGNOR-255672 serotonin smallmolecule CHEBI:28790 ChEBI HTR1E protein P28566 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264288 MAPK3 protein P27361 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser333 KGLVSPQsPQKSDCQ 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni "Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway." SIGNOR-58489 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation Ser505 SPVAGVHsPMASSGN 9606 BTO:0000093 15383283 t miannu "P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators." SIGNOR-250103 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000599 10187842 t "inferred from 70% family members" lperfetto "We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution." SIGNOR-270180 AURKA protein O14965 UNIPROT WDR62 protein O43379 UNIPROT "up-regulates activity" phosphorylation Ser33 PARRGQSsPPPAPPI -1 25501809 t lperfetto "AURKA activity promotes WDR62 spindle localization|We next purified recombinant full-length WDR62 (GST–WDR62-FL) for in vitro kinase assays with active AURKA and demonstrated that WDR62 was a direct phosphorylation target of AURKA|In addition, our quantitative phosphoproteomic analysis of in-vitro-phosphorylated WDR62 identified S32 and S33 as significantly phosphorylated in the presence of active AURKA|Alanine replacement of the five putative phosphorylation sites (S32/S33/S49/T50/S52-AAAAA) of WDR62 attenuated interphase microtubule association induced by AURKA coexpression" SIGNOR-271713 RIPK1 protein Q13546 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "up-regulates activity" phosphorylation Ser728 PSPARSSsYSEANEP 9606 27858941 t miannu "Upon TNF stimulation, RIP1 phosphorylates DAB2IP on Serine 604, inducing a conformational switch that allows formation of the complex." SIGNOR-254763 "nitric oxide" smallmolecule CHEBI:16480 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 f lperfetto "The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment." SIGNOR-272279 TGFB1 protein P01137 UNIPROT "Activated PSC" phenotype SIGNOR-PH224 SIGNOR up-regulates 9606 BTO:0000988 38540204 t miannu "Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction" SIGNOR-277679 PRKCG protein P05129 UNIPROT GRIN1 protein Q05586 UNIPROT "up-regulates activity" phosphorylation Ser890 ITSTLASsFKRRRSS 10116 BTO:0000938 15936117 t miannu "Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890." SIGNOR-263176 Ub:E2 complex SIGNOR-C497 SIGNOR UNK protein Q9C0B0 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271219 MAPK14 protein Q16539 UNIPROT NFATC4 protein Q14934 UNIPROT "down-regulates activity" phosphorylation Ser170 GGAFFSPsPGSSSLS 10029 BTO:0001131 11997522 t miannu "P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity." SIGNOR-250108 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MCRIP1 protein C9JLW8 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 25728771 t "inferred from 70% family members" lperfetto "When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation" SIGNOR-270188 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 26214522 t Luana "In this study, we have demonstrated that the PTPN1 gene, which encodes PTP1B, was a direct target of MECP2 and that PTP1B protein levels were dramatically increased in Mecp2-mutant mice and in fibroblasts derived from patients with RTT." SIGNOR-264546 vandetanib chemical CHEBI:49960 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258306 LRRK2 protein Q5S007 UNIPROT ARFGAP1 protein Q8N6T3 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000142 22363216 t gcesareni "Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid." SIGNOR-196267 FGF2 protein P09038 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 20974802 f gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription" SIGNOR-168998 IRAK2 protein O43187 UNIPROT IL1R1 protein P14778 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 35486320 t miannu "Two additional proximal mediators were identified that are required for IL-1R–induced NF-κB activation: IRAK-2, a Pelle family member, and MyD88, a death domain–containing adapter molecule. IRAK-2 preferentially bound IL-1RI. A truncated version of IRAK-2 that lacked the first 96 amino acids [IRAK-2(97-590)] did not associate with IL-1RI, which suggests that the NH2-terminal segment docks with the cytoplasmic domain of IL-1RI." SIGNOR-273854 ENG protein P17813 UNIPROT BMP10 protein O95393 UNIPROT "up-regulates activity" binding 9606 BTO:0003767 21737454 t miannu "Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays." SIGNOR-276657 ammonium smallmolecule CHEBI:28938 ChEBI "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "up-regulates quantity" "precursor of" 9606 30158707 t miannu "Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction." SIGNOR-267823 "GABA-B receptor" complex SIGNOR-C336 SIGNOR GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 30541966 t miannu "GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase." SIGNOR-264965 CBP/p300 complex SIGNOR-C6 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 10944526 t lperfetto "Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo." SIGNOR-217220 MRPL21 protein Q7Z2W9 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262372 SP1 protein P08047 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18025157 f "We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein." SIGNOR-255748 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni "Receptor internalization, altered;intracellular localization" SIGNOR-97554 ATM protein Q13315 UNIPROT ELF4 protein Q99607 UNIPROT "down-regulates activity" phosphorylation 9606 21616937 t miannu "Elf4 is phosphorylated by Atm after gamma irradiation, leading to its degradation.|Thus, Atm promotes Elf4 protein degradation after gamma irradiation via phosphorylation at these sites." SIGNOR-278466 TLE1 protein Q04724 UNIPROT SIX3 protein O95343 UNIPROT "up-regulates activity" binding -1 12441302 t lperfetto "Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation" SIGNOR-234595 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM50 protein Q86XT4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271190 GNG3 protein P63215 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-252685 AP3S1 protein Q92572 UNIPROT "AP-3 complex" complex SIGNOR-C247 SIGNOR "form complex" binding 9606 21097499 t lperfetto "Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)" SIGNOR-260680 GLI1 protein P08151 UNIPROT MYCN protein P04198 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni "GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin" SIGNOR-188872 GSK690693 chemical CHEBI:90677 ChEBI AKT1 protein P31749 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252462 CATSPER4 protein Q7RTX7 UNIPROT "CatSpermasome complex" complex SIGNOR-C574 SIGNOR "form complex" binding 9606 34225353 t miannu "The cation channel of sperm (CatSper) is essential for sperm motility and fertility1,2. CatSper comprises the pore-forming proteins CATSPER1-4 and multiple auxiliary subunits, including CATSPERβ, γ, δ, ε, ζ, and EFCAB91,3-9. " SIGNOR-280738 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 10090 BTO:0000459 18621737 t lperfetto "The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively." SIGNOR-179446 MAPK7 protein Q13164 UNIPROT KLF4 protein O43474 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23612709 f miannu "The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion" SIGNOR-255455 L-ornithine smallmolecule CHEBI:15729 ChEBI M2_polarization phenotype SIGNOR-PH55 SIGNOR "up-regulates activity" 25386178 f apalma "In general, M2 type macrophages act as anti-inflammatory cells via diversion of arginine away from NOS or via the synthesis of downstream products derived from the ornithine that is generated via arginase" SIGNOR-256075 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr332 ILAIHDSyKPEFHSD 10029 BTO:0000246 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248391 Hexocyclium chemical CHEBI:5707 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 2704370 t miannu "In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium." SIGNOR-258389 RNF8 protein O76064 UNIPROT TPP1 protein O14773 UNIPROT "up-regulates activity" ubiquitination 9606 22101936 t miannu "Our data demonstrate that RNF8 directly ubiquitylates and stabilizes TPP1 at telomeres.|Taken together, these results suggest that RNF8 dependent K63 linked, but not K48 linked ubiquitin chain formation on TPP1 is required to promote TPP1 stability and function at telomeres." SIGNOR-278574 PRKACA protein P17612 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Thr686 QQKIRKYtMRRLLQE 9606 18799465 t lperfetto "Pka directly phosphorylated erbb2 on thr-686, a highly conserved intracellular regulatory site that was required for the pka-mediated synergistic enhancement of neuregulin-induced erbb2-erbb3 activation and proliferation in scs." SIGNOR-181191 PTPN11 protein Q06124 UNIPROT SLC25A4 protein P12235 UNIPROT "down-regulates activity" dephosphorylation 9606 29255148 t miannu "Specifically, SHP2-mediated dephosphorylation of ANT1 at Tyr 191 is essential for mitochondrial homeostasis and mitigation of NLRP3 inflammasome activation.|The interaction between SHP2 and ANT1 (Fig.\u00a0 xref ), and the opposite effects of SHP2 and ANT1 shRNAs in the activation of NLRP3 inflammasome (Figs.\u00a0 xref and xref ) raised the possibility that the SHP2 may inhibit ANT1 to suppress NLRP3 inflammasome activation.|To further determine which tyrosine phosphorylation site of ANT1 is dephosphorylated by SHP2, we created the dephosphorylated mutant of ANT1, in which tyrosine was replaced with phenylalanine (Y to F mutation)." SIGNOR-277124 STK38L protein Q9Y2H1 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Ser282 NRRQLAYsTVGTPDY 9606 BTO:0000007 16314523 t lperfetto "Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity." SIGNOR-142518 "Obatoclax mesylate" chemical CID:46930996 PUBCHEM BCL2L2 protein Q92843 UNIPROT "down-regulates activity" "chemical inhibition" -1 23515850 t lperfetto "Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro" SIGNOR-262024 SMURF1 protein Q9HCE7 UNIPROT ODF2 protein Q5BJF6 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272683 ANK2 protein Q01484 UNIPROT CACNA1A protein O00555 UNIPROT "up-regulates quantity" binding 10090 24394417 t miannu "Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo." SIGNOR-266706 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230394 t gcesareni "Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A|Collectively, these results implicate PKA as the principal mitochondria-based S112 kinase." SIGNOR-67383 AURKB protein Q96GD4 UNIPROT KIF4A protein O95239 UNIPROT "up-regulates activity" phosphorylation Thr799 PPKLRRRtFSLTEVR -1 28992084 t miannu "Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis." SIGNOR-265992 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser338 PAPKLVEsPKEGKGS 9534 BTO:0000298 14623875 t llicata "DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase." SIGNOR-251088 SPOP protein O43791 UNIPROT INF2 protein Q27J81 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 28448495 t miannu "SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J)." SIGNOR-272798 PITX3 protein O75364 UNIPROT MTA1 protein Q13330 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 SIGNOR-C123 21368136 t 1 miannu "we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3." SIGNOR-239770 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR KLC1 protein Q07866 UNIPROT down-regulates phosphorylation 9606 21385839 t "inferred from 70% family members" gcesareni "Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro." SIGNOR-270176 EFCAB9 protein A8MZ26 UNIPROT "CatSpermasome complex" complex SIGNOR-C574 SIGNOR "form complex" binding 9606 34225353 t miannu "The cation channel of sperm (CatSper) is essential for sperm motility and fertility1,2. CatSper comprises the pore-forming proteins CATSPER1-4 and multiple auxiliary subunits, including CATSPERβ, γ, δ, ε, ζ, and EFCAB91,3-9. " SIGNOR-280733 TMEM262 protein E9PQX1 UNIPROT "CatSpermasome complex" complex SIGNOR-C574 SIGNOR "form complex" binding 9606 34225353 t miannu "The cation channel of sperm (CatSper) is essential for sperm motility and fertility1,2. CatSper comprises the pore-forming proteins CATSPER1-4 and multiple auxiliary subunits, including CATSPERβ, γ, δ, ε, ζ, and EFCAB91,3-9. " SIGNOR-280734 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK2 protein P24941 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258087 GATA1 protein P15976 UNIPROT CBFB protein Q13951 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004475 19825991 f miannu "Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors." SIGNOR-254190 SHANK3 protein Q9BYB0 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR "up-regulates quantity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264700 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr299 AGLTPPTtPPHKANQ 9606 BTO:0000887 11741533 t gcesareni "Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298" SIGNOR-112774 MTOR protein P42345 UNIPROT ELP1 protein O95163 UNIPROT "up-regulates activity" phosphorylation Ser1174 SETSSVVsGSEMSGK 29925953 t lperfetto "Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174" SIGNOR-275541 RBX1 protein P62877 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "form complex" binding 9606 22649780 t gcesareni "The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors" SIGNOR-234799 PTEN protein P60484 UNIPROT "SL1 complex" complex SIGNOR-C464 SIGNOR "down-regulates quantity by destabilization" 16055704 f lperfetto "PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex" SIGNOR-269645 CCND1 protein P24385 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "form complex" binding 9606 7736585 t gcesareni "D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb," SIGNOR-32298 PI-103 chemical CHEBI:90524 ChEBI PIK3CA protein P42336 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258266 FZD2 protein Q14332 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada "Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)" SIGNOR-80604 PSENEN protein Q9NZ42 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates cleavage 9606 12522139 t gcesareni "Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex." SIGNOR-97113 MEF2C protein Q06413 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000167 15356291 f miannu "Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential." SIGNOR-254583 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM69 protein Q86WT6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271188 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Thr635 SQCGYSStIVHVPPP 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250820 PTPN1 protein P18031 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation 9606 15632081 t gcesareni "Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs" SIGNOR-252639 SOCS3 protein O14543 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" binding 9606 23454976 t miannu "SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition" SIGNOR-253051 ABL1 protein P00519 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation Tyr580 REDSARVyENVGLMQ 9606 18827006 t miannu "Direct phosphorylation of SHP-2 by Abl kinases (Y580) promotes sustained activation of SHP-2 signaling and proliferation, and c-Abl/Abl-Related Gene-dependent activation of tyrosine kinase X further potentiates SHP-2 signaling by phosphorylating SHP-2 on Y63.|Endogenous Abl kinases phosphorylate SHP-2 on Y580 and induce sustained ERK phosphorylation in response to PDGF." SIGNOR-278217 VRK1 protein Q99986 UNIPROT H2AX protein P16104 UNIPROT "up-regulates activity" phosphorylation Ser140 GKKATQAsQEY 9606 25923214 t miannu "In response to DNA damage induced by ionizing radiation, histone H2AX is phosphorylated in Ser139 by VRK1." SIGNOR-278370 RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 9606 23661684 f lperfetto SIGNOR-255323 ODC1 protein P11926 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "down-regulates quantity" "chemical modification" 9606 14617280 t miannu "Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)" SIGNOR-256037 PPM1L protein Q5SGD2 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000142;BTO:0000671 17456047 t gcesareni "Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation" SIGNOR-154554 FFAR2 protein O15552 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257342 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257303 KAT2B protein Q92831 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269620 TLR2 protein O60603 UNIPROT TICAM2 protein Q86XR7 UNIPROT "up-regulates activity" binding 10090 22664090 t scontino "To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group" SIGNOR-266747 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser68 LRDAIRQsNQILRER 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto "In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I" SIGNOR-158659 BHLHE40 protein O14503 UNIPROT BHLHE40 protein O14503 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 14672706 f lperfetto "We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression." SIGNOR-253715 ABI1 protein Q8IZP0 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9010225 t gcesareni "Our results are in agreement with previous report showing that abi-1, the putative mouse homologue of e3b1, is a abl binding protein" SIGNOR-45994 EFNA3 protein P52797 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni "The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells." SIGNOR-52312 EIF3I protein Q13347 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 9774674 t gcesareni "Another receptor-associated protein is trip-1, which interacts with and is phosphorylated by tbrii and contains five wd-40 repeats. The association of wd-40 repeat proteins may then allow them to play a role in signaling by the serine/threonine kinase receptors." SIGNOR-60700 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 t esanto "Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89225 DGC complex SIGNOR-C217 SIGNOR "GABA-A (a5-b1-g2) receptor" complex SIGNOR-C335 SIGNOR "up-regulates quantity" binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu " In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses." SIGNOR-265438 SIK2 protein Q9H0K1 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates 10090 24841198 f lperfetto "Moreover, SIK2 was shown to down-regulate the carbohydrate-responsive element-binding protein (ChREBP)-mediated lipogenesis in hepatocytes through the inhibitory phosphorylation of p300/Ser89 and to prevent steatosis in mice" SIGNOR-265746 FAM3C protein Q92520 UNIPROT LIFR protein P42702 UNIPROT "up-regulates activity" binding 9606 BTO:0000584 35680099 t miannu "Interleukin-like EMT inducer (ILEI) a cytokine from the FAM3 family, also functions as a ligand for LIFR-gp130 heterodimer and mediates intracellular signal through STAT activation." SIGNOR-277986 TLK1 protein Q9UKI8 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "up-regulates activity" phosphorylation -1 11314006 t "The effect has been demonstrated using Q9UKI8-2" lperfetto "Purified tlk1b phosphorylated histone h3 at s(10) with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone h3 is a physiological substrate for tlk1b. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events." SIGNOR-265370 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 t lperfetto "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex" SIGNOR-118576 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR EDC3 protein Q96F86 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 20051463 t miannu "14-3-3 binding to EDC3 resulted in a significant decrease in the binding of several key mRNA regulatory factors such as PABP and Y-box-binding protein 1 to EDC3." SIGNOR-262630 "CID 132010322" chemical CID:132010322 PUBCHEM BRD2 protein P25440 UNIPROT "down-regulates activity" "chemical inhibition" 9606 31969702 t Luana "ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4" SIGNOR-261103 CLASP1 protein Q7Z460 UNIPROT CLIP1 protein P30622 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15631994 t lperfetto "CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability." SIGNOR-265091 FBXO3 protein Q9UK99 UNIPROT SMURF1 protein Q9HCE7 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272441 ITCH protein Q96J02 UNIPROT CFLAR protein O15519 UNIPROT "down-regulates quantity" ubiquitination 10090 16469705 t gcesareni "Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation." SIGNOR-245307 IST1 protein P53990 UNIPROT SPAST protein Q9UBP0 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 23897888 t Gianni "Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery." SIGNOR-269047 IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "chemical modification" 9606 29090344 t miannu "Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases." SIGNOR-253135 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT "up-regulates activity" phosphorylation Tyr218 PPRDFAAyRS 8992971 t "EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor." SIGNOR-251337 CDK2 protein P24941 UNIPROT RAD54L protein Q92698 UNIPROT "down-regulates activity" phosphorylation Ser49 QIQECFLsPFRKPLS -1 29295984 t miannu "Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM." SIGNOR-273599 CYP27B1 protein O15528 UNIPROT calcitriol smallmolecule CHEBI:17823 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000671 12050193 t lperfetto "The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha." SIGNOR-270559 ZBTB46 protein Q86UZ6 UNIPROT "Neuroendocrine cell differentiation" phenotype SIGNOR-PH232 SIGNOR up-regulates 9606 BTO:0000584 30312731 f miannu "Most tumors progress to castration-resistant prostate cancer (CRPC) and develop the neuroendocrine (NE) phenotype under androgen deprivation therapy (ADT).Herein, we show that an immunocyte expression protein, ZBTB46, induces inflammatory response gene expression and contributes to NE differentiation of prostate cancer cells. ZBTB46 induces NE marker expressions of prostate cancer." SIGNOR-277990 "prostaglandin G2(1-)" smallmolecule CHEBI:82629 ChEBI "prostaglandin H2(1-)" smallmolecule CHEBI:57405 ChEBI "up-regulates quantity" "precursor of" -1 7592599 t Luana "[14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2," SIGNOR-269777 CSNK2A1 protein P68400 UNIPROT CERS5 protein Q8N5B7 UNIPROT "up-regulates activity" phosphorylation Ser354 DDRSDVEsSSEEEDV 9606 BTO:0000007 26887952 t miannu "Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. " SIGNOR-273985 EVI5 protein O60447 UNIPROT PLK1 protein P53350 UNIPROT down-regulates 9606 16439210 f gcesareni "Evi5 antagonizes scf(betatrcp)-dependent emi1 ubiquitination and destruction by binding to a site adjacent to emi1's dsgxxs degron and blocking both degron phosphorylation by polo-like kinases and subsequent betatrcp binding." SIGNOR-143683 PTPN11 protein Q06124 UNIPROT KRAS protein P01116 UNIPROT "up-regulates activity" dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t irozzo "Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling." SIGNOR-255982 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM47 protein Q96LD4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271001 PPP2CB protein P62714 UNIPROT ATM protein Q13315 UNIPROT "down-regulates activity" dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 15510216 t "Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro." SIGNOR-248601 U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11739736 f miannu "The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing." SIGNOR-263945 SETD5 protein Q9C0A6 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" methylation Lys37 APATGGVkKPHRYRP -1 31515109 t miannu "SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription." SIGNOR-264620 DLX5 protein P56178 UNIPROT MSX2 protein P35548 UNIPROT "down-regulates activity" binding 10090 BTO:0000947 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240925 SNUPN protein O95149 UNIPROT "U1 snRNP complex" complex SIGNOR-C480 SIGNOR "up-regulates quantity" relocalization 9606 BTO:0000567 9670026 t miannu "Here, we describe the isolation and cDNA cloning of a 45 kDa protein, termed snurportin1, which interacts specifically with m3G-cap but not m7G-cap structures. Snurportin1 enhances the m3G-capdependent nuclear import of U snRNPs in both Xenopus laevis oocytes and digitonin-permeabilized HeLa cells, demonstrating that it functions as an snRNP-specific nuclear import receptor." SIGNOR-272080 MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation 10090 17299140 t lperfetto "Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK." SIGNOR-42402 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR PTCH1 protein Q13635 UNIPROT down-regulates cleavage Asp1405 CPGYPETdHGLFEDP 9606 23074268 t gcesareni "Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain." SIGNOR-256437 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 18676833 t gcesareni "We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage." SIGNOR-179808 LMNA protein P02545 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000944 16415042 f "Cleaved by CASP6" amattioni "Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy.|We conclude that A-type lamins act as inhibitors of adipocyte differentiation, possibly by affecting PPARgamma2 and insulin signaling." SIGNOR-45455 PRKACA protein P17612 UNIPROT RARA protein P10276 UNIPROT "down-regulates activity" phosphorylation Ser369 YVRKRRPsRPHMFPK 9606 20215566 t miannu " Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity. " SIGNOR-276282 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-165208 SYK protein P43405 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 11331248 t gcesareni "Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k." SIGNOR-107046 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 1939237 t lperfetto "Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence." SIGNOR-22424 TFEB protein P19484 UNIPROT GOLPH3L protein Q9H4A5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 32978159 f lperfetto "Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14)" SIGNOR-276793 mifepristone chemical CHEBI:50692 ChEBI LIFR protein P42702 UNIPROT "down-regulates activity" "chemical modification" 9606 BTO:0000584 36359879 t miannu "In conclusion, we identified a LIF/LIFR pathway that promotes/maintains oncogenicity in PDAC cell lines. Using docking and pharmacological experiments, we have shown that mifepristone, a clinically approved anti-steroidal agent, functions as a LIFR antagonist, directly binding the LIFR complex and preventing its activation in PDAC cell lines. Present results support the repositioning of mifepristone in the treatment of LIFR expressing PDAC." SIGNOR-278032 PRKCZ protein Q05513 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249251 SF3B2 protein Q13435 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270664 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-252876 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 11581251 t "inferred from 70% family members" lperfetto "Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL." SIGNOR-270207 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7824938 t gcesareni "Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain." SIGNOR-33914 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257906 CSNK2A1 protein P68400 UNIPROT NASP protein P49321 UNIPROT "down-regulates activity" phosphorylation Ser497 TEEMPNDsVLENKSL 9606 29733298 t miannu "Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways. " SIGNOR-273627 WWTR1 protein Q9GZV5 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001615 22470139 f miannu "Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation." SIGNOR-255606 UNC80 protein Q8N2C7 UNIPROT UNC79 protein Q9P2D8 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22196327 t miannu "The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80." SIGNOR-265183 GHSR protein Q92847 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257054 clobetasol chemical CHEBI:205919 ChEBI NR3C1 protein P04150 UNIPROT "up-regulates activity" "chemical activation" 9606 4594577 t SimoneGraziosi "The clinical evaluation of a new topical corticosteroid, clobetasol propionate. An international controlled trial." SIGNOR-269217 GATA3 protein P23771 UNIPROT PPARG protein P37231 UNIPROT down-regulates "transcriptional regulation" 9606 15632071 f fspada "Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity" SIGNOR-210025 CDK6 protein Q00534 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 11986303 t lperfetto "Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown)." SIGNOR-87113 AKT1 protein P31749 UNIPROT CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Ser282 FFAKRKRsAPEKSSG 9606 BTO:0000150 23421998 t lperfetto "Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination" SIGNOR-252535 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 8500166 f "This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates." SIGNOR-254980 "Ribonuclease MRP complex" complex SIGNOR-C570 SIGNOR "ribosomal RNA" smallmolecule CHEBI:18111 ChEBI "up-regulates quantity" "chemical modification" 9606 40413743 t miannu "Human RNase MRP is a ribonucleoprotein (RNP) enzyme that processes precursor rRNA (pre-rRNA) at ITS1 site 2 and may have additional activities.Using a genome-wide forward genetic screening that leveraged the requirement of RNase MRP and RNase P for reporter translation, we identified two poorly characterized yet highly enriched human genes, c18orf21 and c3orf17, which we named ribonuclease MRP subunit P24 (RMP24) and RMP64, respectively. We demonstrate that these two genes are specifically required for the activity of human RNase MRP but not RNase P. The protein products of RMP24 and RMP64 associate extensively and exclusively with the only known human RNase MRP-specific component, MRP RNA, but not with the RNase P-specific H1 RNA. Our findings establish Rmp24 and Rmp64 as human protein components unique to RNase MRP." SIGNOR-280690 ADX-47273 chemical CID:11383075 PUBCHEM MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates "chemical activation" 9606 Other t "Selleck|inferred from family member" gcesareni SIGNOR-270276 creatine smallmolecule CHEBI:16919 ChEBI CKB protein P12277 UNIPROT "up-regulates activity" "chemical activation" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265809 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT "up-regulates activity" cleavage Gly1446 TPLQLFEgRRNRRRR -1 17204478 t lperfetto "MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a)." SIGNOR-263428 MARCHF9 protein Q86YJ5 UNIPROT FCGR2B protein P31994 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001522 19457934 t miannu "MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. " SIGNOR-271541 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t lperfetto "The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation." SIGNOR-235881 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr90 AIKIIDKtQLNPTSL 9606 15319445 t gcesareni "Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1." SIGNOR-259431 RACGAP1 protein Q9H0H5 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260512 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 10488065 t gcesareni "Edg-3 and edg-5 couple not only to gibut also to gqand g13." SIGNOR-70664 RIPK1 protein Q13546 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 20404851 t lperfetto "Collectively, TRIF forms a multiprotein signaling complex along with TRAF6, TRADD, Pellino-1 and RIP1 for the activation of TAK1, which in turn activates the NF-_B and MAPK pathways." SIGNOR-216325 USF1 protein P22415 UNIPROT CTSD protein P07339 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 9731700 f miannu "Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription." SIGNOR-255595 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Thr514 TTTPKGGtPAGSARG 10116 16611631 t lperfetto "Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-146015 ATP2A2 protein P16615 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 16402920 t lperfetto "In the present study, we have analysed the expression and functional characteristics of SERCA2c relative to SERCA2a and SERCA2b isoforms upon their stable heterologous expression in HEK-293 cells (human embryonic kidney 293 cells). All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells." SIGNOR-262050 HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000759 14614508 t "CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo" SIGNOR-253584 HIF1A protein Q16665 UNIPROT KDM7A protein Q6ZMT4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271572 RPS24 protein P62847 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262427 CCL20 protein P78556 UNIPROT CCR6 protein P51684 UNIPROT "up-regulates activity" binding 9606 BTO:0000782;BTO:0002042 11035086 t miannu "Liver and activation-regulated chemokine (LARC), also designated macrophage inflammatory protein-3alpha (MIP-3alpha), Exodus, or CCL20, is a C-C chemokine that attracts immature dendritic cells and memory T lymphocytes, both expressing CCR6. LARC/MIP-3α is exerting its activity through binding to CCR6 (11, 12, 18, 19, 20), which is not shared by any other known chemokine. CCR6 is found to be expressed on immature dendritic cells and memory T lymphocytes as well as on B lymphocytes, in various lymphoid organs, and in pancreas" SIGNOR-278040 CABIN1 protein Q9Y6J0 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates 9606 17172641 f gcesareni "Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity." SIGNOR-151208 MYO10 protein Q9HD67 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 27580874 f miannu "Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments." SIGNOR-268284 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "A4/b1 integrin" complex SIGNOR-C162 SIGNOR "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259016 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr966 QICKGMEyLGTKRYI 9606 BTO:0000007 20304997 t lperfetto "Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity" SIGNOR-236290 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270432 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f lperfetto "We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2" SIGNOR-235361 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT "up-regulates activity" binding 9606 9267021 t "Cytochrome C released from mitochondria" lperfetto "Once released from mitochondria, cytochrome c binds to Apaf-1, which may trigger the activation of caspase-3 in the presence of dATP." SIGNOR-50585 FOS protein P01100 UNIPROT CYP19A1 protein P11511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19022561 t miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254879 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 19920149 t gcesareni "Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7" SIGNOR-161766 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 11502070 t lperfetto "Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization." SIGNOR-109716 CDK1 protein P06493 UNIPROT NSFL1C protein Q9UNZ2 UNIPROT "down-regulates activity" phosphorylation Ser140 AVERVTKsPGETSKP 9606 12810701 t lperfetto "Now, we have found that p47, which mainly localizes to the nucleus during interphase, is phosphorylated on serine-140 by cdc2 at mitosis. The phosphorylated p47 does not bind to golgi membranes." SIGNOR-102350 FAS protein P25445 UNIPROT FADD protein Q13158 UNIPROT "up-regulates activity" binding 9606 21959933 t lperfetto "Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd." SIGNOR-176651 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser288 PESEDEEsYDTESEF 9606 BTO:0000782 8622692 t llicata "Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation." SIGNOR-40506 MMP14 protein P50281 UNIPROT ADAM9 protein Q13443 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0000007 22632802 t Giulio "Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9|Western blotting using antibodies against ectodomain of ADAM9 detected a fragment (around 26 kDa) of ADAM9 in the conditioned culture medium from cells cotransfected with wild-type MT1-MMP, but not in that with catalytic activity-dead MT1-MMP (Figure 6A, top)." SIGNOR-260301 PCF11 protein O94913 UNIPROT "CFII complex" complex SIGNOR-C387 SIGNOR "form complex" binding 9606 BTO:0000567 30139799 t lperfetto "Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1." SIGNOR-266119 PRKCA protein P17252 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates phosphorylation Ser1105 LDRKRHNsISEAKMR 9606 9660757 t gcesareni "These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity." SIGNOR-58859 SHC1 protein P29353 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0000782 8995379 t gcesareni "T cell activation effects an increase in grap association with p36/38, shc, sos, and dynamin." SIGNOR-45528 EIF2B1 protein Q14232 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269139 ATM protein Q13315 UNIPROT RNF40 protein O75150 UNIPROT "up-regulates activity" phosphorylation Ser114 ALLRCHEsQGELSSA 9606 BTO:0000007 21362549 t miannu "ATM-Mediated Phosphorylation of RNF20 and RNF40 in Response to DNA Damage and Its Requirement for Damage-Induced H2B Monoubiquitylation " SIGNOR-276315 TGFBR1 protein P36897 UNIPROT ACVR1 protein Q04771 UNIPROT "up-regulates activity" phosphorylation 9606 29376829 t miannu "This directly demonstrates that TGFBR1 can activate ACVR1 in vivo.|We show that in response to TGF-\u03b2, TGFBRI phosphorylates and activates ACVR1, which phosphorylates SMAD1/5." SIGNOR-279490 GPR183 protein P32249 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256994 RAD18 protein Q9NS91 UNIPROT FANCD2 protein Q9BXW9 UNIPROT "up-regulates activity" ubiquitination 9606 26871286 t miannu "In summary, these findings suggest a model, where Rad18 promotes monoubiquitination of FANCD2, and associates with a functional complex involving Rad51, BRCA2, and FANCD2 in the repair of CPT induced stalled or collapsed forks.|In this study we focused on the role of Rad18 mediated activation of FANCD2 and its functional relationship with BRCA2 and Rad51 proteins in repair of CPT induced lesions." SIGNOR-278712 CNR2 protein P34972 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256979 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-122059 N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI "up-regulates quantity" "precursor of" 9606 33179964 t miannu "The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure." SIGNOR-267307 FGF2 protein P09038 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 11390973 t lperfetto "we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2).These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity." SIGNOR-86121 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 t lperfetto "Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation" SIGNOR-252585 NAMPT protein P43490 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates 19299583 f lperfetto "Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression." SIGNOR-253721 LYN protein P07948 UNIPROT HCLS1 protein P14317 UNIPROT "up-regulates activity" phosphorylation Tyr378 EPEPENDyEDVEEMD 9606 9104825 t "Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252" SIGNOR-251400 "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001109 phosphorylation:Thr286 EEVDLACtPTDVRDV 17205132 t miannu "FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1. We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8." SIGNOR-271633 SERPING1 protein P05155 UNIPROT F12 protein P00748 UNIPROT "down-regulates activity" binding 9606 BTO:0000131 26707513 t lperfetto "C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1)." SIGNOR-263517 OST4 protein P0C6T2 UNIPROT "OST-A complex" complex SIGNOR-C535 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272061 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 21460634 t lperfetto "mTORC1, which is often referred to as the gatekeeper to autophagy, is a key regulator of the Ulk1-Atg13-FIP200 kinase complex.11,14,25 Under nutrient-rich conditions, active mTORC1 associates with and inactivates the Ulk1-Atg13-FIP200 complex by phosphorylating Ulk1 and Atg13." SIGNOR-183903 CSNK2A1 protein P68400 UNIPROT FAF1 protein Q9UNN5 UNIPROT "down-regulates activity" phosphorylation Ser291 DVHMVSDsDGDDFED 9534 12832043 t llicata "We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites.|Therefore we assume that CK2‐mediated FAF1 phosphorylation influences the nuclear localization of FAF1 | it implies that the major function of FAF1 might not be in the cytoplasm as an interacting partner of Fas." SIGNOR-250864 HTR3C protein Q8WXA8 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu "The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. " SIGNOR-264320 EIF3E protein P60228 UNIPROT MAD2L1 protein Q13257 UNIPROT "down-regulates quantity" "translation regulation" 9606 "BTO:0000815; BTO:0001938" 20453879 f irozzo "Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression." SIGNOR-259157 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257909 TYRO3 protein Q06418 UNIPROT CBLB protein Q13191 UNIPROT "up-regulates activity" phosphorylation Tyr133 KEGKERMyEEQSQDR 9606 31531847 t miannu "TAM receptor Tyro3 phosphorylates tyrosine residues 133 and 363 of Cbl-b." SIGNOR-279576 RACK1 protein P63244 UNIPROT LARP4B protein Q92615 UNIPROT "up-regulates activity" binding 9606 BTO:0005238 20573744 t miannu "Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex." SIGNOR-260941 SF3B5 protein Q9BWJ5 UNIPROT SF3b complex SIGNOR-C442 SIGNOR "form complex" binding 9606 32140746 t lperfetto "Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a)." SIGNOR-268407 AIMP1 protein Q12904 UNIPROT "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR "form complex" binding 9606 32644155 t miannu "In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes)." SIGNOR-270359 PTCH1 protein Q13635 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates binding 9606 11331587 t "Type I noncanonical;P-cyclina B (CCNB)." gcesareni "In addition, we demonstrate that endogenous ptc1 and endogenous cyclin B1 interact in vivo. The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. Thus, we propose that ptc1 participates in a G2/M checkpoint by regulating the localization of MPF." SIGNOR-199147 GLI1 protein P08151 UNIPROT GLI1 protein P08151 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209617 PKG proteinfamily SIGNOR-PF77 SIGNOR "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI "down-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266504 HOXD13 protein P35453 UNIPROT EPHA7 protein Q15375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16314414 f miannu "We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation." SIGNOR-142453 aclidinium chemical CHEBI:65346 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 19653626 t Luana "This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects." SIGNOR-258151 CHKB protein Q9Y259 UNIPROT "choline phosphate(1-)" smallmolecule CHEBI:295975 ChEBI "up-regulates quantity" "chemical modification" 27149373 t lperfetto "Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes" SIGNOR-275634 SSR1 protein P43307 UNIPROT "TRAP complex" complex SIGNOR-C577 SIGNOR "form complex" binding 9606 28218252 t miannu "In eukaryotic cells, one-third of all proteins must be transported across or inserted into the endoplasmic reticulum (ER) membrane by the ER protein translocon. The translocon-associated protein (TRAP) complex is an integral component of the translocon, assisting the Sec61 protein-conducting channel by regulating signal sequence and transmembrane helix insertion in a substrate-dependent manner." SIGNOR-280791 NRG1 protein Q02297 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3." SIGNOR-26061 thiocyanate smallmolecule CHEBI:18022 ChEBI Cell_killing phenotype SIGNOR-PH149 SIGNOR up-regulates 9606 BTO:0000133 9922160 f lperfetto "Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids.| Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity." SIGNOR-270592 HTR7 protein P34969 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257381 PRKACA protein P17612 UNIPROT PARP1 protein P09874 UNIPROT "up-regulates activity" phosphorylation Ser785 LRGGSDDsSKDPIDV 9606 BTO:0001412 25069723 t miannu " In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). " SIGNOR-276653 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249398 GUCY1B2 protein O75343 UNIPROT GUCY1A2-B2 complex SIGNOR-C137 SIGNOR "form complex" binding 9606 10977868 t gcesareni "This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity" SIGNOR-243974 Ub:E2 complex SIGNOR-C497 SIGNOR SH3RF2 protein Q8TEC5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271203 HDAC1 protein Q13547 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16431920 f fspada "These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome" SIGNOR-143955 MAPK1 protein P28482 UNIPROT DAZAP1 protein Q96EP5 UNIPROT "down-regulates activity" phosphorylation Thr269 FTSYIVStPPGGFPP 9606 BTO:0000007 16848763 t miannu "Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ" SIGNOR-262970 SGK2 protein Q9HBY8 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 t lperfetto "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis." SIGNOR-249130 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI AHR protein P35869 UNIPROT "up-regulates activity" "chemical activation" -1 31995776 t miannu "This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs." SIGNOR-268736 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser516 PQVLAQPsTSRKRPR 9606 BTO:0002201 12855706 t lperfetto "Chk2 is also autophosphorylated following dna damage. It is proposed that autophosphorylation of chk2 may contribute to chk2 activation. To fully understand the regulation of chk2, we mapped an in vitro chk2 autophosphorylation site at c-terminal serine 516 site (ser-516). Ser-516 of chk2 is phosphorylated following radiation in vivo, and this phosphorylation depends on the kinase activity of chk2." SIGNOR-103544 GNAQ protein P50148 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 17606614 t gcesareni "Recently, the dbl-family guanine nucleotide exchange factor (gef) p63rhogef/geft has been described as a novel mediator of galpha(q/11) signaling to rhoa based on its ability to synergize with galpha(q/11) resulting in enhanced rhoa signaling in cells." SIGNOR-156534 ACO2 protein Q99798 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI "down-regulates quantity" "chemical modification" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266244 PBK protein Q96KB5 UNIPROT TP53RK protein Q96S44 UNIPROT "up-regulates activity" phosphorylation Ser250 RLRGRKRsMVG 9606 28412249 t miannu "In this study, we provide evidence showing that TOPK promotes metastasis of colorectal carcinoma, which is mediated through its phosphorylation of PRPK at Ser250.|Therefore, we conclude that TOPK directly promotes metastasis of colorectal cancer by modulating PRPK." SIGNOR-278236 M protein P0DTC5 UNIPROT MAVS protein Q7Z434 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 33110251 t miannu "Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions." SIGNOR-262515 9b protein P59636 UNIPROT MAVS protein Q7Z434 UNIPROT "down-regulates quantity by destabilization" 9606 25135833 f miannu "SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6." SIGNOR-260241 "Skp1-Pam E3" complex SIGNOR-C537 SIGNOR ZEB2 protein O60315 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272187 MAP2K4 protein P45985 UNIPROT MAPK13 protein O15264 UNIPROT "up-regulates activity" phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 t done miannu "p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation." SIGNOR-273956 MAPK1 protein P28482 UNIPROT TXNIP protein Q9H3M7 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr349 HRLESPTtPLLDDMD 9606 BTO:0000018 31320475 t miannu "ERK-dependent Txnip ubiquitination and proteasome degradation depended upon phosphorylation of a PXTP motif threonine (Thr349) located within the C-terminal α-arrestin domain and proximal to a previously characterized E3 ubiquitin ligase-binding site. " SIGNOR-277468 PRKD1 protein Q15139 UNIPROT KIDINS220 protein Q9ULH0 UNIPROT unknown phosphorylation Ser918 RTITRQMsFDLTKLL 10116 10998417 t lperfetto "Our results provide the first physiological substrate for PKD and indicate that Kidins220 is phosphorylated by PKD at serine 919 in vivo." SIGNOR-249052 4E2RCat chemical CID:2287236 PUBCHEM EIF4G1 protein Q04637 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000414 21507972 t miannu "Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers." SIGNOR-260188 FUS protein P35637 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "inferred from family member" "This conclusion is also supported by the analysis of alternative splicing events inhFUS+/+;Smn+/‚àímice. As shown in Fig.6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected inhFUS+/+mice, is not further modified by SMN decrease" SIGNOR-270231 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 12193595 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-91742 MBOAT7 protein Q96N66 UNIPROT acyl-CoA smallmolecule CHEBI:17984 ChEBI "down-regulates quantity" "chemical modification" -1 18772128 t miannu "The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils." SIGNOR-267244 GSK3B protein P49841 UNIPROT HSF1 protein Q00613 UNIPROT "down-regulates activity" phosphorylation Ser303 RVKEEPPsPPQSPRV -1 8940068 t "Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1." SIGNOR-251216 CAMK2A protein Q9UQM7 UNIPROT CLCN3 protein P51790 UNIPROT "up-regulates activity" phosphorylation Ser109 ERHRRINsKKKESAW 14754994 t lperfetto "Identification of an N-terminal amino acid of the CLC-3 chloride channel critical in phosphorylation-dependent activation of a CaMKII-activated chloride current|The N-terminus of CLC-3, which contains a CaMKII consensus sequence, was phosphorylated by CaMKII in vitro, and mutation of the serine at position 109 (S109A) abolished the CaMKII-dependent Cl(-) conductance, indicating that this residue is important in the gating of CLC-3 at the plasma membrane." SIGNOR-275863 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257910 "Caspase 1 complex" complex SIGNOR-C220 SIGNOR IL1B protein P01584 UNIPROT "up-regulates activity" cleavage Asp116 DNEAYVHdAPVRSLN -1 1919001 t lperfetto "IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta. " SIGNOR-256376 PIM1 protein P11309 UNIPROT YWHAZ protein P63104 UNIPROT "up-regulates activity" phosphorylation Ser64 SSWRVVSsIEQKTEG 9606 BTO:0001321 34697370 t miannu "PIM1 phosphorylates the AR and 14-3-3 ζ and coordinates their interaction. PIM1 phosphorylation of the AR and 14-3-3 ζ enhances their interaction and shifts their occupancy on chromatin, resulting in 14-3-3 ζ co-regulation of AR, likely by recruiting other AR co-regulators such as hnRNPK and TRIM28." SIGNOR-277574 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser642 PRLGSTFsLDTSMSM 9606 BTO:0000782 11024037 t lperfetto "However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. " SIGNOR-249057 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 t gcesareni "Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase." SIGNOR-33137 PIK3CA protein P42336 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000586 16293724 f gcesareni "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin." SIGNOR-141814 TWIST2 protein Q8WVJ9 UNIPROT ICAM1 protein P05362 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255514 MMUT protein P22033 UNIPROT (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI "down-regulates quantity" "chemical modification" 9606 1978672 t miannu "Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA)." SIGNOR-269108 MAPK9 protein P45984 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134572 CARS1 protein P49589 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 11347887 t miannu "Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine." SIGNOR-270473 AMPK complex SIGNOR-C15 SIGNOR DNMT1 protein P26358 UNIPROT "down-regulates activity" phosphorylation Ser714 DNIPEMPsPKKMHQG -1 28143904 t lperfetto "Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity" SIGNOR-264788 ZNF521 protein Q96K83 UNIPROT EBF1 protein Q9UH73 UNIPROT down-regulates binding 9606 BTO:0000776 14630787 t miannu "Ehzf inhibits the transcriptional activity of early b-cell factor (ebf), a transcription factor essential for specification of the b-cell lineage /ability to interact with the neural and hematopoietic transcription factor olf1/ebf1 and inhibit its binding to dna" SIGNOR-119300 JNK proteinfamily SIGNOR-PF15 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto "Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities." SIGNOR-105762 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio "Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation." SIGNOR-255120 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Thr430 PPLPPRAtPSRPGEA 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-85000 SUCLG1 protein P53597 UNIPROT "Succinyl-CoA GTP variant" complex SIGNOR-C399 SIGNOR "form complex" binding 9606 32627745 t miannu "Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS)." SIGNOR-266263 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser147 EDLCQAFsDVILAVN 9606 BTO:0000567 11242082 t lperfetto "Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation." SIGNOR-105719 LEPR protein P48357 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" 9606 BTO:0003336 25343030 f miannu "Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake." SIGNOR-263510 ponatinib chemical CHEBI:78543 ChEBI RIPK1 protein Q13546 UNIPROT "down-regulates activity" "chemical inhibition" 9606 25801024 t Federica "Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3" SIGNOR-261082 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr931 VCDSGVEtSFRKLSF 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto "All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391)." SIGNOR-70461 SSR2 protein P43308 UNIPROT "TRAP complex" complex SIGNOR-C577 SIGNOR "form complex" binding 9606 28218252 t miannu "In eukaryotic cells, one-third of all proteins must be transported across or inserted into the endoplasmic reticulum (ER) membrane by the ER protein translocon. The translocon-associated protein (TRAP) complex is an integral component of the translocon, assisting the Sec61 protein-conducting channel by regulating signal sequence and transmembrane helix insertion in a substrate-dependent manner." SIGNOR-280792 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 21059642 t "The effect has been demonstrated using Q01196-8" gcesareni "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." SIGNOR-169330 CSK protein P41240 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9534 BTO:0001538 9624175 t miannu "We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances." SIGNOR-262741 DGC complex SIGNOR-C217 SIGNOR NRXN3 protein Q9HDB5 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 11470830 t miannu "In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan." SIGNOR-265450 RNF5 protein Q99942 UNIPROT MAVS protein Q7Z434 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys461 GPEENEYkSEGTFGI 9606 BTO:0000007 20483786 t miannu "In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase. " SIGNOR-271489 CDK1 protein P06493 UNIPROT EP300 protein Q09472 UNIPROT "down-regulates quantity" phosphorylation Ser1038 STSATQSsPAPGQSK 9606 24530506 t miannu "Loss of CDK1 decreased p300 phosphorylation, but increased the p300 level.|Our results showed that phosphorylation of p300 by CDK1 at Ser1038 and Ser2039 repressed the proliferation and metastasis activity of lung cancer cells in vitro." SIGNOR-278239 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT "up-regulates activity" phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu "We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14." SIGNOR-276096 PLCD4 protein Q9BRC7 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI up-regulates "chemical modification" 9606 8395015 t gcesareni "Hydrolysis of phosphatidylinositol 4,5-bisphosphate (pip2) by phosphatidylinositol-specific phospholipase c (pi-plc) generates two second messengers, inositol 1,4,5-trisphosphate and 1,2-diacylglycerol." SIGNOR-39041 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT "up-regulates activity" phosphorylation Ser356 VDGSGDTsSNEEIGS -1 12107178 t llicata "ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled." SIGNOR-250870 PAK5 protein Q9P286 UNIPROT PACSIN1 protein Q9BY11 UNIPROT "up-regulates activity" phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu "We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo." SIGNOR-263025 GNB/GNG complex SIGNOR-C202 SIGNOR ADCY6 protein O43306 UNIPROT "down-regulates activity" binding 9534 BTO:0000298 9707174 t "Marta Tosoni" "These results demonstrate that adenylyl cyclase types V and Vi are inhibited by Gbetagamma dimers." SIGNOR-278047 NFATC1 protein O95644 UNIPROT GPC6 protein Q9Y625 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 21871017 t miannu "NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype." SIGNOR-264022 NEK9 protein Q8TD19 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 14660563 t lperfetto "A previous study (19) using the peptide substrate demonstrated that nek9 was able to phosphorylate in vitro the thr210 residue within the activation loop, thus indicating the potential ability of nek9 to autophosphorylate.Nek9 forms a stable, approximately 600-kda complex with fact in the interphase nuclei. Its active form is characterized by phosphorylation-dependent electrophoretic mobility shift and phosphorylation at a conserved residue within the activation loop (thr(210))" SIGNOR-119897 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 SIGNOR-C17 24173284 t lperfetto "The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A" SIGNOR-167779 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2E2 protein Q96LR5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271317 ponatinib chemical CHEBI:78543 ChEBI FGFR3 protein P22607 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23468082 t miannu "Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family." SIGNOR-259279 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t llicata "CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin." SIGNOR-250947 frovatriptan chemical CHEBI:134991 ChEBI HTR1B protein P28222 UNIPROT "up-regulates activity" "chemical activation" -1 9986723 t miannu "As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold)." SIGNOR-259075 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 3352609 t lperfetto "The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex" SIGNOR-24543 IKBKB protein O14920 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22056382 f "Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation" SIGNOR-253585 PRKAA2 protein P54646 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 SIGNOR-C15 21945940 t lperfetto "Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion." SIGNOR-176642 TAL1 protein P17542 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR "up-regulates activity" 10090 BTO:0004911 29713515 f "The truncated form TAL1-s is required for erythroid progenitors differentiation, while the full-length protein TAL1-l is required for megakaryocytic differentiation of progenitor cells." SIGNOR-259969 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2Q1 protein Q7Z7E8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271372 MED1 protein Q15648 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266667 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-252082 SPI1 protein P17947 UNIPROT Lymphopoiesis phenotype SIGNOR-PH111 SIGNOR "up-regulates activity" 10090 BTO:0000725 8079170 f "Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor." SIGNOR-259956 EPHB1 protein P54762 UNIPROT NRCAM protein Q92823 UNIPROT "up-regulates activity" phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 t miannu "EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase." SIGNOR-262862 CDK1 protein P06493 UNIPROT MORC2 protein Q9Y6X9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr733 PIKLSPAtPSRKRSV 9606 BTO:0000567 36967563 t miannu "Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation." SIGNOR-277838 SIRT1 protein Q96EB6 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-256662 PIM1 protein P11309 UNIPROT NDRG1 protein Q92597 UNIPROT "down-regulates activity" phosphorylation Ser330 LMRSRTAsGSSVTSL 9606 33398037 t miannu "Collectively, we find that PIM1 expression leads to increased levels of NDRG1 pS330, and PIM1 dependent NDRG1 phosphorylation decreases NDRG1 protein stability.|NDRG1 is phosphorylated by PIM1 at serine 330 (pS330), and the level of NDRG1 pS330 is associated higher grade prostate tumors." SIGNOR-279308 MIB1 protein Q86YT6 UNIPROT RYK protein P34925 UNIPROT down-regulates ubiquitination 9606 21875946 t gcesareni "We discovered that ryk both physically and functionally interacts with the e3 ubiquitin ligase mind bomb 1 (mib1).We Found that overexpressed ryk and mib1 colocalized and that the overexpression of mib1 leads to the loss of surface ryk expression. In addition, biochemical studies revealed that mib1 promotes the ubiquitination and degradation of ryk. Endogenous ryk and mib1 were required for the wnt-dependent activation of wnt/ctnnb1 signaling" SIGNOR-176282 MAPK3 protein P27361 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 t gcesareni "Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated sheddingwe show that extracellular signal-regulated kinase (erk) acts as an intermediate in protein kinase c-regulated trka cleavage. We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735. In addition, we show that erk and tace associate. This association is favored by erk activation and by the presence of threonine 735. In contrast to the erk route, the p38 mapk was able to stimulate trka cleavage in cells devoid of tace activity, indicating that other proteases are also involved in trka shedding." SIGNOR-89625 trimipramine chemical CHEBI:9738 ChEBI SLC6A3 protein Q01959 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9537821 t miannu "At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter." SIGNOR-258740 LSM4 protein Q9Y4Z0 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270650 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT "down-regulates activity" phosphorylation Ser36 ELQRRRRsLALPGLQ -1 15946941 t miannu " We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro." SIGNOR-276035 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser618 APTPPKRsSSFREMD 9606 18161990 t lperfetto "The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl." SIGNOR-160215 DEAF1 protein O75398 UNIPROT HTR1A protein P08908 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14507979 f lperfetto "Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism." SIGNOR-254124 B4GALT1 protein P15291 UNIPROT lactose smallmolecule CHEBI:17716 ChEBI "up-regulates quantity" "chemical modification" 9606 16157350 t miannu "Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins." SIGNOR-268469 BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 8358790 t lperfetto "Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered." SIGNOR-249612 "denileukin diftitox" smallmolecule SID:125240988 ChEBI IL2RA protein P01589 UNIPROT "up-regulates activity" "chemical activation" 9606 15757436 t miannu "Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. " SIGNOR-259392 ZW10 protein O43264 UNIPROT "RZZ complex" complex SIGNOR-C357 SIGNOR "form complex" binding 9606 20462495 t lperfetto "The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico." SIGNOR-265012 TNC protein P24821 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 7559467 t lperfetto "The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin." SIGNOR-253306 SMAD6 protein O43541 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 SIGNOR-C85 12857866 t gcesareni "Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4" SIGNOR-103621 TNFSF11 protein O14788 UNIPROT TNFRSF11B protein O00300 UNIPROT up-regulates binding 9606 11733492 t gcesareni "Receptor activator of nf-kappa b ligand (rankl, also known as odf and opgl), a member of the tumor necrosis factor (tnf) family, triggers osteoclastogenesis by forming a complex with its receptor, rank." SIGNOR-112539 TPO protein P07202 UNIPROT 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI "up-regulates quantity" "chemical modification" 9606 16098474 t scontino "TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues." SIGNOR-267030 PRKCD protein Q05655 UNIPROT BEST1 protein O76090 UNIPROT "down-regulates activity" phosphorylation Ser358 SAQFRRAsFMGSTFN 9606 19635817 t Manara "We have identified a PKC phosphorylation site (S358) located in the C terminal region of hBest1 critical for channel rundown. Phosphorylation of this site by PKC activators and PP2A inhibitors reduces channel rundown." SIGNOR-260880 SERPINC1 protein P01008 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 t gcesareni "In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp." SIGNOR-41232 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Ser77 YEPEGSAsPTPPYLK -1 17318175 t lperfetto "Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling." SIGNOR-249191 phentolamine chemical CHEBI:8081 ChEBI ADRA1B protein P35368 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258446 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MFN1 protein Q8IWA4 UNIPROT "up-regulates activity" phosphorylation Thr562 LPRSLASTPTAPTTP 10090 BTO:0002572 25801171 t Barakat "Finally, in Mfn1 -/- cells re-expressing the MFN1 T562A mutant, phosphorylation was undetectable even in the presence of EGF. Taken together, these data indicate that ERK phosphorylates MFN1 at T562." SIGNOR-274134 CSNK2A1 protein P68400 UNIPROT WAS protein P42768 UNIPROT up-regulates phosphorylation Ser483 KRSRAIHsSDEGEDQ 9606 12769847 t gcesareni "Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule." SIGNOR-101264 EIF3_complex complex SIGNOR-C401 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR "form complex" binding 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269162 AP1S1 protein P61966 UNIPROT "AP-1 complex" complex SIGNOR-C248 SIGNOR "form complex" binding 9606 21097499 t lperfetto "Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)" SIGNOR-260684 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161577 MAPK3 protein P27361 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 t gcesareni "Wstf, a specific component of two chromatin remodeling complexes (swi/snf-type winac and iswi-type wich), was phosphorylated by the stimulation of mapk cascades in vitro and in vivo. Ser-158 residue in the wac (wstf/acf1/cbpq46) domain, located close to the n terminus of wstf, was identified as a major phosphorylation target" SIGNOR-188164 PTPN12 protein Q05209 UNIPROT PSTPIP1 protein O43586 UNIPROT "down-regulates activity" dephosphorylation Tyr345 PERNEGVyTAIAVQE 10090 11711533 t "We also demonstrate that PTP-PEST dephosphorylates PSTPIP at tyrosine 344. Importantly, we identified tyrosine 344 as the main phosphorylation site of PSTPIP by performing tryptic phosphopeptide maps. |The biological functions of the complexes formed between PSTPIP and SH2 domain-containing tyrosine kinases may be to transmit the signals from activated EGF and PDGF receptor.|Furthermore, we show that PSTPIP is phosphorylated downstream of the activated PDGF and EGF receptors. This phosphorylation of PSTPIP is most likely mediated by c-Abl" SIGNOR-248656 NOXA1 protein Q86UR1 UNIPROT NOX3 protein Q9HBY0 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20943948 t lperfetto "Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation" SIGNOR-264711 F7 protein P08709 UNIPROT "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR "form complex" binding 9606 BTO:0000131 32665005 t lperfetto "During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury." SIGNOR-263555 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1D protein P25100 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258457 RAPGEF4 protein Q8WZA2 UNIPROT RAP1B protein P61224 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9534 BTO:0000298 10777494 t miannu "Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well." SIGNOR-263955 VPS41 protein P49754 UNIPROT "HOPS tethering complex" complex SIGNOR-C549 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273689 CALM1 protein P0DP23 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 11807557 t miannu "Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias." SIGNOR-253410 ADK protein P55263 UNIPROT ATP smallmolecule CHEBI:15422 ChEBI "down-regulates quantity" "chemical modification" 9606 33961946 t miannu "Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S)." SIGNOR-267839 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2409 LHGDDQDsEDEVLTI 9606 8318012 t lperfetto "The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157." SIGNOR-37831 Ub:E2 complex SIGNOR-C497 SIGNOR ANKIB1 protein Q9P2G1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271232 TM9SF4 protein Q92544 UNIPROT MTOR protein P42345 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 29125601 t miannu "TM9SF4 inhibited mTOR activity in HEK293 cells. Under nutrient starvation, TM9SF4 functions to facilitate mTOR inactivation, resulting in an enhanced autophagic flux, which serves to protect cells from apoptotic cell death." SIGNOR-266703 F2R protein P25116 UNIPROT KLF6 protein Q99612 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254849 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser29 ATKAARKsAPSTGGV 9606 18508628 t "Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription." gcesareni "In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes." SIGNOR-178708 NSD3 protein Q9BZ95 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0002181 28205554 t irozzo "Indeed, dose-dependent TR-FRET and affinity pull-down assay confirmed the interaction of NSD3-s with MYC. Supporting functional significance of the interaction, co-expression of NSD3-s, but not the MYC-binding defective fragment of NSD3-s (1–347), stabilized MYC protein and increased MYC transcriptional activity as revealed by a MYC-driven reporter assay." SIGNOR-259199 solifenacin chemical CHEBI:135530 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" -1 21524581 t Luana "The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference" SIGNOR-258313 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser20 HVAGGPPsPEVGSPL 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-84980 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-201695 PRKACA protein P17612 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata "Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. " SIGNOR-188177 MAPK12 protein P53778 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 t gcesareni "Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target" SIGNOR-65589 NOP58 protein Q9Y2X3 UNIPROT "U3 snoRNP" complex SIGNOR-C589 SIGNOR "form complex" binding 9606 29414516 t miannu "The small subunit processome is the first precursor of the small eukaryotic ribosomal subunit. Eukaryotic ribosome biogenesis is initiated by the seven-subunit UtpA complex (Utp4, Utp5, Utp8, Utp9, Utp10, Utp15 & Utp17). UtpA binding and the presence of additional parts of the 5′ ETS appear to be required for the subsequent recruitment of the six-subunit UtpB complex (Utp1/Pwp2, Utp6, Utp12, Utp13, Utp18 & Utp21) and the U3 snoRNP (U3 snoRNA, Nop1/fibrillarin, Snu13, Nop56 & Nop58)" SIGNOR-280838 MARK4 protein Q96L34 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser420 KHPTPGSsDPLIQPS -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273936 PRKACA protein P17612 UNIPROT PSEN1 protein P49768 UNIPROT unknown phosphorylation Ser310 PEAQRRVsKNSKYNA -1 14576165 t miannu "PKA-mediated phosphorylation of PS1 is completely inhibited by mutation of Ser310.phosphorylation of Ser310 does not inhibit the caspase-mediated cleavage of PS1, and the biological function of this phosphorylation event remains to be determined in further experiments." SIGNOR-250036 PRKCD protein Q05655 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t gcesareni "Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm." SIGNOR-97287 USP8 protein P40818 UNIPROT STAM protein Q92783 UNIPROT "up-regulates quantity" binding 9606 BTO:0000567 16520378 t "Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells." SIGNOR-266904 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr213 SASFPHTtPSMCLNP 10090 BTO:0000667 17475908 t miannu "All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells." SIGNOR-262671 PCDH19 protein Q8TAB3 UNIPROT GABRA5 protein P31644 UNIPROT "up-regulates quantity by stabilization" binding 10116 BTO:0003102 SIGNOR-C335 29360992 t miannu "Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. " SIGNOR-267219 ZBTB16 protein Q05516 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 BTO:0002882 9710637 f fcortellessa "PLZF overexpression leads to apoptosis." SIGNOR-261686 CDK1 protein P06493 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Thr269 GGKRSRLtPVSPESS 9606 SIGNOR-C17 20974803 t gcesareni "Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis." SIGNOR-169016 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 18593525 f gcesareni "Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release." SIGNOR-179288 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol chemical CHEBI:75722 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258150 BGJ-398 chemical CHEBI:63451 ChEBI FGFR1 protein P11362 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190263 HOXA10 protein P31260 UNIPROT IGFBP1 protein P08833 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003697 17350963 f miannu "The functional role of HOXA10 in IGFBP1 expression was further explored using human endometrial stromal cells (HSC). Overexpression of HOXA10 in HSC resulted in a decrease of IGFBP1 mRNA, whereas silencing HOXA10 caused an increase of IGFBP1 mRNA, even in the presence of H + dbcAMP. These data demonstrate that HOXA10 negatively influences IGFBP1 expression in decidualizing cells." SIGNOR-254467 CELF6 protein Q96J87 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 9606 BTO:0001109 31534127 t miannu "CELF6 binds to the 3'UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest." SIGNOR-269044 MTOR protein P42345 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 SIGNOR-C3 18570873 t llicata "Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation" SIGNOR-179113 MAPK8 protein P45983 UNIPROT WDR62 protein O43379 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr1053 PSSSLPQtPEQEKFL 9606 BTO:0000007 30566428 t lperfetto "WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053" SIGNOR-271710 IRX2 protein Q9BZI1 UNIPROT CCL5 protein P13501 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003885 26560478 f Luana "Our results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression. " SIGNOR-266043 SMAD4 protein Q13485 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR "form complex" binding 9606 20957627 t lperfetto "Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus." SIGNOR-255267 PTPRG protein P23470 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" dephosphorylation Tyr313 SSEPVGIyQGFEKKT -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254716 HEY1 protein Q9Y5J3 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19917614 f lperfetto "Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis." SIGNOR-235819 CALM1 protein P0DP23 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t gcesareni "The calmodulin-binding region is located between amino acids 51 and 96" SIGNOR-82505 POLR2D protein O15514 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266164 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 18636076 t gcesareni "Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian target of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin." SIGNOR-179483 YY1 protein P25490 UNIPROT POSTN protein Q15063 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21839814 f miannu "In this study we demonstrate that the ability of the human POSTN promoter to drive transcription mostly depends on the activity of YingYang-1 (YY1) zinc finger transcription factor. YY1, whose regulatory role in biology includes, besides transcriptional control, also chromatin remodeling, DNA damage repair and tumorigenesis, acts as a strong negative modulator of the POSTN expression." SIGNOR-255621 PRKACA protein P17612 UNIPROT CACNA1S protein Q13698 UNIPROT "up-regulates activity" phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 t miannu "To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2." SIGNOR-263112 PRKAA1 protein Q13131 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser355 EADLPEPsEKQPAAA -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275440 MC4R protein P32245 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" 9606 22215617 t lperfetto "We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus." SIGNOR-253067 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT "down-regulates activity" phosphorylation 9606 25855382 t miannu "In this study we linked these regulatory events mechanistically, by showing that Plk1 induces proteasomal degradation of SUZ12 and ZNF198 by site specific phosphorylation.|Plk1 phosphorylates SUZ12 and ZNF198 in vitro." SIGNOR-278423 NEK6 protein Q9HC98 UNIPROT KIF20A protein O95235 UNIPROT "down-regulates activity" phosphorylation Ser244 LSTSLKRsVYIESRI 9606 BTO:0000567 28630147 t done miannu "We show that Nek9, Nek6, and the kinesin Mklp2 form a signaling module, which is required for Mklp2 to localize to the central spindle in anaphase. Nek6 also phosphorylates Mklp2 at Ser244, inhibiting its bundling activity until anaphase onset." SIGNOR-273891 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275775 LCK protein P06239 UNIPROT CHN2 protein P52757 UNIPROT "down-regulates activity" phosphorylation Tyr153 KMTTNPIyEHIGYAT 9606 BTO:0000661 19201754 t miannu "We now demonstrate Lck-dependent phosphorylation of beta2-chimaerin in response to TCR triggering. We identify Tyr-153 as the Lck-dependent phosphorylation residue and show that its phosphorylation negatively regulates membrane stabilization of beta2-chimaerin, decreasing its GAP activity to Rac. " SIGNOR-276240 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT "up-regulates activity" phosphorylation Ser859 RRENSSDsPKELKRR 9606 BTO:0002181 25452387 t miannu "The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. " SIGNOR-276445 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity" phosphorylation Ser66 QGSPPDIsPYEVPPL 10090 BTO:0000783;BTO:0002284 16407209 t "Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity." SIGNOR-255544 SOX5 protein P35711 UNIPROT COL2A1 protein P02458 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10980415 f miannu "Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1" SIGNOR-251759 Nalmefene chemical CHEBI:7457 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258812 SMARCA2 protein P51531 UNIPROT GBAF complex SIGNOR-C467 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269779 OXTR protein P30559 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257065 MNAT1 protein P51948 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 30477538 t miannu "Collectively, these results indicate that MNAT1 increases p53 ubiquitination, thus promoting its proteasomal degradation.|These suggest that MNAT1 decreases p53 expression by the proteasome." SIGNOR-278831 FZD7 protein O75084 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 22944199 t gcesareni "Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism." SIGNOR-198831 EGFR protein P00533 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 9606 14967450 t lperfetto "The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation." SIGNOR-121965 AKT1 protein P31749 UNIPROT TTC3 protein P53804 UNIPROT up-regulates phosphorylation Ser378 AYTPRSLsAPIFTTS 9606 20059950 t llicata "Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context" SIGNOR-252508 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 16331690 t gcesareni "There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712." SIGNOR-142945 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser36 AEKQARGsTTLQESR 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275765 PTPN1 protein P18031 UNIPROT KRT8 protein P05787 UNIPROT "down-regulates activity" dephosphorylation Tyr267 IAEVKAQyEDIANRS 9606 BTO:0000182 24003221 t lperfetto "Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine." SIGNOR-265495 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t gcesareni "We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function" SIGNOR-126732 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 t gcesareni "We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function" SIGNOR-126736 MYCBP2 protein O75592 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001321 32814769 t miannu "We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop." SIGNOR-267149 "leukotriene D4(1-)" smallmolecule CHEBI:63166 ChEBI CYSLTR1 protein Q9Y271 UNIPROT "up-regulates activity" "chemical activation" 9606 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257475 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser233 VSSQHRYsTPHAFTF 9606 12551925 t gcesareni "For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1." SIGNOR-37466 VPS39 protein Q96JC1 UNIPROT "HOPS tethering complex" complex SIGNOR-C549 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273690 CCNC protein P24863 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 15546612 t "Leads to a following ubiquitination and degradation" gcesareni "Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo." SIGNOR-130592 ITCH protein Q96J02 UNIPROT NFE2 protein Q16621 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0000007 18718448 t lperfetto "Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination| Interestingly, Itch suppressed the transactivation activity of p45/NF-E2 by adding a Lys63-linked polyubiquitin chain. Confocal microscopy revealed that ubiquitinated p45/NF-E2 became localized in the cytoplasm when Itch was over-expressed. Thus, Itch-mediated ubiquitination of p45/NF-E2 does not target the protein for proteasomal degradation, but instead retains p45/NF-E2 in the cytoplasm, where it cannot function as a transactivator." SIGNOR-275553 CSNK1E protein P49674 UNIPROT DVL3 protein Q92997 UNIPROT "down-regulates activity" phosphorylation Ser311 EINFENMsNDDAVRV -1 24993822 t miannu "Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3." SIGNOR-276647 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR RAPSN protein Q13702 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000944 19158078 t miannu "We found that rapsyn was polyubiquitinated by KLHL8-containing E3 ligase, but not by KEAP1-containing E3 ligase, clearly indicating that rapsyn is a direct substrate of KLHL8-containing E3 ligase in mammals. We next examined the effect of KLHL-8 depletion on the ubiquitination of rapsyn by performing RNAi experiments in mammalian cells. We found that knockdown of KLHL8 in 3T3 cells reduced the level of rapsyn ubiquitination (Fig. 5C), again indicating that the maintenance mechanism for rapsyn stability is conserved in mammals.The in vitro ubiquitination of mammalian rapsyn by CUL3-containing E3 ligase and the effect of KLHL8 knockdown on the ubiquitination of rapsyn." SIGNOR-271782 ATAT1 protein Q5SQI0 UNIPROT TUBA1B protein P68363 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272245 MAPK14 protein Q16539 UNIPROT MAPK10 protein P53779 UNIPROT down-regulates 9606 20626350 f gcesareni "Jnk and p38 mapk activation have antagonistic effects in many cases. Froma a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab1" SIGNOR-166608 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Thr305 TDAATMKtFCGTPEY 10090 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-248654 GSK3B protein P49841 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser302 APGSGPSsPNNSSGS 9606 21118993 t lperfetto "The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation" SIGNOR-170148 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIK4 protein Q16099 UNIPROT "up-regulates activity" "chemical activation" 9606 27586965 t miannu "Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors" SIGNOR-264473 ACD protein Q96AP0 UNIPROT RPA3 protein P35244 UNIPROT "down-regulates activity" binding SIGNOR-C306 18680434 t lperfetto "The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA" SIGNOR-263329 PLK1 protein P53350 UNIPROT TEX14 protein Q8IWB6 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser437 QKAATVKsDIYSFSM 9606 BTO:0001363 22405274 t miannu "We show that phosphorylation of Tex14 by Plk1 during metaphase is required for proteosome dependent degradation of Tex14 and transition from metaphase to anaphase. Phosphorylation of Tex14 Ser431 by Plk1 promotes Tex14 depletion." SIGNOR-273529 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu62 NLERECVeETCSYEE -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263679 NPY protein P01303 UNIPROT NPY2R protein P49146 UNIPROT up-regulates binding 9606 9549761 t gcesareni "Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors." SIGNOR-56568 CDK5 protein Q00535 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser68 PSDLSPEsPMLSSPP -1 22577147 t lperfetto "Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta" SIGNOR-264893 IFNAR1 protein P17181 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation 9606 21631354 t miannu "These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity" SIGNOR-260435 NOP56 protein O00567 UNIPROT "U3 snoRNP" complex SIGNOR-C589 SIGNOR "form complex" binding 9606 29414516 t miannu "The small subunit processome is the first precursor of the small eukaryotic ribosomal subunit. Eukaryotic ribosome biogenesis is initiated by the seven-subunit UtpA complex (Utp4, Utp5, Utp8, Utp9, Utp10, Utp15 & Utp17). UtpA binding and the presence of additional parts of the 5′ ETS appear to be required for the subsequent recruitment of the six-subunit UtpB complex (Utp1/Pwp2, Utp6, Utp12, Utp13, Utp18 & Utp21) and the U3 snoRNP (U3 snoRNA, Nop1/fibrillarin, Snu13, Nop56 & Nop58)" SIGNOR-280839 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21892142 t gcesareni "Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk" SIGNOR-176494 CTTNBP2NL protein Q9P2B4 UNIPROT STRN4 protein Q9NRL3 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 23015759 t miannu "Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A." SIGNOR-261701 FYN protein P06241 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249339 CSNK2A1 protein P68400 UNIPROT CDK1 protein P06493 UNIPROT up-regulates phosphorylation Ser39 MKKIRLEsEEEGVPS 9606 15788687 t lperfetto "Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment." SIGNOR-134846 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2C protein O00762 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271322 PRKCD protein Q05655 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 18332134 t Manara "In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation." SIGNOR-260875 IKBKB protein O14920 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C14 23332762 t gcesareni "Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation." SIGNOR-192614 NDUFB5 protein O43674 UNIPROT "NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262168 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val48 KVDGTSHvTGKGVTV -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263589 "ruxolitinib phosphate" chemical CHEBI:66917 ChEBI JAK1 protein P23458 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23061804 t miannu "Ruxolitinib is a selective inhibitor of Janus kinases (JAK) 1 and 2, which are involved in the signalling pathway of various cytokines and growth factors essential to haematopoiesis." SIGNOR-259170 CHD8 protein Q9HCK8 UNIPROT SOX2 protein P48431 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 32839322 t Gianni "Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells" SIGNOR-268921 CEBPB protein P17676 UNIPROT S100A9 protein P06702 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001370 9706399 t "Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells." SIGNOR-254044 KRT1 protein P04264 UNIPROT APC protein P25054 UNIPROT "up-regulates activity" phosphorylation 9606 18359618 t "Regulation of catabolism" miannu "Phosphorylation of this central repeat region of APC significantly enhances its affinity for β-catenin. When the repeats are phosphorylated by the cooperative action of CK1 and GSK3β, the binding interaction is significantly altered and enhanced." SIGNOR-251879 DCAF4 protein Q8WV16 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 32014991 t miannu "DCAF4-mediated ubiquitination of OPTN facilitates the degradation of DBR-exposed SOD1. OPTN is involved in degradation of DBR-exposed SOD1. These data demonstrate that DCAF4-including CRL4 complex mediates OPTN ubiquitination at lysine 501, and this ubiquitination is absent in the ALS-related OPTNmut." SIGNOR-272211 UQCRQ protein O14949 UNIPROT "CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262197 TGFBR2 protein P37173 UNIPROT ZFYVE9 protein O95405 UNIPROT "up-regulates activity" binding 9606 9865696 t lperfetto "Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex" SIGNOR-245093 CSNK1A1 protein P48729 UNIPROT ERG protein P11308 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser39 EMTASSSsDYGQTSK -1 26344095 t miannu "Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites." SIGNOR-276935 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" phosphorylation Ser242 IPNGFGTsPLTPSAR 10090 BTO:0000142 12796778 t llicata "Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function." SIGNOR-250677 AKT2 protein P31751 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 BTO:0000150 12244303 t gcesareni "Akt-induced t157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced g1 arrest.[__]Thus, cytoplasmic relocalization of p27(kip1), secondary to akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained." SIGNOR-93122 PPP1R3B protein Q86XI6 UNIPROT GYS2 protein P54840 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 t miannu "In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)" SIGNOR-271732 RSPO3 protein Q9BXY4 UNIPROT LGR5 protein O75473 UNIPROT up-regulates binding 9606 21693646 t gcesareni "Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation" SIGNOR-174535 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 BTO:0000527 11514572 t gcesareni "Tc45 dephosphorylated delta egfr in u87mg glioblastoma cells and inhibited mitogen-activated protein kinase erk2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping tc45-d182a mutant, which is capable of forming stable complexes with tc45 substrates, suppressed the activation of erk2 but not phosphatidylinositol 3-kinase. The activation results in reduced egfr phosphorylation after egf stimulation. Introduction of the alpha(1) cytoplasmic domain peptide into cells induces phosphatase activation and inhibits egf-induced cell proliferation and anchorage-independent growth of malignant cells." SIGNOR-109804 EXT1 protein Q16394 UNIPROT WNT8B protein Q93098 UNIPROT "up-regulates activity" 9606 24860992 f miannu "Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern." SIGNOR-264020 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" lperfetto "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-244715 DRD3 protein P35462 UNIPROT GNB5 protein O14775 UNIPROT "up-regulates activity" binding 9606 21303898 t miannu "The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC" SIGNOR-264994 MRGPRX2 protein Q96LB1 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256787 ASXL1 protein Q8IXJ9 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" binding 9606 21047783 t miannu "Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ. " SIGNOR-260064 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Thr507 FGESRAStFCGTPDY 9606 11959144 t "PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex" SIGNOR-248637 CHEK1 protein O14757 UNIPROT PABIR1 protein Q96E09 UNIPROT "down-regulates activity" phosphorylation Ser37 GGLRRSNsAPLIHGL 9606 BTO:0000018 33108758 t miannu "Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression." SIGNOR-266380 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258272 PTEN protein P60484 UNIPROT PINK1 protein Q9BXM7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11494141 f miannu "Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase)." SIGNOR-260056 "phosphatidylinositol bisphosphate" smallmolecule CHEBI:37328 ChEBI CAPZA1 protein P52907 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132 12788695 t lperfetto "We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations." SIGNOR-261843 ABR protein Q12979 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260525 A2M protein P01023 UNIPROT MMP2 protein P08253 UNIPROT "down-regulates activity" binding -1 9344465 t lperfetto "Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261803 BRCA2 protein P51587 UNIPROT "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR "form complex" binding 9606 BTO:0000007 14636569 t lperfetto "These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer" SIGNOR-263207 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM52 protein Q96A61 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270956 PTPRF protein P10586 UNIPROT BCAR1 protein P56945 UNIPROT "down-regulates quantity by destabilization" dephosphorylation 9606 10320483 t lperfetto "LAR specifically dephosphorylates and destabilizes p130Cas and may play a role in regulating cell adhesion-mediated cell survival.|Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas." SIGNOR-276998 ID3 protein Q02535 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR "down-regulates activity" binding 10090 BTO:0004058 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241158 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163796 CCNA1 protein P78396 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 15829981 f lperfetto "Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth." SIGNOR-252255 GRK2 protein P25098 UNIPROT PDCL protein Q13371 UNIPROT "down-regulates activity" phosphorylation 9606 10884381 t miannu "The phosphorylation of purified phosducin and PhLP by recombinant GRK2 proceeds rapidly and stoichiometrically (0.82 +/- 0.1 and 0.83 +/- 0.09 mol of P (i)/mol of protein, respectively)." SIGNOR-279178 GNAI2 protein P04899 UNIPROT ADCY5 protein O95622 UNIPROT "down-regulates activity" binding 7108 BTO:0001240 8119955 t "Marta Tosoni" "Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3" SIGNOR-278075 vandetanib chemical CHEBI:49960 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258308 POLR3D protein P05423 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266130 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT "up-regulates activity" phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 10748061 t Luana "RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription." SIGNOR-259852 "MECP2/SIN3A/HDAC complex" complex SIGNOR-C360 SIGNOR BDNF protein P23560 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004102 14593184 t Luana "Moreover, increased Bdnf transcription involves dissociation of the MeCP2–histone deacetylase–mSin3A repression complex from its promoter." SIGNOR-265071 EDN1 protein P05305 UNIPROT MC1R protein Q01726 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9767234 f miannu "MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression." SIGNOR-252386 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr498 KTPPAPKtPPSSGEP -1 9199504 t miannu "Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective." SIGNOR-250086 PRKCQ protein Q04759 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249283 MAPK11 protein Q15759 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" 9606 BTO:0001255 12839928 f miannu "Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes." SIGNOR-263512 lanreotide chemical CHEBI:135901 ChEBI SSTR5 protein P35346 UNIPROT "up-regulates activity" "chemical activation" 9606 26416534 t miannu "Lanreotide Autogel (known as lanreotide Depot in the USA) is a synthetic octapeptide analog of somatostatin with a longer half-life than the native molecule and with selectivity for somatostatin receptor (SSTR) 2 and, to a lesser extent, SSTR 5" SIGNOR-259243 MRTFB protein Q9ULH7 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni "Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf." SIGNOR-174316 GSK3B protein P49841 UNIPROT OGT protein O15294 UNIPROT "up-regulates activity" phosphorylation Ser4 sVGNVADS 10090 BTO:0000142 23395175 t miannu "We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation." SIGNOR-276481 SMO protein Q99835 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 17251915 t gcesareni "As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp." SIGNOR-152817 SDHB protein P21912 UNIPROT "Succinate dehydrogenase-Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR "form complex" binding 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively." SIGNOR-266272 SYP protein P08247 UNIPROT VAMP2 protein P63027 UNIPROT "up-regulates quantity" binding 9606 17331077 t miannu "Synaptophysin I interacts with VAMP2 and controls its subcellular distribution. On the SV membrane, VAMP2 is engaged in a complex with synaptophysin I, which is mutually exclusive with the formation of fusogenic SNARE complexes. This model implicates synaptophysin I in escorting VAMP2 to the sites where exocytosis must take place exclusively after the arrival of the appropriate stimulus. We show that, at early stages along the secretory pathway, synaptophysin I directs sorting of VAMP2 to vesicles exhibiting limited availability for constitutive exocytosis." SIGNOR-264102 BCR protein P11274 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 19023129 t miannu "Overexpression of Bcr WT inhibited PPARgamma transcriptional activity (XREF_FIG).|Point-mutation and in vitro kinase analysis showed that PPAR\u03b3 was phosphorylated by Bcr at serine 82." SIGNOR-279441 CSNK1A1 protein P48729 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Thr1493 NPPPSPAtERSHYTM 9606 16341017 t lperfetto "We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6)" SIGNOR-143034 SREBF1 protein P36956 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17921436 t miannu "Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9." SIGNOR-255222 MAPK14 protein Q16539 UNIPROT ATF6 protein P18850 UNIPROT "up-regulates activity" phosphorylation Thr166 NKTENGLtPKKKIQV 10090 BTO:0002572 25135476 t miannu "This observation not only confirms the specific role for IFN-γ-induced p38 MAPK-dependent phosphorylation of ATF6 at the T166 site but also indicates a connection between phosphorylation and proteolytic activation." SIGNOR-276841 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr740 TGESDGGyMDMSKDE -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248667 SYVN1 protein Q86TM6 UNIPROT CPT2 protein P23786 UNIPROT "down-regulates quantity" ubiquitination 9606 33207079 t miannu "Taken together, these data suggest that HRD1 selectively and specifically downregulates intracellular CPT2 levels.|These results demonstrate that HRD1 ubiquitinates CPT2, which is processed through Lys-48-linked ubiquitin chains." SIGNOR-278723 BECN1 protein Q14457 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f miannu "Autophagy initiation signaling requires both the ULK1 kinase and the BECLIN 1–VPS34 core complex to generate autophagosomes, double-membraned vesicles that transfer cellular contents to lysosomes." SIGNOR-219545 CTNND1 protein O60716 UNIPROT CDH3 protein P22223 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0003564 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252124 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR LIN28A protein Q9H9Z2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269238 BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 t amattioni "Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)" SIGNOR-55546 FYCO1 protein Q9BQS8 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 26468287 t Giulio "The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures." SIGNOR-260597 TACR3 protein P29371 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257438 TMOD1 protein P28289 UNIPROT TPM3 protein P06753 UNIPROT "down-regulates activity" binding 9606 8002995 t irozzo "Tropomodulin is a 40.6-kDa protein that binds to one end of the rod-like tropomyosin and inhibits its cooperativity and binding to actin. [.] we demonstrate that it is the N-terminus of tropomyosin that interacts with tropomodulin. Among several tropomyosin isoforms tested, hTM5 encoded by the human gamma-tropomyosin gene has the highest affinity toward human erythrocyte tropomodulin." SIGNOR-259111 COLGALT2 protein Q8IYK4 UNIPROT COL3A1 protein P02461 UNIPROT "up-regulates activity" glycosylation -1 19075007 t "Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues." SIGNOR-261158 calcitriol smallmolecule CHEBI:17823 ChEBI calcitetrol smallmolecule CHEBI:47799 ChEBI "up-regulates quantity" "precursor of" 30080183 t lperfetto "Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH)." SIGNOR-270570 DOK1 protein Q99704 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257672 PRPF19 protein Q9UMS4 UNIPROT RPA1 protein P27694 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000567 24332808 t miannu "PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment." SIGNOR-272076 CBL protein P22681 UNIPROT FLT3 protein P36888 UNIPROT "down-regulates activity" binding 10090 BTO:0001516 19276253 t "Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo." SIGNOR-255739 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120016 CAST protein P20810 UNIPROT CAPN3 protein P20807 UNIPROT "down-regulates activity" binding 9606 BTO:0000590 25969760 t lperfetto "In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain" SIGNOR-251603 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Thr509 PVFDLTTtPKGGTPA 10116 16611631 t lperfetto "Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-146011 PRKCA protein P17252 UNIPROT GRM1 protein Q13255 UNIPROT "down-regulates activity" phosphorylation Thr695 GSKKKICtRKPRFMS 9606 10823959 t lperfetto "Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s)." SIGNOR-249043 CNTNAP1 protein P78357 UNIPROT CNTN1 protein Q12860 UNIPROT "up-regulates activity" relocalization 10090 BTO:0001221 11069942 t Gianni "These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr." SIGNOR-269073 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT "down-regulates activity" phosphorylation Thr830 DSAEGSHtSGQSNGR 9606 BTO:0001109 28114302 t miannu "Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression." SIGNOR-276510 CDK2 protein P24941 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates phosphorylation Ser158 FVSHSHIsPIKPTEA 9606 19066288 t llicata "We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1" SIGNOR-182761 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 12853467 t "14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling." SIGNOR-251485 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT "down-regulates activity" phosphorylation Ser67 DERVKEPsQDTVATE 31938050 t lperfetto "Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization." SIGNOR-275852 PRKACA protein P17612 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser429 PQRERKSsSSSEDRN 10116 BTO:0001009 11510412 t "The in vitro phosphorylation of a site unique to B-Raf (Ser429) has been proposed to be responsible for the negative regulation of the isoenzyme by Akt. Using phosphopetide mapping and site-directed mutagenesis we showed that Ser429 is phosphorylated upon cAMP elevation in PC12 cells and proposed that PKA is a major kinase phosphorylating the B-Raf-specific site in vivo" SIGNOR-259922 PGLS protein O95336 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI "up-regulates quantity" "chemical modification" 9606 31586547 t miannu "The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG)." SIGNOR-267058 "Dynorphin A" smallmolecule CHEBI:4727 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257552 GSK3A protein P49840 UNIPROT MAF protein O75444 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159361 "phosphatidylinositol bisphosphate" smallmolecule CHEBI:37328 ChEBI AKT1 protein P31749 UNIPROT "up-regulates activity" "chemical activation" 9606 18249092 t gcesareni "Furthermore, overall PKB activity, primarily consisting of cytosolic enzyme, was dependent upon levels of PI(3,4)P2, while only membrane-associated PKB activity was dependent upon PI(3,4,5)P3 levels. We conclude that PI(3,4,5)P3 and PI(3,4)P2 have distinct roles in determining PKB phosphorylation and activity. Thus, when investigating PI3K-PKB pathways, the importance of both lipids must be considered" SIGNOR-252432 MYC protein P01106 UNIPROT CCNA2 protein P20248 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "These results suggest that e2f1 and cyclin a2 may be induced by c-myc to mediate the onset of mammary cancer, whereas overexpression of cyclins d1 and e may occur later to facilitate tumor progression." SIGNOR-102728 "Doxorubicin hydrochloride" chemical CHEBI:31522 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 1963303 t miannu "DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives." SIGNOR-259324 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT "down-regulates activity" dephosphorylation Ser386 HQLFRGFsFVAITSD 10090 15206906 t "RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity" SIGNOR-248322 CDC42BPA protein Q5VT25 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 t lperfetto "More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above." SIGNOR-188785 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f "�The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation." SIGNOR-254977 serotonin smallmolecule CHEBI:28790 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI "up-regulates quantity" "precursor of" 9606 31024440 t brain lperfetto "Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA)." SIGNOR-264187 SFXN1 protein Q9H9B4 UNIPROT L-serine chemical CHEBI:17115 ChEBI "up-regulates quantity" relocalization 9606 30442778 t lperfetto "SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism." SIGNOR-268245 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates relocalization 9606 18596912 t fspada "The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform" SIGNOR-179400 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258233 PRKCA protein P17252 UNIPROT GRIN1 protein Q05586 UNIPROT "up-regulates activity" phosphorylation Ser896 SSFKRRRsSKDTSTG 10116 BTO:0000938 15936117 t miannu "Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890." SIGNOR-263177 PLK1 protein P53350 UNIPROT NUP35 protein Q8NFH5 UNIPROT "down-regulates activity" phosphorylation 9606 29065306 t miannu "Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association." SIGNOR-279252 ILK protein Q13418 UNIPROT PARVB protein Q9HBI1 UNIPROT "up-regulates activity" phosphorylation 9606 15159419 t miannu "These results indicate that affixin directly associates with \u03b1-actinin only when its CH2 domain is phosphorylated by ILK.|This may indicate that phosphorylation of the CH2 domain by ILK induces a conformational change of the CH2 domain of affixin, which enables affixin to interact with alpha-actinin to evoke the subsequent maturation of the FA complex." SIGNOR-278259 PLCB2 protein Q00722 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate(6-)" smallmolecule CHEBI:203600 ChEBI "up-regulates quantity" "chemical modification" 9606 23994464 t apalma "The first phase of this signal is likely mediated by phospholipase C≈í‚⧠(PLC≈í‚â§) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores" SIGNOR-255017 FASTKD5 protein Q7L8L6 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu "DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU." SIGNOR-261226 FBXO9 protein Q9UK97 UNIPROT TTI1 protein O43156 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23263282 t miannu "Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins." SIGNOR-271997 POU3F4 protein P49335 UNIPROT POU3F3 protein P20264 UNIPROT "up-regulates activity" binding -1 9105675 t miannu "POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes." SIGNOR-220127 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "down-regulates quantity" "chemical modification" 9606 31422819 t miannu "This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-268058 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni "This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses." SIGNOR-191670 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248293 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 22926518 t miannu "The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors." SIGNOR-256181 IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15864272 t gcesareni "The only type ii ifn, ifn-g, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2" SIGNOR-135952 FCGR2B protein P31994 UNIPROT TLR4 protein O00206 UNIPROT "down-regulates activity" 9606 24445665 f lperfetto "Triggering of FcgammaRIIB also subverted the normal activation of DCs by the TLR4 agonist lipopolysaccharide. In addition, triggering of FcgammaRIIB by immune complexes might affect the differentiation of moDCs. When moDCs develop from monocytes invitro in the presence of immune complexes, their differentiation is hampered and they no longer produce IL-12 in response to TLR4 agonists." SIGNOR-249525 MAP3K7 protein O43318 UNIPROT PTPN3 protein P26045 UNIPROT unknown phosphorylation Ser359 PAMRRSLsVEHLETK 9606 9341175 t gcesareni "Mutation of ser359 and ser853 to alanine significantly reduced the association between 14-3-3beta and ptph1. Furthermore, association of ptph1 and 14-3-3beta was detected in several cell lines and was regulated in response to extracellular signals" SIGNOR-52781 MEF2D protein Q14814 UNIPROT MYH1 protein P12882 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 15728583 t lperfetto "Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation" SIGNOR-238751 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248747 FSTL1 protein Q12841 UNIPROT DIP2A protein Q14689 UNIPROT "up-regulates activity" binding 9606 BTO:0005562 20054002 t miannu "We identified DIP2A as a novel FSTL1-binding partner from the membrane fraction of endothelial cells. Co-immunoprecipitation assays revealed a direct physical interaction between FSTL1 and DIP2A. The work in the current study identifies DIP2A as a novel receptor for FSTL1 that mediates Akt activation and cell survival and function in cardiovascular cells in vitro." SIGNOR-266603 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH23 protein Q9H251 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265839 HNRNPU protein Q00839 UNIPROT ZFY protein P08048 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 17174306 f lperfetto "In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs." SIGNOR-262287 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Ser58 SRGGARAsPATQPPP 9606 12478298 t lperfetto "In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites" SIGNOR-96410 SLC24A2 protein Q9UI40 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 30173760 t miannu "K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+)" SIGNOR-264399 STK4 protein Q13043 UNIPROT PRDX1 protein Q06830 UNIPROT "down-regulates activity" phosphorylation Thr18 PAPNFKAtAVMPDGQ -1 23386615 t miannu "Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183." SIGNOR-276486 TUT4 protein Q5TAX3 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 f lperfetto "Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells." SIGNOR-268355 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75641 FBXL7 protein Q9UJT9 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 10090 BTO:0002268 25778398 t miannu "Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation." SIGNOR-272437 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni "Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells." SIGNOR-179404 hsa-mir-494-3p mirna URS0000535FDD_9606 RNAcentral CXCR4 protein P61073 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001061 24644030 t "The constitutive overexpression of miR-494 downregulated the protein level of CXCR4, leading to suppression of proliferation, invasion, and migration of prostate cancer." SIGNOR-277942 DAPK3 protein O43293 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000776 17339337 t gcesareni "A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53." SIGNOR-153495 SP1 protein P08047 UNIPROT SLC19A1 protein P41440 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 15652157 f "Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation." SIGNOR-254064 CDK12 protein Q9NYV4 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Thr169 TEAPAVVtEEEDDDE 9606 BTO:0004828 32483448 t lperfetto "Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway" SIGNOR-273110 TGFB1 protein P01137 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251798 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 t gcesareni "Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1." SIGNOR-180548 MED13L protein Q71F56 UNIPROT "CKM complex" complex SIGNOR-C406 SIGNOR "form complex" binding 9606 23563140 t miannu "The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation." SIGNOR-266702 MDH2 protein P40926 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI "down-regulates quantity" "chemical modification" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-268100 HADH protein Q16836 UNIPROT (S)-3-hydroxylauroyl-CoA smallmolecule CHEBI:27668 ChEBI "down-regulates quantity" "chemical modification" 9606 16176262 t miannu "3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs." SIGNOR-280348 HTR1B protein P28222 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256863 PRKCA protein P17252 UNIPROT CTNND1 protein O60716 UNIPROT "down-regulates activity" phosphorylation Ser879 LIDRNQKsDKKPDRE 9606 22798526 t miannu "PKC\u03b1 phosphorylation of p120 at S879 is a critical phospho-switch mediating disassociation of p120 from VE-cadherin that results in AJ disassembly.|We surmised that PKCalpha may function to disrupt AJs by signaling dissociation of p120 from VE-cadherin." SIGNOR-278261 MALT1 protein Q9UDY8 UNIPROT CBM complex SIGNOR-C555 SIGNOR "form complex" binding 9606 15122200 t miannu "CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways." SIGNOR-276295 NCS1 protein P62166 UNIPROT DRD2 protein P14416 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000938 12351722 t miannu "Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization." SIGNOR-263964 JAK1 protein P23458 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 17259970 t milica "Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity." SIGNOR-152914 (S)-3-hydroxylauroyl-CoA smallmolecule CHEBI:27668 ChEBI 3-oxolauroyl-CoA smallmolecule CHEBI:27868 ChEBI "up-regulates quantity" "precursor of" 9606 16176262 t miannu "3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs." SIGNOR-280352 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 11085989 f miannu "We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation." SIGNOR-263500 ANK3 protein Q12955 UNIPROT DMD protein P11532 UNIPROT "up-regulates quantity" relocalization 10090 BTO:0001103 19109891 t miannu "We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4." SIGNOR-266715 DIABLO protein Q9NR28 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 10929711 t gcesareni "Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release." SIGNOR-80212 CTH protein P32929 UNIPROT "L-selenocysteine zwitterion" smallmolecule CHEBI:57843 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275821 FZD4 protein Q9ULV1 UNIPROT DVL3 protein Q92997 UNIPROT "up-regulates activity" binding 9606 27096005 t areggio "Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin." SIGNOR-258961 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249682 ATAT1 protein Q5SQI0 UNIPROT TUBA3D protein P0DPH8 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272246 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-261726 ABI1 protein Q8IZP0 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 17395426 t gcesareni "Here we uncover a novel interaction between abi-1 and the cbl ubiquitin ligase and show that abi-1 mediates cbl accumulation to the plasma membrane upon stimulation by egf." SIGNOR-154162 ULK1 protein O75385 UNIPROT STING1 protein Q86WV6 UNIPROT "down-regulates activity" phosphorylation Ser366 QEPELLIsGMEKPLP 9606 24119841 t miannu "Collectively, our data indicates that cGAS is essential for the activation of AMPK and ULK1 suppression of STING (XREF_FIG) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity (XREF_FIG).|Collectively, our data indicates that cGAS is essential for the activation of AMPK/ULK1 suppression of STING ( xref ) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity ( xref )." SIGNOR-279316 miR-29b mirna URS0000150A7D_9606 RNAcentral SP1 protein P08047 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 21730352 f miannu "We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation." SIGNOR-256244 TLN1 protein Q9Y490 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257619 BMP2 protein P12643 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 12589053 f fspada "Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma." SIGNOR-98369 domperidone chemical CHEBI:31515 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 1975644 t miannu "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells." SIGNOR-258380 KDM5B protein Q9UGL1 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264303 S1PR2 protein O95136 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257401 NR2F2 protein P24468 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 9826778 t gcesareni "The orphan nuclear receptor, coup-tf ii, inactivates myogenesis by post-transcriptional regulation of myod function: coup-tf ii directly interacts with p300 and myod." SIGNOR-62248 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257400 PTPN5 protein P54829 UNIPROT GRIN2A protein Q12879 UNIPROT "down-regulates activity" dephosphorylation 9606 27857196 t miannu "STEP inhibition by TC-2153 enhanced Tyr phosphorylation of GluN2A (XREF_FIG, 1 EGTA+TC-2153, n = 5, P < 0.05 compared with 1mM EGTA) without altering phosphorylation of Src (XREF_FIG, 1 EGTA+TC-2153, n = 5, P> 0.05 compared with 1 EGTA).|These findings confirm that not only GluN2B and Fyn but also GluN2A are substrates of STEP." SIGNOR-277089 TIGIT protein Q495A1 UNIPROT ARRB2 protein P32121 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 24817116 t lperfetto "With TIGIT/PVR engagement, cytoplasmic TIGIT was phosphorylated at Tyr-225 and Tyr-231 residues. Phosphorylated Tyr-225 recruits adaptor protein beta arrestin 2|TIGIT/PVR signaling mediates suppression of IFN- gamma production via the NF-kappaB pathway. We identified a new adaptor β-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells." SIGNOR-261482 WT1 protein P19544 UNIPROT NPHS1 protein O60500 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15504938 t "The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner" SIGNOR-252299 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256728 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser855 QRVLDTSsLTQSAPA 9606 BTO:0000007 19864431 t lperfetto "Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855))" SIGNOR-174882 PAK3 protein O75914 UNIPROT MYO6 protein Q9UM54 UNIPROT "up-regulates activity" phosphorylation Thr405 TAGGTKGtVIKVPLK -1 11517222 t miannu "P21-activated kinase 3 phosphorylated myosin VI, and the site was identified as Thr(406). The phosphorylation of myosin VI significantly facilitated the actin-translocating activity of myosin VI. " SIGNOR-250244 SCF(TBL1) complex SIGNOR-C533 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys671 EDKPQDYkKRLSVEL 9606 BTO:0000007 20181957 t miannu "Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC). " SIGNOR-271947 SIRT1 protein Q96EB6 UNIPROT HYOU1 protein Q9Y4L1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 22564731 f miannu "Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress." SIGNOR-255143 MAPK1 protein P28482 UNIPROT PPP1R9B protein Q96SB3 UNIPROT unknown phosphorylation Ser15 GPGGPLRsASPHRSA 9606 15728359 t lperfetto "We have identified three sites phosphorylated by ERK2 (Ser-15 and Ser-205) and cyclin-dependent PK 5 (Cdk5) (Ser-17), within the actin-binding domain of spinophilin." SIGNOR-249435 MAPK8IP1 protein Q9UQF2 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 20508646 t "Interferes with binding to Noth1-ICD." gcesareni "Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them." SIGNOR-165713 PRKCD protein Q05655 UNIPROT EP300 protein Q09472 UNIPROT down-regulates phosphorylation Ser89 SELLRSGsSPNLNMG 9606 12379484 t lperfetto "Inhibition of histone acetyltransferase function of p300 by pkcdeltawe found that pkcdelta but not classical pkc, specifically phosphorylates p300 at serine 89 in vitro and in vivo. This phosphorylation causes inhibition of p300 intrinsic hat activity." SIGNOR-94263 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates activity" dephosphorylation Ser667 SSLIRKRsTRRSVRG 9606 BTO:0000007 24333728 t "Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp" SIGNOR-272506 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 17078951 t "The effect has been demonstrated using P10636-8" lperfetto "Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422" SIGNOR-150360 SKIL protein P12757 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 10531062 t lperfetto "Thus, SnoN can interact with Smad4 and Smad2 and inhibit their abilities to activate transcription." SIGNOR-227479 glycogen smallmolecule CHEBI:28087 ChEBI PYGB protein P11216 UNIPROT "up-regulates activity" "chemical activation" 9606 3346228 t "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267951 PAF1C complex SIGNOR-C471 SIGNOR TCEA1 protein P23193 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 20178742 t miannu "HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription." SIGNOR-269838 PRKCG protein P05129 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 BTO:0000887 15769444 t lperfetto "Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction." SIGNOR-134636 MAPK1 protein P28482 UNIPROT MYB protein P10242 UNIPROT unknown phosphorylation Ser532 KIKQEVEsPTDKSGN -1 8960373 t lperfetto "Functional analysis of phosphorylation at serine 532 of human c-Myb by MAP kinase| Expression of a constitutively active form of Ras together with c-Myb in transient transfection experiments had no effect on the transcriptional activity of c-Myb, while expression of a polypeptide containing the c-Myb C-terminal domain stimulated c-Myb activity. This effect is reduced upon MAPK-dependent phosphorylation of serine 532." SIGNOR-249420 NCOA4 protein Q13772 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 10347167 t miannu "We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar." SIGNOR-67684 AMPK complex SIGNOR-C15 SIGNOR CCNY protein Q8ND76 UNIPROT "up-regulates activity" phosphorylation Ser326 SARKRSAsADNLTLP 9606 32723157 t lperfetto "Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16" SIGNOR-273001 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT "up-regulates activity" phosphorylation Ser44 GLKFMQAsEDLLKEH 9606 BTO:0000093 8245015 t miannu "An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells." SIGNOR-250303 PTGS2 protein P35354 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000007 32995789 f miannu "Given our finding that COX-2 signaling does not regulate viral entry or replication, the role of COX-2 induction upon SARS-CoV-2 infection remains an area for future investigation. Rather than directly affecting viral entry or replication, COX-2 induction may regulate the severe lung inflammation and injury seen in COVID-19 patients (35, 36), though it is unclear whether COX-2 would be beneficial, neutral, or detrimental to disease. COX-2 could enhance lung injury in COVID-19, as PGE2 has been reported to induce IL-1β and exacerbate lung injury in bone marrow transplant mice" SIGNOR-262509 Ub:E2 complex SIGNOR-C497 SIGNOR CUL9 protein Q8IWT3 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271114 FFAR1 protein O14842 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257272 CHEK1 protein O14757 UNIPROT CDC25C protein P30307 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser216 SGLYRSPsMPENLNR 9606 20068082 t gcesareni "The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216)." SIGNOR-163158 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248754 miR-23b mirna URS0000283D0A_9606 RNAcentral GLS protein O94925 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 21135128 t "MiR-130 reduces adipogenesis by repressing PPARγ biosynthesis and suggest that perturbations in this regulation is linked to human obesity." SIGNOR-255930 HRH1 protein P35367 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257163 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000938 8387505 t "inferred from 70% family members" lperfetto "The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases" SIGNOR-270002 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto "Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1)." SIGNOR-134477 PRKCA protein P17252 UNIPROT FERMT3 protein Q86UX7 UNIPROT "up-regulates activity" phosphorylation Ser484 LSLQRTGsGGPGNHP 9606 BTO:0000565 25609252 t miannu " PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38). " SIGNOR-266415 CDKN2A protein P42771 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 16161044 t gcesareni "The cdk-inhibitor p16 is a tumor suppressor gene that is inactivated in many forms of cancer. In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm." SIGNOR-140409 SOCS5 protein O75159 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 15590694 t miannu "SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation." SIGNOR-271522 PRKAA1 protein Q13131 UNIPROT BTRC protein Q9Y297 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser82 SLRQTYNsCARLCLN 9606 BTO:0002419 31406304 t miannu "Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1. " SIGNOR-277475 CREB1 protein P16220 UNIPROT POMC protein P01189 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001073 11081181 t lperfetto "Transcriptional activation of the proopiomelanocortin gene by cyclic AMP-responsive element binding protein|Further, expression of a dominant inhibitory mutant of CREB reduced cAMP stimulated transcription of the full length POMC promoter and the PTRE." SIGNOR-268620 SPAG9 protein O60271 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates binding 9606 BTO:0000222 17074887 t "p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors." gcesareni "Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants." SIGNOR-150147 MARCHF5 protein Q9NX47 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 32015503 t miannu "MARCH5 promotes ubiquitination of MCL1 and NOXA.|Together, this suggests that degradation of MCL1 by MARCH5 depends on binding to NOXA, but degradation of NOXA may be promoted by additional E3-ligases if MCL1 levels become limited, or can simply no longer be degraded." SIGNOR-278700 ANKRD11 protein Q6UB99 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" binding 9606 BTO:0000093 18840648 t miannu "Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53." SIGNOR-266734 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18332116 f irozzo "HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a" SIGNOR-256300 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARA protein P10276 UNIPROT "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." SIGNOR-256194 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser29 IEDSQPEsQVLEDDS 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" SIGNOR-100645 GSK3B protein P49841 UNIPROT JUNB protein P17275 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr255 EARSRDAtPPVSPIN 9606 BTO:0000567 22710716 t miannu " Thus, JunB phosphorylation at S251 and T255 by GSK3β is primed by phosphorylation at S259 by a yet to-be-identified kinase.Phosphorylation at S251, T255 and S259 is required for JunB degradation." SIGNOR-276417 NDUFB10 protein O96000 UNIPROT "NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262163 APH1A protein Q96BI3 UNIPROT NCSTN protein Q92542 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni "By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain." SIGNOR-93259 SIRT5 protein Q9NXA8 UNIPROT IDH2 protein P48735 UNIPROT "up-regulates activity" "catalytic activity" 9606 27113762 t Monia "Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes." SIGNOR-261212 CTNND2 protein Q9UQB3 UNIPROT CDH2 protein P19022 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0001109 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252131 ULK1 protein O75385 UNIPROT SQSTM1 protein Q13501 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser403 ESLSQMLsMGFSDEG 9606 25040165 t miannu "ULK1 phosphorylates p62 at the Ser403 site." SIGNOR-278349 "HIF-1 complex" complex SIGNOR-C418 SIGNOR PFKFB3 protein Q16875 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11744734 t "PFKFB3, is highly induced by hypoxia and the hypoxia mimics cobalt and desferrioxamine. This induction could be replicated by the use of an inhibitor of the prolyl hydroxylase enzymes responsible for the von Hippel Lindau (VHL)-dependent destabilization and tagging of HIF-1α. The absolute dependence of the PFKFB3 gene on HIF-1 was confirmed by its overexpression in VHL-deficient cells and by the lack of hypoxic induction in mouse embryonic fibroblasts conditionally nullizygous for HIF-1α" SIGNOR-267388 ATP13A1 protein Q9HD20 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0004093 29650961 f doi.org/10.1101/185272 francesca "Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions" SIGNOR-261217 EEF1A1 protein P68104 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 BTO:0000608 37973952 t "Marta Tosoni" "Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription" SIGNOR-278105 "diallyl disulfide" chemical CHEBI:4488 ChEBI hsa-miR-200b-5p mirna URS000012A1DD_9606 RNAcentral "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0004953 23851184 t Parnian "The results indicated that DADS can suppress gastric cell proliferation and induce apoptosis through up-regulation of miR-22 and miR-200b expression." SIGNOR-278847 hsa-miR-30d-5p mirna URS000005CF5F_9606 RNAcentral BECN1 protein Q14457 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001611 24345332 t parnian "MiR-30d down-regulates beclin 1 expression by directly targeting its 3′-UTR." SIGNOR-280433 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "precursor of" 9606 31422819 t miannu "This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-267515 IL22RA1 protein Q8N6P7 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 12087100 t gcesareni "Il-22 activates jak1 and tyk2" SIGNOR-90165 MAPK8 protein P45983 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 t gcesareni "By site-directed mutagenesis studies, we have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in prostate cancer cells. Further studies with the inhibitor of jun kinase (jnk) and phosphorylation mutant of bcl-xl reveal the augmentative role of jnk-mediated bcl-xl phosphorylation in apoptosis of prostate cancer cells. In summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl to permit prostate cancer cells to die by apoptosis" SIGNOR-99219 GTF3A protein Q92664 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR "up-regulates activity" relocalization 9606 8907699 t lperfetto "One of the major functions of TFIIIA is to program the 5S RNA gene for transcription by binding directly to the ICR, which subsequently directs an ordered assembly of general factors to form a functional transcription complex." SIGNOR-269309 DOK1 protein Q99704 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257678 MMP2 protein P08253 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272387 CD70 protein P32970 UNIPROT CD27 protein P26842 UNIPROT up-regulates binding 9606 BTO:0000776 12324477 t gcesareni "The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner." SIGNOR-93435 TARS1 protein P26639 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 25824639 t miannu "Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding." SIGNOR-270503 IL20 protein Q9NYY1 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 11163236 t gcesareni "An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis." SIGNOR-151874 Gbeta proteinfamily SIGNOR-PF4 SIGNOR STMN1 protein P16949 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 9731215 t "inferred from 70% family members" lperfetto "Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs." SIGNOR-270082 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser255 SSQMKSMsTFIEEAY 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265226 MAPK1 protein P28482 UNIPROT MYO9B protein Q13459 UNIPROT unknown phosphorylation Thr1346 RATGAALtPTEERRT 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262777 DOK1 protein Q99704 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257677 HECTD4 protein Q9Y4D8 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001321 32814769 t miannu "We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop." SIGNOR-267148 SMARCA4 protein P51532 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 19571879 t miannu "Tert activates wnt reporter plasmids in a brg1-dependent manner." SIGNOR-186607 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser429 PQRERKSsSSSEDRN 9606 BTO:0000007 10869359 t "Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo" SIGNOR-251472 "diarsenic trioxide" chemical CHEBI:30621 ChEBI PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR "down-regulates quantity by destabilization" "chemical inhibition" 9606 24344243 t "ATO was shown to degrade PML-RARa via its PML moiety further reinforcing the idea that APL is addicted to the PML-RARa oncoprotein" SIGNOR-259924 MAP1LC3C protein Q9BXW4 UNIPROT ATG3 protein Q9NT62 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 22170151 t lperfetto "Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe" SIGNOR-191552 MAPK1 protein P28482 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" phosphorylation 9606 9872331 t miannu "ERK2 phosphorylates Stat3 on three serine-containing peptides and decreases its tyrosine phosphorylation induced by EGF treatment.|Here, we report that ERK2 activated by its upstream kinase, MEK1, represses Stat3 transcriptional activity induced by Src or Jak-2." SIGNOR-279635 "C3 convertase complex (C3bBb)" complex SIGNOR-C314 SIGNOR C3 protein P01024 UNIPROT "up-regulates activity" cleavage Arg748 ASHLGLArSNLDEDI 9606 BTO:0000089 26489954 t lperfetto "In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC)." SIGNOR-263478 SIRT1 protein Q96EB6 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21633182 t miannu "Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms." SIGNOR-268032 CDK5 protein Q00535 UNIPROT PHACTR3 protein Q96KR7 UNIPROT "down-regulates quantity" phosphorylation Ser318 QGRESKGsPKKRLDV 10116 BTO:0000938 21487013 t miannu "We show that scapinin is phosphorylated at a highly conserved site in the central region of the protein (Ser-277) by Cdk5 in vitro. Expression of a scapinin phospho-mimetic mutant (S277D) restored normal axon elongation without affecting actin binding. Instead, phosphorylated scapinin was sequestered in the cytoplasm of neurons and away from the axon. " SIGNOR-273607 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Thr404 SSMSTEQtLASDTDS 9606 11062067 t lperfetto "The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro." SIGNOR-83715 SP1 protein P08047 UNIPROT CYP1B1 protein Q16678 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12801909 f miannu "It was suggested that mutual interaction of XRE2 and XRE3 is important for transcriptional regulation, and that the Sp1 binding to the Sp1-like motif (-824) enhances both the constitutive and inducible transcriptional activities of the human CYP1B1 gene." SIGNOR-255196 GNAI1 protein P63096 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR down-regulates 9606 BTO:0003191 23691483 t "Marta Tosoni" "GNAI1 can signifi cantly inhibit the migration and metastasis of HCC cells." SIGNOR-278878 DLL3 protein Q9NYJ7 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR "up-regulates activity" binding 9606 BTO:0000776 16140393 t lperfetto "Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate." SIGNOR-209747 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys666 IRAGDTTkFDVEVLK 9606 BTO:0000007 28448495 t miannu "SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J)." SIGNOR-272803 isoprenaline chemical CHEBI:64317 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 8982677 t miannu "K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists." SIGNOR-258576 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Pyl) smallmolecule CHEBI:15185 ChEBI "up-regulates quantity" "chemical modification" 9606 27911719 t lperfetto "RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)" SIGNOR-269494 "Av/b1 integrin" complex SIGNOR-C175 SIGNOR UTF1 protein Q5T230 UNIPROT "up-regulates quantity by expression" 10090 18757303 f lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253275 CDK2 protein P24941 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates activity" phosphorylation Thr611 ETLPISStPSKSVLP BTO:0001938 15024056 t llicata "We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins." SIGNOR-250731 HES1 protein Q14469 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165 BTO:0000887 10066785 f lperfetto "Notch signaling up-regulated hes1 mrna expression within 1 h and subsequently reduced expression of myod mrna." SIGNOR-235596 "Trifunctional enzyme" complex SIGNOR-C564 SIGNOR (S)-3-hydroxypalmitoyl-CoA smallmolecule CHEBI:27402 ChEBI "up-regulates quantity" "chemical modification" 9606 30850536 t miannu "Membrane-bound mitochondrial trifunctional protein (TFP) catalyzes β-oxidation of long chain fatty acyl-CoAs, employing 2-enoyl-CoA hydratase (ECH), 3- hydroxyl-CoA dehydrogenase (HAD), and 3-ketothiolase (KT) activities consecutively. " SIGNOR-280311 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser186 PVLRQSIsFSGLPSG -1 14688255 t miannu "We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated." SIGNOR-250152 ATG7 protein O95352 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT "up-regulates activity" binding 10090 22170151 t lperfetto "Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe" SIGNOR-191540 SNRPD1 protein P62314 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270635 pazopanib chemical CHEBI:71219 ChEBI FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257735 PRKAA1 protein Q13131 UNIPROT SCD protein O00767 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21478464 f miannu "Tr4 transactivation is inhibited via phosphorylation by metformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression." SIGNOR-173161 (E)-hexadec-2-enoyl-CoA(4-) smallmolecule CHEBI:61526 ChEBI (S)-3-hydroxypalmitoyl-CoA smallmolecule CHEBI:27402 ChEBI "up-regulates quantity" "precursor of" 9606 30850536 t miannu "Membrane-bound mitochondrial trifunctional protein (TFP) catalyzes β-oxidation of long chain fatty acyl-CoAs, employing 2-enoyl-CoA hydratase (ECH), 3- hydroxyl-CoA dehydrogenase (HAD), and 3-ketothiolase (KT) activities consecutively. " SIGNOR-280312 SGK2 protein Q9HBY8 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 t lperfetto "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis." SIGNOR-252990 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Ser161 QKATPGSsRKTCRYI 9606 BTO:0000567 15525512 t llicata "Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. " SIGNOR-250605 GNA12 protein Q03113 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 23450633 t gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." SIGNOR-192108 ATG10 protein Q9H0Y0 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR up-regulates binding 9606 18704115 t lperfetto "Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein." SIGNOR-226699 TERF2IP protein Q9NYB0 UNIPROT "Shelterin complex" complex SIGNOR-C306 SIGNOR "form complex" binding 9606 BTO:0000567 15383534 t lperfetto "Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins." SIGNOR-263319 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 BTO:0000671 15694384 t llicata "Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925." SIGNOR-133841 PPP3CB protein P16298 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 11062529 t gcesareni "The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c." SIGNOR-84047 MLLT11 protein Q13015 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 "BTO:0001939; BTO:0002768; BTO:0000815" 26079538 f irozzo "In addition, enhanced AF1q expression promotes breast cancer cell proliferation, migration, mammosphere formation, and chemo-resistance." SIGNOR-259107 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR YAP1 protein P46937 UNIPROT "down-regulates activity" binding 9606 23431053 t miannu "The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation." SIGNOR-265823 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PML protein P29590 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis." SIGNOR-270034 MAPK3 protein P27361 UNIPROT IL16 protein Q14005 UNIPROT up-regulates phosphorylation Ser845 SIRQRISsFETFGSS 9606 14768064 t lperfetto "The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response." SIGNOR-121856 UNC5C protein O95185 UNIPROT DCC protein P43146 UNIPROT "down-regulates activity" binding 9606 BTO:0001484 25881791 t miannu "In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists." SIGNOR-268165 KISS1R protein Q969F8 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256893 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser485 QDNGAEDsGDTEDEL 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair" SIGNOR-165419 ARAP2 protein Q8WZ64 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260455 CDON protein Q4KMG0 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 19470755 t lperfetto "Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity" SIGNOR-185762 ZWILCH protein Q9H900 UNIPROT "RZZ complex" complex SIGNOR-C357 SIGNOR "form complex" binding 9606 BTO:0000567 20462495 t lperfetto "The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico." SIGNOR-265014 LRP1B protein Q9NZR2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002940 27626682 f irozzo "Conversely, in Calu-1 cells, which express higher endogenous levels of the receptor, siRNA-mediated LRP1B knockdown significantly enhanced cellular proliferation. Taken together, these findings demonstrate that, consistent with the postulated tumor suppressor function, overexpression of full-length Lrp1b leads to impaired cellular proliferation, while LRP1B knockdown has the opposite effect." SIGNOR-259089 TIAM2 protein Q8IVF5 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260578 maraviroc chemical CHEBI:63608 ChEBI CCL4L1 protein Q8NHW4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194009 TFE3 protein P19532 UNIPROT HEXA protein P06865 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 24448649 f lperfetto "Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A)." SIGNOR-276824 TSC2 protein P49815 UNIPROT TSC1 protein Q92574 UNIPROT "up-regulates activity" binding 9606 BTO:0000142;BTO:0000671 10807585 t lperfetto "Furthermore, tsc2 is directly phosphorylated by akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1." SIGNOR-77400 DLG3 protein Q92796 UNIPROT "NMDA receptor_2C" complex SIGNOR-C349 SIGNOR "up-regulates activity" relocalization BTO:0000227 32904533 t lperfetto "DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses." SIGNOR-266008 FYN protein P06241 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Tyr487 DNSSDSDyDLHGAQR -1 11298344 t "Tyrosine-mutated CD5 molecules have been used to show that residues Y429 and Y463 are targeted in vivo by protein tyrosine kinases following cell stimulation with anti-CD3 mAb or pervanadate. This is in agreement with data from direct in vitro kinase assays using purified recombinant Lck and Fyn protein tyrosine kinases." SIGNOR-251152 tazarotene chemical CHEBI:32184 ChEBI RARG protein P13631 UNIPROT "up-regulates activity" "chemical activation" 9534 19058965 t Luana "Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. " SIGNOR-258029 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 21808241 t "MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction." SIGNOR-175837 RALGAPA1 protein Q6GYQ0 UNIPROT RalGAP1 complex SIGNOR-C468 SIGNOR "form complex" binding 10090 BTO:0000011 21148297 t miannu "Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA." SIGNOR-269791 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT down-regulates phosphorylation Ser162 LRRYTTFsKRKTGIM 10090 16537394 t lperfetto "Mimicking phosphorylation of serine-162, a target of protein kinase c-alpha, with an aspartic acid substitution (srf-s162d) completely inhibited srf-dna binding and blocked alpha-actin gene transcription pkc? Highly phosphorylated serine-162." SIGNOR-234461 BCL2 protein P10415 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates 9606 14585074 f amattioni "Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi" SIGNOR-89189 PAPOLA protein P51003 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 19224921 f lperfetto "Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner." SIGNOR-268325 ATF2 protein P15336 UNIPROT YTHDC2 protein Q9H6S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001911 24269672 t lperfetto "Collectively, these data show that YTHDC2 plays an important role in tumor cells growth and activation/recruitment of c-Jun and ATF-2 to the YTHDC2 promoter is necessary for the transcription of YTHDC2, and that HDAC activity is required for the efficient expression of YTHDC2 in both of hepatocyte and HCC cells." SIGNOR-269001 LRFN5 protein Q96NI6 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu "The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons." SIGNOR-264093 PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC -1 22306293 t "PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor" SIGNOR-267716 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni "Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6." SIGNOR-166506 SENP3 protein Q9H4L4 UNIPROT "Rix1 complex" complex SIGNOR-C373 SIGNOR "form complex" binding 9606 BTO:0000007 22190735 t miannu "LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes." SIGNOR-265468 VHL protein P40337 UNIPROT "HIF-1 complex" complex SIGNOR-C418 SIGNOR down-regulates ubiquitination 9606 10944113 t miannu "Here we show that the product of the von hippel-lindau (vhl) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of hif-1 alpha under normoxic conditions via interaction with the core of the oxygen-dependent degradation domain of hif-1 alpha." SIGNOR-80969 UVRAG protein Q9P2Y5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" binding 9606 18843052 t lperfetto "Although both human atg14 and uvrag interact with beclin 1 and vps34." SIGNOR-181554 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr246 LCFSPNRyWLCAATG 9606 12400005 t gcesareni "We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246" SIGNOR-94800 "Brivanib alaninate" chemical CID:11154925 PUBCHEM FGFR1 protein P11362 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190717 BTK protein Q06187 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation 9606 29290977 t miannu "Phosphorylation of MDM2 by BTK suppresses its ubiquitination activity." SIGNOR-278330 "Food intake" phenotype SIGNOR-PH152 SIGNOR "folic acid" smallmolecule CHEBI:27470 ChEBI up-regulates 9606 19706381 f lperfetto "The U.S. Reference Daily Intake (Daily Value) for FA is 0.4 mg for adults to aid in the prevention of birth defects and anemia, or double this amount for pregnant or lactating women." SIGNOR-268262 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto "Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions." SIGNOR-252359 "Trifunctional enzyme" complex SIGNOR-C564 SIGNOR water smallmolecule CHEBI:15377 ChEBI "down-regulates quantity" "chemical modification" 9606 30850536 t miannu "Membrane-bound mitochondrial trifunctional protein (TFP) catalyzes β-oxidation of long chain fatty acyl-CoAs, employing 2-enoyl-CoA hydratase (ECH), 3- hydroxyl-CoA dehydrogenase (HAD), and 3-ketothiolase (KT) activities consecutively. " SIGNOR-280313 GALR2 protein O43603 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257356 ZAP70 protein P43403 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates phosphorylation Tyr138 SPTLVIAyLMMRQKM 9606 12447358 t gcesareni "We report here that vhr, a vaccinia virus vh1-related dual-specific protein phosphatase that inactivates the mitogen-activated kinases erk2 and jnk, is phosphorylated at y138 by zap-70. Tyr138 phosphorylation was required for vhr to inhibit the erk2-elk-1 pathway" SIGNOR-95877 MAPK10 protein P53779 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates phosphorylation Ser73 EAPRTLAsPKKKDLS 9606 11718727 t gcesareni "We demonstrate that purified scg10 can be phosphorylated by two subclasses of mitogen-activated protein (map) kinases, c-jun n-terminal/stress-activated protein kinase (jnk/sapk) and p38 map kinase;jnk3/sapkbeta phosphorylation occurs at ser-62 and ser-73, residues that result in reduced microtubule-destabilizing activity for scg10." SIGNOR-112114 PTPN6 protein P29350 UNIPROT SH3BP2 protein P78314 UNIPROT down-regulates dephosphorylation 9606 16649996 t gcesareni "Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling" SIGNOR-146508 ACAA2 protein P42765 UNIPROT "3-oxo-fatty acyl-CoA" smallmolecule CHEBI:15489 ChEBI "up-regulates quantity" "chemical modification" 9606 38656551 t miannu "Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial β oxidation, which plays an important role in fatty acid metabolism." SIGNOR-280390 ITCH protein Q96J02 UNIPROT BCL10 protein O95999 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000661 15082780 t miannu "The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation. " SIGNOR-271413 FYN protein P06241 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15537652 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Here we provide evidence that fyn kinase, a member of the src kinase family, is involved in the uvb-induced phosphorylation of histone h3 at serine 10" SIGNOR-130274 DAB2IP protein Q5VWQ8 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" binding 9606 BTO:0002195 27858941 t miannu "In vascular smooth muscle cells (VSMCs) treated with IFN-γ, DAB2IP directly binds to JAK2 and inhibits its kinase activity, limiting JAK-dependent STAT1/3 and PI3K–AKT phosphorylation and activation" SIGNOR-254760 EED protein O75530 UNIPROT SUZ12/EED complex SIGNOR-C76 SIGNOR "form complex" binding 9606 16712789 t miannu "Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2." SIGNOR-146755 MYF5 protein P13349 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR "up-regulates activity" BTO:0001103 17495111 f "Simone Vumbaca" "In summary, the absence of Myf5 clearly reduced the initial expansion of satellite cell-derived transient amplifying cells and resulted in a shift of the ratio of satellite cell subpopulations but did not affect the specification and generation of specific subpopulations of satellite cell-derived cells such as reserve cells, amplifying cells, and differentiating mature myogenic cells." SIGNOR-255643 ELF1 protein P32519 UNIPROT CD68 protein P34810 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 12676954 f "Band shift experiments show that PU.1 associates with the -89 site whereas, Elf-1 preferentially binds the -106 Ets binding site and enhances CD68 activity in vitro." SIGNOR-254282 PRKDC protein P78527 UNIPROT TDP1 protein Q9NUW8 UNIPROT up-regulates phosphorylation Ser81 PKRQKSGsQEDLGWC 9606 19851285 t lperfetto "Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk)" SIGNOR-188776 ZAP70 protein P43403 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates activity" phosphorylation Tyr1203 IFPARDTyHPMSEYP 9606 BTO:0000661 14766232 t lperfetto "Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin." SIGNOR-247039 PKA proteinfamily SIGNOR-PF17 SIGNOR LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser951 GFHPRRSsQGATQMP 19018281 t miannu " Our results demonstrate that PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650. " SIGNOR-276175 OPRL1 protein P41146 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257209 PGAM1 protein P18669 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "down-regulates quantity" "chemical modification" 9606 24786789 t miannu "Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle." SIGNOR-266511 SMAD5 protein Q99717 UNIPROT GADD45G protein O95257 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268942 AKT3 protein Q9Y243 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t gcesareni "We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity." SIGNOR-78697 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT "up-regulates activity" phosphorylation Ser537 DNSMSVPsPTSATKT 10090 BTO:0000964 34048556 t lperfetto "Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity." SIGNOR-268341 selumetinib chemical CHEBI:90227 ChEBI ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0001950 25487801 t Luana "Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections. " SIGNOR-262313 COLGALT2 protein Q8IYK4 UNIPROT COL1A2 protein P08123 UNIPROT "up-regulates activity" glycosylation -1 19075007 t "Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues." SIGNOR-261157 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 18971378 t gcesareni "In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)" SIGNOR-181811 IFNA1 protein P01562 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-104641 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 22298955 t gcesareni "Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation." SIGNOR-195603 H4C1 protein P62805 UNIPROT BRD2 protein P25440 UNIPROT "up-regulates activity" relocalization 9606 acetylation:Lys21 GGAKRHRkVLRDNIQ 12776177 t lperfetto "Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals." SIGNOR-262062 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258082 HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 14614508 f "Overexpression of HES-1 fully repressed PPAR-g even in the presence of the ACREB inhibitor, showing that HES-1 acts downstream of CREB" SIGNOR-254743 FFAR4 protein Q5NUL3 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257158 MAPK3 protein P27361 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 t lperfetto "Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling" SIGNOR-200884 Laminin-5 complex SIGNOR-C184 SIGNOR "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "up-regulates activity" binding 2032285 t lperfetto "Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes." SIGNOR-253252 "lysophosphatidylinositol 22:6" smallmolecule CHEBI:138556 ChEBI GPR55 protein Q9Y2T6 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257507 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT "up-regulates activity" phosphorylation Ser347 RSDIESSsDEEDSEP 9606 BTO:0000007 26887952 t miannu "Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. " SIGNOR-273989 DPP10 protein Q8N608 UNIPROT KCND2 protein Q9NZV8 UNIPROT "up-regulates activity" relocalization 9534 BTO:0000298 15454437 t Luisa "Coexpression of DPP10 changes the subcellular localization of Kv4.2 expressed in COS-7 cells by promoting surface trafficking.DPP10 accelerates Kv4.2 inactivation at high and low voltages" SIGNOR-269006 ERG protein P11308 UNIPROT ICAM1 protein P05362 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22235125 f miannu "It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1." SIGNOR-253917 PTPRH protein Q9HD43 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation 10029 BTO:0000246 12907755 t "Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR" SIGNOR-248802 GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt." SIGNOR-252682 ZDHHC2 protein Q9UIJ5 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" palmitoylation Cys5 cIVTTKKY 9606 23836932 t "Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation." SIGNOR-261290 AKT1 protein P31749 UNIPROT XIAP protein P98170 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 BTO:0001023 14645242 t lperfetto "Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin." SIGNOR-119488 CENPE protein Q02224 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 20383333 f lperfetto "Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology" SIGNOR-252013 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 30060484 f miannu "The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization. " SIGNOR-249519 BAZ1B protein Q9UIG0 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Tyr143 ATQASQEy 9606 19092802 t gcesareni "We show that wstf phosphorylates tyr 142 of h2a.x, and that wstf activity has an important role in regulating several events that are critical for the dna damage response" SIGNOR-182831 RACK1 protein P63244 UNIPROT PPP2CA protein P67775 UNIPROT "up-regulates activity" binding 9606 24726876 t miannu "RACK1 Mediates the Formation of the IRF3-RACK1-PP2A Complex and Promotes the Dephosphorylation of IRF3.Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection." SIGNOR-260945 ATP smallmolecule CHEBI:15422 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates "chemical inhibition" 9606 21399626 t lperfetto "Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive" SIGNOR-217481 RFX3 protein P48380 UNIPROT FOXJ1 protein Q92949 UNIPROT "up-regulates activity" binding 9606 BTO:0000939 23822649 t miannu "RFX3 acts as a transcriptional co-activator to FOXJ1 that enhances the expression of cilia-associated genes. FOXJ1 is an important regulator of cilia gene expression during ciliated cell differentiation, with RFX3 as a transcriptional co-activator to FOXJ1, helping to induce the expression of cilia genes in the process of ciliated cell differentiation of basal/progenitor cells." SIGNOR-266929 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CRKL protein P46109 UNIPROT up-regulates phosphorylation Tyr207 IPEPAHAyAQPQTTT 9606 BTO:0001271 9053848 t lperfetto "Tyrosine 207 in crkl is the bcr/abl phosphorylation sitephosphorylation of y207 provides a binding site for the crkl sh2 domain and potentially for other sh2-containing proteins." SIGNOR-46893 haloperidol chemical CHEBI:5613 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258523 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr447 ASSPSRAtRDNPTTS 9606 22820163 t lperfetto "Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1" SIGNOR-198357 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "Analysis of the expression of the fzd receptors during somitogenesis demonstrated that fzd7 is expressed in the hypaxial region of the somite, suggesting an interaction with wnt7a." SIGNOR-198919 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR RAD51 protein Q06609 UNIPROT "up-regulates activity" phosphorylation Tyr315 ETRICKIyDSPCLPE 9606 BTO:0002882 11684015 t lperfetto "RAD51 is one of six mitotic human homologs of the E. coli RecA protein (RAD51-Paralogs) that play a central role in homologous recombination and repair of DNA double-strand breaks (DSBs).|Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance." SIGNOR-271707 PFKFB3 protein Q16875 UNIPROT "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "down-regulates quantity" "chemical modification" -1 9404080 t "A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively." SIGNOR-267271 COPS6 protein Q7L5N1 UNIPROT "COP9 signalosome variant 1" complex SIGNOR-C489 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270768 PTEN protein P60484 UNIPROT NR5A1 protein Q13285 UNIPROT "down-regulates activity" dephosphorylation 9606 27838257 t miannu "The fact that SF-1 and PIP3 is robustly dephosphorylated by PTEN, yet SF-1 and PIP2 is resistant to phosphorylation by p110 PI3-kinases, suggests that nuclear proteins like SF-1 can help decouple PTEN signaling in the nucleus from p110 signaling.|We also showed that PTEN can dephosphorylate the SF-1 and PIP3 product of the IPMK reaction, and that PTEN inhibits SF-1 transcriptional activity." SIGNOR-277117 SMURF1 protein Q9HCE7 UNIPROT SMAD6 protein O43541 UNIPROT "down-regulates activity" relocalization 9606 22298955 t lperfetto "Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm." SIGNOR-105931 MYO1E protein Q12965 UNIPROT "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 10116 BTO:0000142 17257598 f miannu "We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta." SIGNOR-265425 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT "down-regulates activity" phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 t lperfetto "Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase" SIGNOR-275936 "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto "GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)" SIGNOR-263777 PRKCB protein P05771 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275442 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" phosphorylation Ser330 GGLCDLSsRY 9606 12639913 t gcesareni "Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor." SIGNOR-249673 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000189 17251915 t gcesareni "Gastrin-releasing peptide receptors (grpr) are coupled primarily to galfaq, and are highly expressed in many cancers, including small-cell lung cancer" SIGNOR-152679 PTK6 protein Q13882 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10980601 t gcesareni "The phosphorylation of and association with bks by brk was also dependent on the sh2-like domain present within bks.bks is a substrate for the kinase activity of brk and has the characteristics of an adaptor protein." SIGNOR-81489 trans-dec-2-enoyl-CoA smallmolecule CHEBI:10723 ChEBI decanoyl-CoA smallmolecule CHEBI:28493 ChEBI "up-regulates quantity" "precursor of" 9606 18479707 t miannu "The mitochondrial FAS II pathway includes a 2-enoyl thioester reductase (ETR1), also known as MECR. This enzyme (MECR/ETR1, EC 1.3.1.38) catalyzes in the fatty acid elongation cycle in the last step, which is the NADPH-dependent reduction of the Cα–Cβ double bond of the enoyl–ACP substrate molecule (Fig. 1)." SIGNOR-280365 PTGS2 protein P35354 UNIPROT "episterol ester" smallmolecule CHEBI:52393 ChEBI "down-regulates quantity" "chemical modification" 9606 19126760 t miannu "After biosynthesis, 2-AG is partially degraded by postsynaptic COX-2, and partly released to the extracellular space.¬†" SIGNOR-264270 N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide chemical CHEBI:94490 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191277 GSK3B protein P49841 UNIPROT CTPS1 protein P17812 UNIPROT "down-regulates activity" phosphorylation Ser575 SDRSGSSsPDSEITE 9606 BTO:0000007 17681942 t miannu "We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity." SIGNOR-276069 TLN1 protein Q9Y490 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257609 FHIT protein P49789 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 BTO:0000551 16407838 f miannu "Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis" SIGNOR-143700 hsa-miR-374b-5p mirna URS000033F45D_9606 RNAcentral AKT1 protein P31749 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003582 26100275 t Parnian "These data suggest that miR-374b may negatively regulate the expression of Wnt16 and AKT1 by directly targeting the 3'-UTR of their mRNA." SIGNOR-278856 CRP protein P02741 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004602 17942113 f miannu "The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP." SIGNOR-252216 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49D1 protein C9J1S8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271270 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr265 KDCGSQKyAYFNGCS 9606 16916748 t lperfetto "The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites." SIGNOR-148917 JAK2 protein O60674 UNIPROT KDM3A protein Q9Y4C1 UNIPROT "up-regulates activity" phosphorylation Tyr1101 PDLGPKMyNAYGLIT 9606 BTO:0000567 30377265 t miannu "KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2 phosphorylates KDM3A at tyrosine 1101 residue." SIGNOR-277884 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000552 20663147 t gcesareni "DeltaNp63alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation" SIGNOR-167156 PTPN6 protein P29350 UNIPROT STAT6 protein P42226 UNIPROT down-regulates 9606 BTO:0000801 9852037 f gcesareni "Expression of an shp-1 transgene in nih 3t3 cells markedly reduces both il-4-dependent stat6 activation and stat6-mediated transcription of il-4-responsive genes" SIGNOR-62578 VRK2 protein Q86Y07 UNIPROT TRiC complex SIGNOR-C539 SIGNOR "down-regulates quantity by destabilization" binding 9606 BTO:0000007 24298020 t miannu "Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme.The results suggest that VRK2 enables the COP1 complex to efficiently attach ubiquitin on the CCT4 by providing a close interaction between CCT4 and the COP1 complex." SIGNOR-272875 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto "We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2." SIGNOR-235671 AHSA1 protein O95433 UNIPROT HSP90AB1 protein P08238 UNIPROT "up-regulates activity" binding 9606 16696853 t miannu "The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity" SIGNOR-252212 UHRF2 protein Q96PU4 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 21952639 t miannu "We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1." SIGNOR-271885 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX2 protein P48431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000596 24942200 t flangone "During neural fate specification, nuclear translocation of ERK1/2 is critical for its activation of Sox2 transcription. More-over, melatonin-induced Sox2 expression, through ERK1/ 2 activation, could locate between base pairs2719 and 1708 in the mouse Sox2 gene." SIGNOR-241977 GNAS protein P63092 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 t lperfetto "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin." SIGNOR-227988 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203512 MTHFD2 protein P13995 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI "up-regulates quantity" "chemical modification" 9606 16100107 t lperfetto "Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase|One of the enzymes in this pathway, the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC),5 catalyzes the interconversion of 5,10-methylenetetrahydrofolate (methylene-THF) and 10-formyltetrahydrofolate (formyl-THF) in mammalian mitochondria." SIGNOR-268255 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000551 19683496 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-187595 PRKACA protein P17612 UNIPROT ARHGAP17 protein Q68EM7 UNIPROT "down-regulates activity" phosphorylation Ser702 LSAPRRYsSSLSPIQ 9606 BTO:0000132 26507661 t lperfetto "Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex." SIGNOR-272155 BIRC3 protein Q13489 UNIPROT RIPK4 protein P57078 UNIPROT "up-regulates activity" polyubiquitination lys51 9606 BTO:0000007 21931591 t miannu "CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation." SIGNOR-272707 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser195 EKLRRRFsSLHFMVE 9606 15703181 t lperfetto "We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195." SIGNOR-133884 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation" SIGNOR-129312 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5099 DVEFDIKsPKFKAEA 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262763 PRKCA protein P17252 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser498 RPLSRTQsSPLPQSP 10116 BTO:0002320 15367659 t lperfetto "We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E" SIGNOR-249269 WWP1 protein Q9H0M0 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT "up-regulates activity" ubiquitination Lys347 EKAGRIEkLESEIQR 9606 BTO:0000007 34404733 t lperfetto "AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation|Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408." SIGNOR-271873 SNAI1 protein O95863 UNIPROT PLAU protein P00749 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19055748 f lperfetto "We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts." SIGNOR-252263 RPS9 protein P46781 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262415 ATRX protein P46100 UNIPROT ZBED1 protein O96006 UNIPROT "up-regulates activity" binding 7227 BTO:0001138 22021382 t 1 miannu "XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression." SIGNOR-239729 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0000007 16476742 t lperfetto "In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin" SIGNOR-144482 CD3 complex SIGNOR-C432 SIGNOR TCR complex SIGNOR-C153 SIGNOR "form complex" binding 9606 12507424 t miannu "The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3Œ≥Œµ, CD3Œ¥Œµ, and Œ∂Œ∂ signaling modules.the TCRŒ±-CD3Œ¥Œµ and TCRŒ≤-CD3Œ≥Œµ interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled Œ±Œ≤ TCR-CD3 complexes containing the Œ∂-chain strictly required both CD3Œ≥ and Œ¥" SIGNOR-269472 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr439 RLMTGDTyTAHAGAK -1 15735735 t miannu "The results show that Arg is stabilized in response to 0.1 mM H2O2 by autophosphorylation of Y-261, consistent with involvement of the Arg kinase function in regulating Arg levels. The results further demonstrate that c-Abl-mediated phosphorylation of Arg on Y-261 similarly confers Arg stabilization.. These findings indicate that abrogation of the Arg kinase function by the Y261F mutation is dependent on phosphorylation of the Y-439 site.). Our results thus indicate that phosphorylation of Arg on Y-261 plays a dual role in retaining the Arg kinase function and preventing Arg degradation by blocking ubiquitination (Figure 6)." SIGNOR-276032 CREB1 protein P16220 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16205321 f gcesareni "The results showed that the nuclear pkcalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-creb content, dna-binding activity of creb, and bcl-xl expression." SIGNOR-140911 HADHA protein P40939 UNIPROT "Trifunctional enzyme" complex SIGNOR-C564 SIGNOR "form complex" binding 9606 30850536 t miannu "Fatty acid β-oxidation is the major energy-producing process in all tissues and is performed by four consecutive reactions that cleave fatty acids. Mitochondrial trifunctional protein (TFP) performs the last three of these four reactions. TFP is composed of two subunits: the α-subunit contains the first two of the remaining three activities (ECH and HAD), while the β-subunit bears the KT activity (Fig. 1)." SIGNOR-280315 PTPN6 protein P29350 UNIPROT NFAT5 protein O94916 UNIPROT "down-regulates activity" dephosphorylation Tyr143 PKRHTVLyISPPPED 9606 BTO:0000007 20351292 t "We confirmed that SHP-1 is inhibitory by overexpressing it, which reduces TonEBP/OREBP transcriptional activity at 500 mosmol/kg. SHP-1 dephosphorylates TonEBP/OREBP at a known regulatory site, Y143, both in vivo and in vitro. It inhibits TonEBP/OREBP by both reducing TonEBP/OREBP nuclear localization, which is Y143 dependent, and by lowering high NaCl-induced TonEBP/OREBP transactivating activity" SIGNOR-248467 MYH9 protein P35579 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004953 32685004 t miannu "Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo." SIGNOR-269284 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 9606 11741541 t lperfetto "Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna" SIGNOR-112813 OTULIN protein Q96BN8 UNIPROT UBC protein P0CG48 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000567 26235645 t miannu "Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors." SIGNOR-270820 PRKACA protein P17612 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates activity" phosphorylation Ser235 TTQLRLLsEDTDSQR 9606 BTO:0000007 33110360 t miannu "We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence." SIGNOR-277538 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-119225 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 t gcesareni "We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model." SIGNOR-137236 IFNB1 protein P01574 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000711 17564708 f miannu "we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ." SIGNOR-255438 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 t lperfetto "Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3." SIGNOR-263604 CTDSPL protein O15194 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" dephosphorylation Ser811 IYISPLKsPYKISEG 9606 15051889 t "ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms." SIGNOR-248305 BZLF1 protein P03206 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 20381110 t scontino "We have shown that Epstein-Barr virus (EBV) IE protein Zta (BZLF1) physically interacts with IRF7, inhibiting its ability to activate the IFN-α, IFN-β, and Tap2 promoters" SIGNOR-266643 BRLF1 protein P03209 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 20381110 t scontino "EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs." SIGNOR-266645 LMP1 protein P03230 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates activity" sumoylation 9606 BTO:0002181 22951831 t scontino "One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses." SIGNOR-266951 LF2 protein P0C725 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 18987133 t scontino "EBV LF2 tegument protein specifically interacts with the central inhibitory association domain of IRF7, and this interaction leads to inhibition of the dimerization of IRF7, which suppresses IFN-alpha production and IFN-mediated immunity." SIGNOR-266632 GTF2F1 protein P35269 UNIPROT GTF2F1 protein P35269 UNIPROT down-regulates phosphorylation Thr389 RGNSRPGtPSAEGGS 9606 10428810 t gcesareni "We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process." SIGNOR-69771 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 12657630 t "IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376|Thus far, we have no compelling evidence that inducible phosphorylation of these IKKgamma domains is important for their assigned functions." SIGNOR-251287 GATA3 protein P23771 UNIPROT GLS2 protein Q9UI32 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 31577957 t Luana "Thus, GATA3 contributes to the elevated expression of GLS2 in luminal-subtype breast cancers." SIGNOR-268034 "Trifunctional enzyme" complex SIGNOR-C564 SIGNOR (S)-3-hydroxypalmitoyl-CoA smallmolecule CHEBI:27402 ChEBI "down-regulates quantity" "chemical modification" 9606 29551309 t miannu "The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex" SIGNOR-280316 HMGB2 protein P26583 UNIPROT GFI1B protein Q5VTD9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19965638 f miannu "HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter." SIGNOR-254429 ITGB4 protein P16144 UNIPROT PMP22 protein Q01453 UNIPROT "up-regulates activity" binding 10090 16436605 t Regulation miannu "PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types." SIGNOR-251896 EIF4E protein P06730 UNIPROT MTFP1 protein Q9UDX5 UNIPROT "up-regulates activity" "translation regulation" 10090 BTO:0002572 28918902 t Barakat "In this study, we demonstrate that mTORC1 stimulates mitochondrial fission via 4E-BP-mediated translational regulation of the mitochondrial fission factor MTFP1. Suppression of mTORC1 activity by pharmacological or genetic means causes mitochondrial hyperfusion, branching, and circularization. This is a consequence of downregulation of MTFP1 levels via the mTORC1/4E-BP pathway, thereby eliciting changes in phosphorylation and localization of the mitochondrial fission factor DRP1" SIGNOR-275429 "AE/b7 integrin" complex SIGNOR-C186 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257727 "Trifunctional enzyme" complex SIGNOR-C564 SIGNOR NAD(1-) smallmolecule CHEBI:57540 ChEBI "down-regulates quantity" "chemical modification" 9606 29551309 t miannu "The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex" SIGNOR-280317 IHH protein Q14623 UNIPROT PTCH2 protein Q9Y6C5 UNIPROT "down-regulates activity" binding 9606 BTO:0001253 9811851 t lperfetto "Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH." SIGNOR-61314 "COP9 signalosome variant 1" complex SIGNOR-C489 SIGNOR "26S Proteasome" complex SIGNOR-C307 SIGNOR "up-regulates activity" binding 9606 26497135 t miannu "The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin–proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. The evolutionary conserved ubiquitin proteasome pathway (UPP) mediates degradation of intracellular proteins in all eukaryotes. This essential process requires three protein complexes: E3 ubiquitin ligases as e.g., cullin-RING ligases (CRLs), CSN and the 26S proteasome." SIGNOR-270795 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 12773393 t lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-249214 SRC protein P12931 UNIPROT KRAS protein P01116 UNIPROT "up-regulates activity" phosphorylation Tyr64 DTAGQEEySAMRDQY 9606 34725361 t miannu "Src phosphorylation promotes the intrinsic exchange rate of KRAS Q61H.|Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells." SIGNOR-278991 PPP4C protein P60510 UNIPROT HDAC3 protein O15379 UNIPROT "down-regulates activity" dephosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 t "Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c)." SIGNOR-248548 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." SIGNOR-235475 RNF168 protein Q8IYW5 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 31225475 f miannu "L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling." SIGNOR-266789 VPS18 protein Q9P253 UNIPROT "HOPS tethering complex" complex SIGNOR-C549 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273688 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr489 DGPYSNPyENSLIPA 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251354 TYK2 protein P29597 UNIPROT KLF10 protein Q13118 UNIPROT "down-regulates activity" phosphorylation 9606 21471442 t miannu "These data strongly supported that Tyk2 phosphorylates TIEG1.|Tyrosine kinase Tyk2-mediated phosphorylation of TIEG1 at Tyr179 promoted noncanonical K-27-linked polyubiquitination, which inhibited TIEG1 nuclear translocation." SIGNOR-279575 RHOBTB3 protein O94955 UNIPROT CCNE1 protein P24864 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 24145166 t miannu "Here we show that RhoBTB3, a Golgi-associated, Rho-related ATPase, regulates the S/G2 transition of the cell cycle by targeting cyclin E for ubiquitylation. Depletion of RhoBTB3 arrested cells in S phase, triggered Golgi fragmentation, and elevated cyclin E levels. On the Golgi, RhoBTB3 bound cyclin E as part of a Cullin3 (CUL3)-dependent RING-E3 ubiquitin ligase complex comprised of RhoBTB3, CUL3, and RBX1." SIGNOR-272131 BCAR1 protein P56945 UNIPROT EGR1 protein P18146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22431919 f miannu "In MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression." SIGNOR-253892 CDK1 protein P06493 UNIPROT NUP210 protein Q8TEM1 UNIPROT "up-regulates activity" phosphorylation Ser1881 SPPSGLWsPAYASH -1 8672508 t miannu "In vitro phosphorylation of GST fusion protein containing the carboxyl-terminal domain of gp210 by cyclin B-p34cdc2 protein kinase generates a phosphopeptide that comigrates with a mitosis-specific phosphopeptide. Ser1880 Is the Mitotic Phosphorylation Site of Gp210." SIGNOR-262699 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2W protein Q96B02 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271374 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT "up-regulates activity" phosphorylation Ser225 TRRVKTQsESGDVSR -1 27292631 t miannu "We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment." SIGNOR-274060 COP1 protein Q8NHY2 UNIPROT MTA1 protein Q13330 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001938 19805145 t miannu "Here we report that MTA1 is an ubiquitinated protein and targeted by the RING-finger E3 ubiquitin-protein ligase constitutive photomorphogenesis protein 1 (COP1) for degradation via the ubiquitin-proteasome pathway." SIGNOR-271891 AKT proteinfamily SIGNOR-PF24 SIGNOR PDE3B protein Q13370 UNIPROT up-regulates phosphorylation Ser295 VIRPRRRsSCVSLGE 9606 10454575 t esanto "Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b." SIGNOR-70205 LCK protein P06239 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 9606 BTO:0000007 9973379 t "Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218.the role of Y218 in CTLA-4 biology is not known at the present" SIGNOR-251371 AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." SIGNOR-251550 TGFB1 protein P01137 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni "These results indicate that (i) tgf- and klf4 regulate myocd transcription positively and negatively, respectively. When __90% of smad4 was down-regulated myocd mrna induction by tgf- was abolished, suggesting that smad4 plays a critical role in transcriptional activation of the myocd gene" SIGNOR-174396 PTPRG protein P23470 UNIPROT DOK2 protein O60496 UNIPROT "up-regulates activity" dephosphorylation Tyr139 CMEENELySSAVTVG -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254698 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT "up-regulates activity" phosphorylation Ser342 RHEAKQRsVQRWREA -1 21423175 t miannu "In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h)." SIGNOR-276316 LEF1 protein Q9UJU2 UNIPROT PITX2 protein Q99697 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 19850024 f gcesareni "These results suggest that wnt/lef1 signaling regulates epaxial myogenesis via pitx2 but that this link is uncoupled in other regions of the body, emphasizing the unique molecular networks that control the development of various muscles in vertebrates. The pitx2 promoter contains tcf/lef binding sites and expression can be induced by licl, which activates the canonical wnt signaling pathway" SIGNOR-188730 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-249440 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000671 9335553 t lperfetto "These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling." SIGNOR-52700 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BGN protein P21810 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15536164 f miannu "Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG." SIGNOR-254797 AURKA protein O14965 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" phosphorylation Ser405 FDDTGKSsLGDMFSP 9606 BTO:0001938 31028180 t lperfetto "Microtubule nucleation during central spindle assembly requires NEDD1 phosphorylation on serine 405 by Aurora A| In the absence of Aurora A, the HURP (also known as DLGAP5) and NEDD1 proteins that are involved in nucleation of microtubules fail to concentrate in the midzone." SIGNOR-272965 SACM1L protein Q9NTJ5 UNIPROT "phosphatidylinositol 4-phosphate" smallmolecule CHEBI:37530 ChEBI "down-regulates quantity" "chemical modification" 9534 22253445 t lperfetto "To investigate whether kinase activity could account for the different effects of the PI kinases on SARS-CoV S-mediated entry and to test whether PI4P lipids directly regulate viral entry independent of PI4KB, VeroE6 cells were transiently transfected with the SAC1 gene, a PI phosphatase that specifically converts PI4P lipids back to PI (27).|These results indicate that PI4P is indispensable for SARS-CoV S-mediated entry and suggest that PI4KB mediates SARS-CoV S entry by regulating the level of cellular PI4P." SIGNOR-260733 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109547 TNF protein P01375 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18647246 f miannu "NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B." SIGNOR-252409 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates activity" phosphorylation Ser348 PSLQSSLsNPNLQAS 9606 BTO:0000567 16306228 t lperfetto "We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression" SIGNOR-249170 MYC protein P01106 UNIPROT CLK3 protein P49761 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002932 32453420 t done miannu "C-Myc enhances transcriptional activation of CLK3 promoter in CCA cells. " SIGNOR-274123 PTPN1 protein P18031 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates dephosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 8940099 t gcesareni "Ptp1b is able to dephosphorylate phosphorylated-tyr-42 on ikappabalpha" SIGNOR-45004 AGPAT5 protein Q9NUQ2 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI up-regulates "chemical modification" 9606 21173190 t lperfetto "The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬†" SIGNOR-267011 PPM1D protein O15297 UNIPROT MDM4 protein O15151 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser403 DLAHSSEsQETISSM 9606 19808970 t lperfetto "Here, we present evidence that Wip1 specifically dephosphorylates MdmX at Ser403 and indirectly suppresses phosphorylation of MdmX at Ser342 and Ser376.|Thus, Wip1 may need to be inhibited in the early stage of DNA damage response to facilitate rapid MdmX degradation." SIGNOR-276951 FBXL18 protein Q96ME1 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 10090 BTO:0002268 25654763 t miannu "F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18." SIGNOR-272449 MTMR3 protein Q13615 UNIPROT "1-phosphatidyl-1D-myo-inositol 3-phosphate(3-)" smallmolecule CHEBI:58088 ChEBI "down-regulates quantity" "chemical modification" 9606 18429927 t miannu "PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns" SIGNOR-269810 S1PR2 protein O95136 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257007 CTNNA3 protein Q9UI47 UNIPROT JUP protein P14923 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000586 21598020 t miannu "Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14" SIGNOR-265494 carfilzomib chemical CHEBI:65347 ChEBI PSMB9 protein P28065 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000898 17591945 t miannu "Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM." SIGNOR-259311 PRKACA protein P17612 UNIPROT CBX3 protein Q13185 UNIPROT up-regulates phosphorylation Ser93 KDGTKRKsLSDSESD 9606 16531993 t gcesareni "We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation." SIGNOR-145109 AKT1 protein P31749 UNIPROT TBC1D4 protein O60343 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 12637568 t gcesareni "Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt" SIGNOR-252594 MDM2 protein Q00987 UNIPROT ASF1A protein Q9Y294 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 26336826 t miannu "We found that MDM2 overexpression also decreased the ASF1A half-life time, indicating an accelerated ASF1A degradation.|We next examined whether the presence of RAD6 is essential for MDM2-induced ASF1A ubiquitination." SIGNOR-278822 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT down-regulates phosphorylation Ser1406 GAGGRRLsSFVTKGY 9606 17206380 t gcesareni "Protein kinase a phosphorylation at thr456 of the multifunctional protein cad antagonizes activation by the map kinase cascade." SIGNOR-151816 cabozantinib chemical CHEBI:72317 ChEBI AXL protein P30530 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000184 26536165 t miannu "Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3." SIGNOR-262241 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR FBXO28 protein Q9NVF7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 31678254 t miannu "Here we report that FBXO28, a poorly characterized F-box protein, is a novel substrate of SCF E3 ligase. Pharmaceutical or genetic inhibition of neddylation pathway that is required for the activation of SCF stabilizes FBXO28 and prolongs its half-life. Meanwhile, FBXO28 is subjected to ubiquitination and cullin1-based SCF complex promotes FBXO28 degradation. CUL1, but not other cullin family members, promotes FBXO28 degradation" SIGNOR-272217 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser511 RREERSLsAPGNLLT 9606 22778263 t lperfetto "Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity" SIGNOR-198154 YAP1 protein P46937 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni "Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis." SIGNOR-199214 FRS2 protein Q8WU20 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates phosphorylation 9606 9632781 t gcesareni "In addition to the direct interactions with grb2, tyrosine-phosphorylated frs2 forms a complex with the sh2 domain-containing protein tyrosine phosphatase shp2. This interaction results in tyrosine phosphorylation of shp2 and complex formation between shp2 and grb2. the catalytic activity of shp2 is essential for a sustained map kinase response and for potentiation of fgf-induced neurite outgrowth in pc12 cells" SIGNOR-58196 PSMC2 protein P35998 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263374 RET protein P07949 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 27994058 t miannu "In detail, RET and PTC3 induced STAT1 overexpression and phosphorylation at Ser 727 and Tyr 701." SIGNOR-279276 OS9 protein Q13438 UNIPROT TRPV4 protein Q9HBA0 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 17932042 t miannu "Here we report that OS-9, a ubiquitously expressed endoplasmic reticulum (ER)-associated protein, interacts with the cytosolic N-terminal tail of TRPV4.Thus, OS-9 regulates the secretory transport of TRPV4 and appears to protect TRPV4 subunits from the precocious ubiquitination and ER-associated degradation. Our data suggest that OS-9 functions as an auxiliary protein for TRPV4 maturation." SIGNOR-261064 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser240 SDQQLNQsMDTGSPA 9606 SIGNOR-C8 11027280 t gcesareni "Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions." SIGNOR-82970 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19029990 f lperfetto "STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others." SIGNOR-249498 APEX1 protein P27695 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "An essential role of BER has been documented by inactivating functions of proteins in the common steps of BER. Thus, the major AP-endonuclease in mammalian cells, APE1, is essential for survival, as shown using knockout mice (Friedberg and Meira 2006). APE1 (also called HAP1 and Apex) carries both an AP-endonuclease activity and a redox function required for activation of several transcription factors" SIGNOR-275721 "Sanglifehrin A" chemical CID:5388925 PUBCHEM IMPDH2 protein P12268 UNIPROT "down-regulates activity" "chemical inhibition" 9606 28076787 t Monia "We show that the mammalian target of SFA is inosine-50 -monophosphate dehydrogenase 2 (IMPDH2); Biochemical characterization reveals that PPIA-SFA does not inhibit the catalytic activity of IMPDH2 but rather, it modulates cell growth via binding to the cystathionine-b-synthase (CBS) domain." SIGNOR-261099 AKT1 protein P31749 UNIPROT BCL3 protein P20749 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser41 KRPLRAPsPEPAAPR -1 28689659 t miannu "Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. " SIGNOR-277358 PGK2 protein P07205 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266506 N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide chemical CHEBI:94490 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191280 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161557 CUDC-101 chemical CID:24756910 PUBCHEM HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20143778 t miannu "By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively." SIGNOR-262258 ACSM3 protein Q53FZ2 UNIPROT butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI "up-regulates quantity" "chemical modification" 9606 40953271 t miannu "Acyl-CoA synthetase medium-chain family member 3 (ACSM3) mainly accounts for catalyzing the MCFAs to produce the corresponding acyl-CoA, which is crucial for FAO" SIGNOR-280411 HTR2B protein P41595 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256886 CSNK2A1 protein P68400 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser81 TQDQQSLsDVEGAYS -1 7983041 t llicata "Although human PR contains 11 potential CKII consensus sequences, CKII in vitro phosphorylated purified PR-B only at Ser81 suggesting that this may be an authentic site for CKII in vivo." SIGNOR-250926 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT "down-regulates activity" 9606 BTO:0000801 10973958 f lperfetto "NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters." SIGNOR-249557 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI AURKA protein O14965 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258232 PRKD1 protein Q15139 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates quantity" phosphorylation Ser324 LTSVSRGsSLKILSK 9606 27127886 t miannu "Inhibition of PKD activity restores membrane expression of CXCR4 and migration towards CXCL12 in BCR responsive cells in vitro.|This cascade consisted on a novel BCR dependent pathway in which PI3K-delta phosphorylates PKD, which in turn phosphorylates CXCR4 at Ser 324/325." SIGNOR-279264 STAT6 protein P42226 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20508200 f lperfetto "Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation." SIGNOR-249538 ZNRF3 protein Q9ULT6 UNIPROT FZD8 protein Q9H461 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 22575959 t "Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6." SIGNOR-260111 ILF2 protein Q12905 UNIPROT NF90-NF45 complex SIGNOR-C443 SIGNOR "form complex" binding -1 18458058 t miannu "Nuclear factor 90 (NF90) and its C-terminally extended isoform, NF110, have been isolated as DNA- and RNA-binding proteins together with the less-studied protein NF45. These complexes have been implicated in gene regulation, but little is known about their cellular roles and whether they are redundant or functionally distinct. We show that heterodimeric core complexes, NF90-NF45 and NF110-NF45, exist within larger complexes that are more labile and contain multiple NF90/110 isoforms and additional proteins. This study identified NF45 as an unstable regulatory subunit of NF90-NF45 complexes and uncovered their critical role in normal cell division. Furthermore, the study revealed that NF90 is functionally distinct from NF110 and is more important for cell growth." SIGNOR-268487 MDM2 protein Q00987 UNIPROT PBXIP1 protein Q96AQ6 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000093 24488098 t miannu ". Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. " SIGNOR-272850 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR MLXIPL protein Q9NP71 UNIPROT "down-regulates activity" relocalization 10116 26984404 t "AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions" SIGNOR-255667 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129260 butyrate smallmolecule CHEBI:17968 ChEBI butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI "up-regulates quantity" "precursor of" 9606 40953271 t miannu "Acyl-CoA synthetase medium-chain family member 3 (ACSM3) mainly accounts for catalyzing the MCFAs to produce the corresponding acyl-CoA, which is crucial for FAO" SIGNOR-280413 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto "Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo." SIGNOR-101115 USP4 protein Q13107 UNIPROT BRAP protein Q7Z569 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 23105109 t miannu "Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15." SIGNOR-272031 MYC protein P01106 UNIPROT HLA-G protein P17693 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 8206526 f miannu "In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene." SIGNOR-254607 KLHL12 protein Q53G59 UNIPROT SEC31A protein O94979 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 22358839 t miannu "By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division." SIGNOR-272010 HIF3A protein Q9Y2N7 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000972 21479871 t Luana "None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2. " SIGNOR-261615 CAD protein P27708 UNIPROT "Pyrimidine biosynthesis" phenotype SIGNOR-PH187 SIGNOR "up-regulates activity" 9606 15096496 f "The CPSase activity of CAD is the major locus of control of de novo pyrimidine biosynthesis" SIGNOR-267196 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser153 SWTRVFQsWWDRNLG 9606 BTO:0000007 10837486 t lperfetto "We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites." SIGNOR-252767 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser639 PDVPRLGsTFSLDTS 9606 BTO:0000782 11024037 t lperfetto "However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. " SIGNOR-249056 Ub:E2 complex SIGNOR-C497 SIGNOR RNF170 protein Q96K19 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271214 PRKACA protein P17612 UNIPROT NF2 protein P35240 UNIPROT up-regulates phosphorylation Ser10 GAIASRMsFSSLKRK 9606 18071304 t lperfetto "Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth," SIGNOR-159840 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" SIGNOR-183612 ASXL3 protein Q9C0F0 UNIPROT THRB protein P10828 UNIPROT "down-regulates activity" binding 9606 BTO:0000972 25450400 t miannu "We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRα and TRβ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRα target genes through its recruitment to the LXR-response elements." SIGNOR-266766 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates activity" phosphorylation Ser128 QHVRAHSsPASLQLG -1 29967145 t miannu "CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro." SIGNOR-277649 TESK2 protein Q96S53 UNIPROT DSTN protein P60981 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVQVADE 9606 BTO:0001363 11418599 t lperfetto "The present study provides evidence that TESK2 can phosphorylate cofilin and ADF specifically at Ser-3. Since actin-depolymerizing and -severing activities of cofilin/ADF are abrogated by phosphorylation at Ser-3, TESK2 seems to play an important role in actin filament dynamics by inhibiting cofilin/ADF activity." SIGNOR-246707 taurine smallmolecule CHEBI:15891 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000007 9009272 t "inferred from family member" miannu "For each mutant GlyR we examined the agonist efficacies of taurine and Œ≤-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where Œ≤-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human Œ±1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and Œ≤-alanine act as full agonists of human Œ±1 GlyRs when expressed in this system." SIGNOR-270259 BIRC2 protein Q13490 UNIPROT CFLAR protein O15519 UNIPROT "down-regulates quantity" ubiquitination 9606 22345097 t miannu "Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability.|Thus, we conclude that API-1 reduces c-FLIP levels by facilitating its degradation through the ubiquitin and proteasome dependent pathway." SIGNOR-278687 ACADS protein P16219 UNIPROT butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI "down-regulates quantity" "chemical modification" 9606 11134486 t miannu "Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids " SIGNOR-280414 ACADS protein P16219 UNIPROT FAD(3-) chemical CHEBI:57692 ChEBI "down-regulates quantity" "chemical modification" 9606 11134486 t miannu "Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids " SIGNOR-280415 GRK6 protein P43250 UNIPROT GRK6 protein P43250 UNIPROT unknown phosphorylation Thr485 LDIEQFStVKGVELE 9534 BTO:0000298 10334944 t "GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established." SIGNOR-251212 GRIA1 protein P42261 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 f miannu "In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses" SIGNOR-264615 CLASP2 protein O75122 UNIPROT MAPRE1 protein Q15691 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 19638411 t lperfetto "GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells" SIGNOR-264829 BBS4 protein Q96RK4 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262560 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254717 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT "up-regulates activity" phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 BTO:0002181 23429703 t miannu "CAD as a direct substrate of S6K1. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. The direct regulation of CAD by S6K1 serves as a mechanism to increase the pool of nucleotides available for the RNA and DNA synthesis that accompanies cell growth." SIGNOR-267443 ACADS protein P16219 UNIPROT crotonoyl-CoA(4-) smallmolecule CHEBI:57332 ChEBI "up-regulates quantity" "chemical modification" 9606 11134486 t miannu "Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids " SIGNOR-280416 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser34 SRSYVTTsTRTYSLG -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248880 CYP11B1 protein P15538 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000048 33117906 t lperfetto "The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone" SIGNOR-268682 Ub:E2 complex SIGNOR-C497 SIGNOR menB protein P23966 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270976 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 17828307 t gcesareni "Fak y397 phosphorylation promotes src sh2 domain binding to fak, presumably leading to conformational src activation with a fak-src complex." SIGNOR-157763 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation" SIGNOR-252351 HCK protein P08631 UNIPROT CSF3R protein Q99062 UNIPROT "up-regulates activity" phosphorylation Tyr787 LTPSPKSyENLWFQA -1 9790917 t "Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. the ability of Hck to phosphorylate the G-CSF-R in vitro, both Y728 and Y763 fit the Src consensus phosphorylation site. we investigated the activation of Hck by the G-CSF-R in intact cells as well as in vitro. These studies revealed recruitment of Hck to activated G-CSF-R, mediated by direct binding via its SH2 domain to multiple phosphotyrosines of the receptor. In addition, we show that Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling." SIGNOR-251264 ACADS protein P16219 UNIPROT FADH2(2-) smallmolecule CHEBI:58307 ChEBI "up-regulates quantity" "chemical modification" 9606 11134486 t miannu "Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids " SIGNOR-280417 butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI crotonoyl-CoA(4-) smallmolecule CHEBI:57332 ChEBI "up-regulates quantity" "precursor of" 9606 11134486 t miannu "Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids " SIGNOR-280418 ECHS1 protein P30084 UNIPROT crotonoyl-CoA(4-) smallmolecule CHEBI:57332 ChEBI "down-regulates quantity" "chemical modification" 9606 40804397 t miannu "The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability." SIGNOR-280419 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser287 EPLSPVSsLQASVPG 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-250728 UNG protein P13051 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 27875297 f lperfetto "Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents. " SIGNOR-264889 MAP4K5 protein Q9Y4K4 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates 9606 9405407 f gcesareni "Here we report the identification of a tnf-responsive serine/threonine protein kinase termed gck related (gckr) that likely signals via mitogen-activated protein kinase (mapk)/extracellular signal-regulated kinase (erk) kinase kinase 1 (mekk1) to activate the sapk pathway." SIGNOR-53779 "KATP channel" complex SIGNOR-C274 SIGNOR potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 9606 28842488 t lperfetto "ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits." SIGNOR-262053 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Tyr204 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 t "Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2" SIGNOR-248535 IGF1R protein P08069 UNIPROT IRS4 protein O14654 UNIPROT up-regulates phosphorylation 9606 9553137 t gcesareni "Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4." SIGNOR-56604 JAK3 protein P52333 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Tyr64 VDTSQVLyEWEQGFS 9606 28821617 t miannu "Jak3 phosphorylates Tyr 30, Tyr 64, and Tyr 86 of beta-catenin in intestinal epithelial cells." SIGNOR-278179 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto "P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-124851 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser8 MPKRKVSsAEGAAKE 9606 10739259 t gcesareni "Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at ser24 and ser28 in hmg-17, and ser20 and ser24 in hmg-14 a third phosphorylation site in hmg-14 was located at either ser6 or ser7phosphorylation of ser6 and ser7 may compromise the binding of hmgn1 protein to the binding domain of importin proteins, which in turn affects the nuclear transport and sub-cellular localization of hmgn1 protein. Protein kinase ck2 could potentially be an enzyme that regulates this process." SIGNOR-76270 SFRP1 protein Q8N474 UNIPROT WNT4 protein P56705 UNIPROT down-regulates binding 9606 BTO:0000671 11287180 t gcesareni "Sfrp-1 binds wnt-4 with considerable avidity and inhibits the dna-binding activity of tcf, an effector of wnt signaling," SIGNOR-106556 SLC8B1 protein Q6J4K2 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 23056385 t lperfetto "This study focuses on NCLX, the recently discovered mitochondrial Na(+)/Ca(2+) exchanger that is linked to Ca(2+) signalling in MIN6 and primary β cells. Suppression either of NCLX expression, using a siRNA construct (siNCLX) or of its activity, by a dominant negative construct (dnNCLX), enhanced mitochondrial Ca(2+) influx and blocked efflux induced by glucose or by cell depolarization." SIGNOR-275732 SEC23IP protein Q9Y6Y8 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "down-regulates quantity" "chemical modification" 9606 22922100 t miannu "Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain." SIGNOR-269651 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 t llicata "These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport." SIGNOR-188123 AKT1 protein P31749 UNIPROT LARP1 protein Q6PKG0 UNIPROT "down-regulates activity" phosphorylation Ser1056 EGRKRCPsQSSSRPA 9606 BTO:0002181 28650797 t SARA "LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation." SIGNOR-260992 FGF14 protein Q92915 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253441 SRC protein P12931 UNIPROT TRIM25 protein Q14258 UNIPROT "up-regulates activity" phosphorylation Tyr278 NSKFDTIyQILLKKK 9606 BTO:0002181 30100205 t miannu "Here, we demonstrated that TRIM25 interacted with c-Src and underwent tyrosine phosphorylation by c-Src kinase upon viral infection and the phosphorylation is required for the complete activation of RIG-I signaling. Analysis using a c-Src inhibitor and TRIM25 mutant, in which tyrosine 278 is substituted by phenylalanine (Y278F), suggested that the phosphorylation positively regulates K63-linked polyubiquitination of RIG-I and subsequent antiviral signaling. " SIGNOR-277405 PLK1 protein P53350 UNIPROT TPT1 protein P13693 UNIPROT down-regulates phosphorylation Ser64 PEGEGTEsTVITGVD 9606 12167714 t lperfetto "Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase" SIGNOR-91348 CD79B protein P40259 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR "form complex" binding 9606 BTO:0000776 32323266 t scontino "BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition." SIGNOR-268197 PTK2 protein Q05397 UNIPROT CTNNB1 protein P35222 UNIPROT unknown phosphorylation Tyr142 AVVNLINyQDDAELA 10090 22264731 t "VEGF pathway" Gianni "VEGF promotes tension-independent FAK activation, rapid FAK localization to cell-cell junctions, binding of the FAK FERM domain to the vascular endothelial cadherin (VE-cadherin) cytoplasmic tail, and direct FAK phosphorylation of β-catenin at tyrosine-142 (Y142) facilitating VE-cadherin-β-catenin dissociation and EC junctional breakdown." SIGNOR-261946 DPP3 protein Q9NY33 UNIPROT KEAP1 protein Q14145 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 35278345 t miannu "The influence of DPP3 on the Keap1-Nrf2/ARE signal pathway suggest a direct involvement of DPP3 in the oxidative stress response [8,14,31,53,99,100]. It was shown that DPP3 competes with Nrf2 through the ETGE motif to bind to Keap1 and consequently enhances the translocation of Nrf2 to the nucleus, thereby driving the expression of an array of genes encoding antioxidative enzymes [99]. More specifically, binding of DPP3 to Keap1 releases Nrf2, and thus, prevents its degradation through the 26S proteasome" SIGNOR-268464 CDK2 protein P24941 UNIPROT MAP3K11 protein Q16584 UNIPROT "up-regulates activity" phosphorylation Ser770 LISRPRPsPLRSRID -1 35843311 t miannu "Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases." SIGNOR-277604 Ub:E2 complex SIGNOR-C497 SIGNOR AREL1 protein O15033 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271286 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT "up-regulates activity" phosphorylation Tyr662 PGDSNPIySQIWSIQ -1 12051764 t miannu "Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2." SIGNOR-274010 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270383 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser31 DLQEVLSsDENGGTY 9606 BTO:0000567 12876286 t llicata "CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites" SIGNOR-250853 FYN protein P06241 UNIPROT DCC protein P43146 UNIPROT "up-regulates activity" phosphorylation Tyr1261 PTLESAQyPGILPSP 10090 BTO:0001909 15557120 t miannu "Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo." SIGNOR-268175 PRKCA protein P17252 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 BTO:0000007 11085981 t lperfetto "In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism." SIGNOR-249062 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM4 protein P08173 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258633 ROCK1 protein Q13464 UNIPROT DAPK3 protein O43293 UNIPROT "up-regulates activity" phosphorylation 9606 25723491 t miannu "ROCK1 phosphorylates and activates ZIPK suggesting that at least some of these physiological functions may require both enzymes." SIGNOR-279102 SH3BP1 protein Q9Y3L3 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260514 SATB2 protein Q9UPW6 UNIPROT IGHM protein P01871 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 14701874 t gianni "The SATB2 protein was shown to bind MAR sequences flanking the enhancer of the endogenous immunoglobulin μ heavy chain (IgH) gene in vivo, and this binding was found to correlate with an increase in the expression of a transfected rearranged μ wild-type gene" SIGNOR-268933 TOMM70 protein O94826 UNIPROT HSP90AA1 protein P07900 UNIPROT "up-regulates activity" binding 9534 12526792 t miannu "The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting." SIGNOR-261379 CASP3 protein P42574 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 t amattioni "Caspase-3 is required for the activation of caspases 6" SIGNOR-64179 TACR2 protein P21452 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257131 STAT5A protein P42229 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 f miannu "The alternative survival and proliferation pathway triggered by higher concentrations of GM-CSF is dependent on the dodecamer assembly and involves the Jak/STAT, Ras/mitogen-activated protein kinase, and PI-3 kinase pathways" SIGNOR-255578 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 t lperfetto "The SH3 domains of c-Abl and Arg bound directly to catalase at a P293FNP site. c-Abl and Arg phosphorylated catalase at Tyr231 and Tyr386 in vitro and in the response of cells to H2O2" SIGNOR-101298 PRKDC protein P78527 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser446 STMQVSHsQVQEPGG -1 8407951 t lperfetto " The carboxyl-terminal transcription activation domain was mapped within a 71-amino acid region that contains both DNA-PK phosphorylation sites. Amino acid substitutions that interfered with phosphorylation by DNA-PK at Ser-435/446 in GAL4-SRF fusion proteins were reduced in transactivation potency. From these data we suggest that DNA-PK phosphorylation may modulate SRF activity in vivo." SIGNOR-248922 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR ROCK1 protein Q13464 UNIPROT up-regulates cleavage 9606 11283607 t gcesareni "Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity." SIGNOR-256460 CSNK1D protein P48730 UNIPROT PRH1 protein P02810 UNIPROT up-regulates phosphorylation Ser24 QDLDEDVsQEDVPLV 9606 BTO:0000007 BTO:0000671 10684652 t lperfetto "Ser22 may be phosphorylated by a g-ck that recognizes an atypical substrate sequence or by a novel kinase. While prp1 secreted from salivary glands is fully phosphorylated at ser8 and 22" SIGNOR-75272 phenylalanine smallmolecule CHEBI:28044 ChEBI tyrosine smallmolecule CHEBI:18186 ChEBI "up-regulates quantity" "precursor of" 9606 NBK536726 t brain lperfetto "L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors" SIGNOR-264172 "1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester" chemical CHEBI:92418 ChEBI CHRM4 protein P08173 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258634 CALM1 protein P0DP23 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t gcesareni "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-114104 "1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate" smallmolecule CHEBI:18348 ChEBI "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI "up-regulates quantity" "precursor of" 9606 23000145 t scontino "Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)." SIGNOR-268450 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248295 TFAP2A protein P05549 UNIPROT SULT1E1 protein P49888 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17187826 f miannu "Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16." SIGNOR-255397 PDGFRB protein P09619 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 BTO:0002057 15489898 t gcesareni "The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells." SIGNOR-247979 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000304 30519351 t miannu "The results showed that TNC induced the cytoplasmic translocation of pFOXO1 via regulation of AKT activation. As shown in Fig. 3C, stimulation of PANC-1 cells with exogenous TNC markedly increased the phosphorylation of AKT and FOXO1. Our study showed that pFOXO1 translocates from the nucleus to the cell cytoplasm after exogenous TNC treatment, which indicates that its transcriptional activity was inhibited." SIGNOR-277740 GTF2E2 protein P29084 UNIPROT TFIIE complex SIGNOR-C458 SIGNOR "form complex" binding 9606 31064989 t lperfetto "The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur." SIGNOR-269361 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Ser88 RPSDEDSsSLESAAS -1 12852856 t lperfetto "Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction" SIGNOR-103356 ALPL protein P05186 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" dephosphorylation 9606 24646911 t miannu "TNAP dephosphorylates overphosphorylated tau once it is released upon neuronal death." SIGNOR-277097 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser29 VSHWQQQsYLDSGIH 9606 BTO:0000007 12432063 t llicata "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin" SIGNOR-250846 ECHS1 protein P30084 UNIPROT water smallmolecule CHEBI:15377 ChEBI "down-regulates quantity" "chemical modification" 9606 40804397 t miannu "The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability." SIGNOR-280420 GMIP protein Q9P107 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260505 MAPK1 protein P28482 UNIPROT IRX2 protein Q9BZI1 UNIPROT "up-regulates activity" phosphorylation Ser64 QAATGFGsPLQYSAD -1 15133517 t miannu "We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation." SIGNOR-263053 PFK proteinfamily SIGNOR-PF79 SIGNOR "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "down-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266470 JAK2 protein O60674 UNIPROT TET2 protein Q6N021 UNIPROT "up-regulates activity" phosphorylation Tyr1964 HETSEPTyLRFIKSL -1 30944118 t miannu "Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin. " SIGNOR-277289 CIB2 protein O75838 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" binding 10090 34162842 t miannu "Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to 'nucleotide empty' or inactive GDP-loaded Rheb. " SIGNOR-269663 Ub:E2 complex SIGNOR-C497 SIGNOR ZNRF4 protein Q8WWF5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271206 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr352 TEVYESPyADPEEIR 9606 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246613 ECHS1 protein P30084 UNIPROT (S)-3-hydroxybutanoyl-CoA smallmolecule CHEBI:15453 ChEBI "up-regulates quantity" "chemical modification" 9606 40804397 t miannu "The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability." SIGNOR-280421 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr2511 VPEHPFLtPSPESPD -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273167 LMX1A protein Q8TE12 UNIPROT CUX2 protein O14529 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 30770393 t miannu "Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem" SIGNOR-263961 MAPKAPK2 protein P49137 UNIPROT LSP1 protein P33241 UNIPROT unknown phosphorylation Ser252 PKLARQAsIELPSMA -1 8995217 t miannu "LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. . Inspection of the human LSP1 protein sequence (22) identifies two serine residues at positions 204 and 252 as potential phosphorylation sites. The results show that LSP1 is a substrate for MAPKAP kinase 2 in vitro and that the phosphorylation site(s) are located in the C-terminal 152 amino acid residues, as predicted from the sequence." SIGNOR-250148 GNAI1 protein P63096 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "down-regulates activity" binding 9606 15922020 t miannu "Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated." SIGNOR-267853 ERG protein P11308 UNIPROT WNT11 protein O96014 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21242973 f miannu "ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts." SIGNOR-254071 CSNK2A1 protein P68400 UNIPROT KIR3DL1 protein P43629 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser388 RTANSEDsDEQDPEE -1 17911614 t miannu "Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far." SIGNOR-276078 MAP2K6 protein P52564 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation 9606 8974401 t gcesareni "A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)" SIGNOR-45369 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1717 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248775 crotonoyl-CoA(4-) smallmolecule CHEBI:57332 ChEBI (S)-3-hydroxybutanoyl-CoA smallmolecule CHEBI:15453 ChEBI "up-regulates quantity" "precursor of" 9606 40804397 t miannu "The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability." SIGNOR-280422 HADH protein Q16836 UNIPROT acetoacetyl-CoA(4-) smallmolecule CHEBI:57286 ChEBI "up-regulates quantity" "chemical modification" 9606 16176262 t miannu "3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs." SIGNOR-280424 ACSM3 protein Q53FZ2 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 40953271 t miannu "Acyl-CoA synthetase medium-chain family member 3 (ACSM3) mainly accounts for catalyzing the MCFAs to produce the corresponding acyl-CoA, which is crucial for FAO" SIGNOR-280412 PEX2 protein P28328 UNIPROT UBE2D2 protein P62837 UNIPROT "up-regulates activity" binding -1 19687296 t miannu "Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle." SIGNOR-253025 "4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid" chemical CHEBI:64210 ChEBI RARB protein P10826 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 19058965 t Luana "Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. " SIGNOR-258035 GDC-0879 chemical CHEBI:83405 ChEBI BRAF protein P15056 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192592 PRKACA protein P17612 UNIPROT ALOX5 protein P09917 UNIPROT "down-regulates activity" phosphorylation Ser524 GMRGRKSsGFPKSVK -1 15280375 t lperfetto "These results indicate that PKA phosphorylates 5-LO on Ser-523, which inhibits the catalytic activity of 5-LO and reduces cellular LT generation." SIGNOR-264410 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 t gcesareni "Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1." SIGNOR-111507 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Ser20 KRPQRATsNVFAMFD 9606 8702756 t miannu "Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase." SIGNOR-261719 BTRC protein Q9Y297 UNIPROT PER1 protein O15534 UNIPROT down-regulates ubiquitination 9606 15917223 t miannu "We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1" SIGNOR-137755 CDK1 protein P06493 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Thr487 APAEDVDtPPRKKKR 9606 21659531 t lperfetto "Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome" SIGNOR-174058 PLK1 protein P53350 UNIPROT ATXN10 protein Q9UBB4 UNIPROT down-regulates phosphorylation Ser77 QVENLASsLQLITEC 9606 21857149 t lperfetto "Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis" SIGNOR-176122 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser527 RFRKRTHsAGTSPTI 10090 BTO:0002572 18498745 t lperfetto "In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8" SIGNOR-236595 FZD3 protein Q9NPG1 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 17251915 t gcesareni "In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor." SIGNOR-152603 idarubicin chemical CHEBI:42068 ChEBI TOP2B protein Q02880 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20824055 t miannu "Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells." SIGNOR-259328 (S)-3-hydroxybutanoyl-CoA smallmolecule CHEBI:15453 ChEBI acetoacetyl-CoA(4-) smallmolecule CHEBI:57286 ChEBI "up-regulates quantity" "precursor of" 9606 16176262 t miannu "3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs." SIGNOR-280425 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269173 clofarabine chemical CHEBI:681569 ChEBI PRIM2 protein P49643 UNIPROT "down-regulates activity" "chemical inhibition" 9606 1707752 t miannu "Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase." SIGNOR-258360 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR IL18 protein Q14116 UNIPROT "up-regulates activity" cleavage Asp71 PLFEDMTdSDCRDNA 9606 BTO:0001370 9334240 t lperfetto "We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products." SIGNOR-256378 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Tyr350 RRSSLKAyGNGYSSN 10029 BTO:0000246 8557631 t "Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors." SIGNOR-251301 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 19153083 t gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-183484 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser80 PPNPEDRsPSPEPIY 9606 23175611 t "The effect has been demonstrated using Q15637-2" gcesareni "Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding." SIGNOR-199793 hsa-miR-610 mirna URS00004DC583_9606 RNAcentral TBL1X protein O60907 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0005814 25491321 t Parnian "Results indicate that miR-610 negatively regulated these proteins via directly binding to their 3’UTRs. These data further confirm that miR-610 suppresses HCC cell tumorigenicity by inhibiting the activity of β-catenin via targeting LRP6 and TBL1X." SIGNOR-278840 PRKAA2 protein P54646 UNIPROT PROX1 protein Q92786 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser79 KLLKRANsYEDAMMP 9606 BTO:0002181 36433955 t miannu "Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation." SIGNOR-277608 Hypoxia stimulus SIGNOR-ST25 SIGNOR hsa-miR-181a-5p mirna URS00003DA300_9606 RNAcentral up-regulates "post transcriptional regulation" 9606 BTO:0000250 26013170 f Parnian "We have identified miR-181a as a potential oncomiR that is upregulated by hypoxia in chondrosarcoma." SIGNOR-278844 HIC1 protein Q14526 UNIPROT ACKR3 protein P25106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23340301 f miannu "we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression." SIGNOR-254238 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 11731619 t gcesareni "In intact hc11 cells, ptp-pest was constitutively associated with jak2, and in response to egf treatment there was an increased level of ptp-pest in jak2 complexes. An in vitro phosphatase assay, using prl-activated jak2 as the substrate and lysates from hc11 cells as the source of ptp-pest, revealed that jak2 could serve as a ptp-pest substrate." SIGNOR-112383 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser222 EEQDRPRsPTGPSNS 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262707 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 20551172 t miannu "We characterize a new Myc-interacting factor, TRPC4AP (transient receptor potential cation channel, subfamily C, member 4-associated protein)/TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein), which is the receptor for a DDB1 (damage-specific DNA-binding protein 1)-CUL4 (Cullin 4) E3 ligase complex for selective Myc degradation through the proteasome. TRPC4AP/TRUSS binds specifically to the Myc C terminus and promotes its ubiquitination and destruction through the recognition of evolutionarily conserved domains in the Myc N terminus. " SIGNOR-271965 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1087 HGHVSNAsISLGESV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262901 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT "down-regulates activity" phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 BTO:0000007 8955135 t "Mutagenesis of BCR Tyr-177 to Phe completely abolished FES-induced BCR binding to the GRB2 SH2 domain, identifying Tyr-177 as an additional phosphorylation site for FES. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1." SIGNOR-251136 SF1 protein Q15637 UNIPROT LHB protein P01229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004467 19106114 f miannu "The human LHB promoter also contains low and high affinity SF1 binding sites. Mutation of these elements or depletion of endogenous SF1 impaired basal and ligand-induced transcription." SIGNOR-254915 PRKD3 protein O94806 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" phosphorylation Ser155 FPLRKTVsEPNLKLR 18692497 t "Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7" lperfetto "Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]." SIGNOR-275932 PBX2 protein P40425 UNIPROT EMX2 protein Q04743 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15494461 f miannu "EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation." SIGNOR-254466 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Ser143 FHPNVSSsHENLEPE 9606 22609948 t lperfetto "We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle" SIGNOR-197063 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t "Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism" SIGNOR-252056 "Complement C1 complex" complex SIGNOR-C309 SIGNOR C4B protein P0C0L5 UNIPROT "up-regulates activity" cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263427 P2RY2 protein P41231 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256759 ASPA protein P45381 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "up-regulates quantity" "chemical modification" 9606 17194761 t miannu "N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain." SIGNOR-267528 hsa-miR-22-5p mirna URS0000142DC3_9606 RNAcentral WNT1 protein P04628 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004953 23851184 t Parnian "MiR-200b and miR-22 directly targeted Wnt-1 gene and synergistically inhibited Wnt signaling pathway. The miR-200b and miR-22 have putative binding sites in the 3' UTRs of Wnt1." SIGNOR-278848 hsa-miR-200b-5p mirna URS000012A1DD_9606 RNAcentral WNT1 protein P04628 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004953 23851184 t Parnian "MiR-200b and miR-22 directly targeted Wnt-1 gene and synergistically inhibited Wnt signaling pathway. The miR-200b and miR-22 have putative binding sites in the 3' UTRs of Wnt1." SIGNOR-278849 MECOM protein Q03112 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 9665135 t miannu "Evi-1 interacts with smad3, an intracellular mediator of tgf-beta signalling, thereby suppressing the transcriptional activity of smad3." SIGNOR-59132 PAK2 protein Q13177 UNIPROT MYC protein P01106 UNIPROT "down-regulates activity" phosphorylation Thr400 T-->E 9606 14749374 t miannu "Here we demonstrate that Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo." SIGNOR-278490 JAK3 protein P52333 UNIPROT EZH2 protein Q15910 UNIPROT "up-regulates activity" phosphorylation Tyr244 AEELKEKyKELTEQQ 9606 28868240 t miannu "These results demonstrate that phosphorylation of EZH2 by JAK3 on the Y244 increases the interaction with Polymerase II and decreases the association with PRC2 components promoting the expression of non-canonical genes.|To explore the mechanism of JAK3 mediated EZH2 activation, the authors performed co-immunoprecipitation assays, which revealed interaction of EZH2 with JAK3 and polymerase II." SIGNOR-278518 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT "up-regulates activity" phosphorylation Thr482 SSQPKVStPVVKQGP 9606 BTO:0000567 30021153 t lperfetto "Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry." SIGNOR-265033 PCC complex SIGNOR-C414 SIGNOR (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI "up-regulates quantity" "chemical modification" 9606 15890657 t miannu "Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively." SIGNOR-267186 PYCARD protein Q9ULZ3 UNIPROT BAX protein Q07812 UNIPROT up-regulates relocalization 9606 16964285 t gcesareni "Asc directly induces bax-mediated apoptosis. Asc induces the translocation of bax to the mitochondria, bax-dependent cycs release from the mitochondria and casp9 activation." SIGNOR-149522 WNT10A protein Q9GZT5 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131619 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT "up-regulates activity" phosphorylation Thr389 RVITQREtENNQMTS -1 21423175 t miannu "In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h)." SIGNOR-276323 FAS protein P25445 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 7538908 t lperfetto "Fas associates with rip. Rip is a novel form of apoptosis-inducing protein" SIGNOR-235430 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273065 PP2B proteinfamily SIGNOR-PF18 SIGNOR BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation 9606 BTO:0000007 10195903 t "inferred from 70% family members" "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis." SIGNOR-269992 ACTN1 protein P12814 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 17243894 f miannu "On most principal neurons in the mammalian brain (e.g., pyramidal neurons of cortex and hippocampus, Purkinje cells of cerebellum, medium spiny neurons of striatum), the postsynaptic specialization is housed on tiny actin rich protrusions called dendritic spines The size, shape, motility, and stability of dendritic spines depend largely on actin, the primary cytoskeleton within spines." SIGNOR-264618 MAPK1 protein P28482 UNIPROT CITED2 protein Q99967 UNIPROT "up-regulates activity" phosphorylation Ser85 VNGGHPPsALAPAAR 9606 23082118 t miannu "CITED2 coactivation is enhanced by activation of MAPK1 and requires T166.|CITED2 is phosphorylated by MAPK1 at S85, T166 and T175." SIGNOR-278409 SGX-523 chemical CHEBI:90624 ChEBI MET protein P08581 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258282 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates "chemical activation" 10090 10448861 t miannu "Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1." SIGNOR-266334 PLEKHF2 protein Q9H8W4 UNIPROT EEA1 protein Q15075 UNIPROT "up-regulates activity" binding -1 22816767 t Giulio "In yeast two-hybrid analysis we identified Phafin2 as a novel interactor of the endosomal-tethering protein EEA1, and Phafin2 colocalized strongly with EEA1 in microdomains of the endosome membrane. Our results suggest that Phafin2 controls receptor trafficking and fluid-phase transport through early endosomes by facilitating endosome fusion in concert with EEA1." SIGNOR-261276 Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-267958 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT "down-regulates activity" phosphorylation Ser121 LMRRSTVsLLDTYQK 23871434 t "Phosphosite positions are derived from Figure S5" lperfetto "AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro" SIGNOR-275483 EP300 protein Q09472 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 9606 11796223 t lperfetto "Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription." SIGNOR-232165 ACAT1 protein P24752 UNIPROT acetoacetyl-CoA(4-) smallmolecule CHEBI:57286 ChEBI "down-regulates quantity" "chemical modification" 9606 31268215 t miannu "The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2 " SIGNOR-280426 CSAD protein Q9Y600 UNIPROT "beta-alanine zwitterion" smallmolecule CHEBI:57966 ChEBI "up-regulates quantity" "chemical modification" 9606 22718265 t miannu "Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms." SIGNOR-267549 "Av/b5 integrin" complex SIGNOR-C178 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu "Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing." SIGNOR-269027 PPARGC1A protein Q9UBK2 UNIPROT ESRRA protein P11474 UNIPROT "up-regulates activity" 10090 18074631 f lperfetto "The PGC1 transcriptional coactivators are major regulators of several crucial aspects of energy metabolism. PGC1alpha controls many aspects of oxidative metabolism, including mitochondrial biogenesis and respiration through the coactivation of many nuclear receptors, and factors outside the nuclear receptor family. ERRalpha, NRF1 and NRF2 are key targets of the PGC1s in mitochondrial biogenesis." SIGNOR-253392 TRIM25 protein Q14258 UNIPROT SFN protein P31947 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 12075357 t miannu "Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest." SIGNOR-271548 LTBP2 protein Q14767 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates activity" binding 9606 BTO:0000452 19681046 t Regulation miannu "LTBP-2 interacts with fibrillin-1. The association of LTBP-2 with the ECM always coincided with that of fibrillin-1, and in fibroblast cultures the appearance of fibrillar fibrillin-1 structures preceded the assembly of LTBP-2 network." SIGNOR-251891 GRPR protein P30550 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256917 GATA1 protein P15976 UNIPROT GP6 protein Q9HCN6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12377757 f miannu "We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment." SIGNOR-254081 "glutamic acid" smallmolecule CHEBI:18237 ChEBI Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270386 ACAT1 protein P24752 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI "up-regulates quantity" "chemical modification" 9606 31268215 t miannu "The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2 " SIGNOR-280427 TNFRSF17 protein Q02223 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates 9606 10903733 f "inferred from 70% of family members" miannu "Overexpression of bcma activates jnk" SIGNOR-269887 FLI1 protein Q01543 UNIPROT MPL protein P40238 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002581 15466856 f miannu "Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo." SIGNOR-254163 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT "up-regulates activity" phosphorylation Ser245 PSTSPRAsVTEESWL 9606 BTO:0001061 31730483 t miannu "Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells." SIGNOR-276770 SPOP protein O43791 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 15897469 t miannu "Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30)." SIGNOR-272659 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys982 ALLADIRkGFQLRKT 9606 BTO:0000007 28448495 t miannu "SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J)." SIGNOR-272806 NEK2 protein P51955 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates phosphorylation Thr318 TPPRGMItKQAKK 9606 10880350 t gcesareni "Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity." SIGNOR-78603 hsa-miR-27a-5p mirna URS00001B341F_9606 RNAcentral FZD7 protein O75084 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004050 24018051 t Parnian "Our observations indicate that FZD7 is a target of miR-27a and miR-27a mediates FZD7 expression via posttranslational suppression." SIGNOR-277966 KDM4C protein Q9H3R0 UNIPROT H3-4 protein Q16695 UNIPROT "down-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 9606 29207681 t miannu "As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation" SIGNOR-263867 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation 9606 16837009 t gcesareni "A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinasesa key step in the activation process is the phosphorylation of the activation loop of one pak kinase domain by another, but little is known about the underlying recognition events that make this phosphorylation specific." SIGNOR-147874 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Tyr92 FYEEIKKyEKLETEE 9606 BTO:0000007 16725308 t miannu "Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. " SIGNOR-266305 CXCL8 protein P10145 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto "Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS" SIGNOR-260257 CHUK protein O15111 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates activity" phosphorylation 9606 26516792 t miannu "Indeed, IKKa and IKKb may directly repress RIPK1 kinase activity by addition of an inhibitory phosphate group on RIPK1.|Mass spectrometry analysis of kinase assays performed with recombinant proteins allowed us to identify Ser166, Ser331, and Ser416 as highly conserved RIPK1 residues phosphorylated by IKKa and IKKb." SIGNOR-278927 CSNK1A1 protein P48729 UNIPROT YWHAQ protein P27348 UNIPROT "down-regulates activity" phosphorylation Ser232 LTLWTSDsAGEECDA -1 9360956 t llicata "This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins. " SIGNOR-250795 MAPK3 protein P27361 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 t lperfetto "Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation." SIGNOR-74304 DLG2 protein Q15700 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR "form complex" binding 9606 23397623 t miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270881 HOXA9 protein P31269 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC" SIGNOR-254211 PPP1CB protein P62140 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 14633703 t "Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells" SIGNOR-248575 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates quantity by destabilization" cleavage Asp390 LPQLTLPdSLTSAAS 9606 11815631 t Giulio "Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage" SIGNOR-260604 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA3 protein Q9Y5H0 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265699 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-192859 GFs stimulus SIGNOR-ST12 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 23300340 f lperfetto "Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation" SIGNOR-245402 CHD2 protein O14647 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates quantity" relocalization 9606 26895424 t miannu "Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage." SIGNOR-264527 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 t gcesareni "DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin." SIGNOR-184785 EGLN3 protein Q9H6Z9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR "up-regulates activity" hydroxylation 9606 BTO:0000567 21620138 t "Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1Œ± and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells." SIGNOR-268146 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203572 ETS1 protein P14921 UNIPROT ECE1 protein P42892 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000396 9595399 f miannu "Endothelial expression of endothelin-converting enzyme-1 beta mRNA is regulated by the transcription factor Ets-1. We conclude that Ets-1 is involved in transcriptional upregulation of ECE-1 beta mRNA in E.A. hy 926 cells induced by phorbol ester." SIGNOR-254080 EGR1 protein P18146 UNIPROT PTGES protein O14684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21983014 f "In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression.|EGR1 downregulation seems to be the major effect of DMC leading to transcriptional inhibition of mPGES-1" SIGNOR-254249 H3C1 protein P68431 UNIPROT "Nucleosome_H2A.Z.2 variant" complex SIGNOR-C323 SIGNOR "form complex" binding -1 24311584 t miannu "In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined." SIGNOR-263711 MAPKAPK2 protein P49137 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" phosphorylation Ser90 IPPARMMsTESANSF 9606 25693418 t miannu "Beclin 1 S90 is phosphorylated by MAPKAPK2 (MK2) and MAPKAPK3 (MK3)." SIGNOR-278342 nalbuphine chemical CHEBI:7454 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 9262330 t miannu "We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine." SIGNOR-258658 SLBP protein Q14493 UNIPROT H2AB2 protein P0C5Z0 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265407 ACAT1 protein P24752 UNIPROT "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "down-regulates quantity" "chemical modification" 9606 31268215 t miannu "The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2 " SIGNOR-280429 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT "up-regulates activity" phosphorylation Tyr206 PGPTRKHyQPYAPPR 8992971 t "EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor." SIGNOR-251334 JAK2 protein O60674 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR "up-regulates activity" phosphorylation 9606 15526160 t miannu "Downstream of JAKs are the signal transducers and activators of transcription (STATs), which are phosphorylated by JAKs." SIGNOR-254999 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "chemical modification" 9606 34674502 t scontino "Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬†" SIGNOR-267044 OPRM1 protein P35372 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256711 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4A protein O75164 UNIPROT "up-regulates activity" "chemical activation" 29981745 t lperfetto "Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3." SIGNOR-273465 IFNA2 protein P01563 UNIPROT HLA-B protein P01889 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 2507660 f Regulation miannu "HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2" SIGNOR-251925 SMARCA5 protein O60264 UNIPROT "B-WICH complex" complex SIGNOR-C447 SIGNOR "form complex" binding 9606 21559432 t miannu "The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription" SIGNOR-268825 CEBPG protein P53567 UNIPROT SFTPD protein P35247 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11912209 t "Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D." SIGNOR-254058 KIRREL3 protein Q8IZU9 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32503885 f miannu "We demonstrate that ectopic Kirrel3 expression in CA1 neurons specifically induces ectopic DG synapse formation, providing direct evidence that Kirrel3 plays an instructive role in synapse development." SIGNOR-269077 Quadazocine chemical CID:115077 PUBCHEM OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258420 PTPN13 protein Q12923 UNIPROT PDCD10 protein Q9BUL8 UNIPROT down-regulates dephosphorylation 9606 17657516 t gcesareni "We also show that ccm3 directly binds to serine/threonine kinase 25 (stk25, ysk1, sok1) and the phosphatase domain of fas-associated phosphatase-1 (fap-1, ptpn13, ptp-bas, ptp-bl)." SIGNOR-157076 ZBTB16 protein Q05516 UNIPROT RSAD2 protein Q8WXG1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003846 19523849 t lperfetto "Promoter regions from the PLZF-regulated transcripts Rsad2 and Ifit2 were fused to luciferase and activity was measured after IFN treatment. Overexpression of PLZF in RCC1 or ACHN cells produced a dose-dependent induction of the reporter promoters. " SIGNOR-261023 TRAF6 protein Q9Y4K3 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" ubiquitination 9606 23185365 t miannu "TRAF6 Interacts with STAT3 and Mediates the Ubiquitination of STAT3.|TRAF6 Represses the Transcriptional Activity of STAT3." SIGNOR-278618 phosphatidylinositol chemical CHEBI:28874 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition." SIGNOR-267001 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates binding 9606 BTO:0001130 1010227 t gcesareni "Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner." SIGNOR-15849 YAP1 protein P46937 UNIPROT CCNA2 protein P20248 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001939 30224758 f lperfetto "By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ." SIGNOR-276563 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT "down-regulates activity" phosphorylation Ser138 KPRTIYSsYQLAALQ -1 11343707 t lperfetto "Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3." SIGNOR-249096 CTNNA3 protein Q9UI47 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000586 21598020 t miannu "Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14" SIGNOR-265493 SKIL protein P12757 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "down-regulates activity" binding 9606 BTO:0000848 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-253303 "beta-D-fructofuranose 2,6-bisphosphate" smallmolecule CHEBI:28602 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR "up-regulates activity" binding 9606 19454274 t "The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux" SIGNOR-267262 MTCP1 protein P56278 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto "Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation" SIGNOR-244413 CDK1 protein P06493 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr287 SAASNTGtPDGPEAP 9606 15125835 t lperfetto "T287 is phosphorylated by cdk1 during mitosis. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis." SIGNOR-124642 MYC protein P01106 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates 9606 11804592 f "in cancer" lperfetto "Oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads" SIGNOR-114281 MCHR1 protein Q99705 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256905 HUWE1 protein Q7Z6Z7 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity" ubiquitination 9606 22277673 t miannu "Importantly, addition of WT HUWE1 to a proteolytic reaction mixture enhanced the degradation of MyoD.|Mass-spectrometry analyses show that HUWE1 can ubiquitinate MyoD at its N-terminal residue, though the preferred sites are - at least in a cell free system - the internal lysines of the protein." SIGNOR-278694 ketoprofen chemical CHEBI:6128 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001061 18667313 t Luana "Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. " SIGNOR-257810 ADCYAP1 protein P18509 UNIPROT ADCYAP1R1 protein P41586 UNIPROT up-regulates binding 9606 8703026 t gcesareni "Type i pacap receptors bind pacap-27 and -38. the potencies of the two forms of pacap are similar for adenylate cyclase stimulation, whereas pacap-38 is more potent than pacap-27 in phospholipase c activation." SIGNOR-43225 HUWE1 protein Q7Z6Z7 UNIPROT TBP protein P20226 UNIPROT "down-regulates quantity" ubiquitination 9606 26393420 t miannu "Having established that Huwe1 mediates TBP ubiquitination in vitro, we then asked which E2 conjugating enzymes work best with Huwe1 in this reaction.|Upregulation of Huwe1 expression during myogenesis induces TBP degradation and myotube differentiation." SIGNOR-278696 STK4 protein Q13043 UNIPROT PRDX1 protein Q06830 UNIPROT "down-regulates activity" phosphorylation Thr183 GWKPGSDtIKPDVQK -1 23386615 t miannu "Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183." SIGNOR-276485 "Activated PSC" phenotype SIGNOR-PH224 SIGNOR IL11 protein P20809 UNIPROT up-regulates 9606 BTO:0000584 30996350 t miannu "IL6 has been implicated in PDAC, and all its family members, like LIF, bind to receptor complexes containing GP130 to activate similar signal cascades, such as the STAT3 pathway. In our initial screens, IL6 and IL11 were also found to be produced by PSCs" SIGNOR-278037 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT "down-regulates activity" phosphorylation Ser592 KCNVKAKsNVDLRRS 9606 BTO:0000007 30279167 t miannu "Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser560" SIGNOR-277800 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT "up-regulates activity" phosphorylation Ser55 NKFLENKsPWRKMVH 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275598 TBK1 protein Q9UHD2 UNIPROT STING1 protein Q86WV6 UNIPROT "up-regulates activity" phosphorylation Ser358 VPSTSTMsQEPELLI 9606 BTO:0000007 18818105 t miannu "MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3. Our results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity. Consistent with its inability to activate IRF-E, the mutation of S358 to alanine impaired the ability of MITA to interact with TBK1 and to enhance the interaction between TBK1 and IRF3" SIGNOR-263136 PHKG1 protein Q16816 UNIPROT PYGM protein P11217 UNIPROT "up-regulates activity" phosphorylation Ser15 QEKRKQIsVRGLAGV 9606 BTO:0002049 22225877 t "It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15" SIGNOR-267398 MTOR protein P42345 UNIPROT EIF4EBP2 protein Q13542 UNIPROT down-regulates phosphorylation 9606 14967450 t gcesareni "Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2)." SIGNOR-122014 RNF5 protein Q99942 UNIPROT JKAMP protein Q9P055 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0000007 19269966 t miannu "RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97." SIGNOR-271483 CDK1 protein P06493 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" phosphorylation Ser91 EGMGEEPsPFRGRSR 24677263 t lperfetto "CDK1-mediated Bcl-2 serine 70 phosphorylation enhances its pro-apoptotic function, whereas CDK1-mediated Bad serine 128 phosphorylation promotes apoptosis. " SIGNOR-267921 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT "up-regulates activity" phosphorylation Tyr677 LPITGPEyATPIIMD -1 23770091 t done miannu "Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding." SIGNOR-273943 PPP2CA protein P67775 UNIPROT RELA protein Q04206 UNIPROT down-regulates dephosphorylation 9606 BTO:0000848 SIGNOR-C13 11591705 t gcesareni "Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela." SIGNOR-110959 COL4A5 protein P29400 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 35267698 t lperfetto "Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]." SIGNOR-272349 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser63 NVKVETQsDEENGRA 9606 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo" SIGNOR-174852 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0001103 28163303 f apalma "During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function" SIGNOR-255112 TFEB protein P19484 UNIPROT CTSF protein Q9UBX1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 30145926 f lperfetto "Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB" SIGNOR-276805 PRKN protein O60260 UNIPROT PLCG1 protein P19174 UNIPROT "down-regulates quantity" ubiquitination 9606 19663908 t miannu "In order to address the functional role of parkin ubiquitination of PLCgamma1, we investigated PLC activity in human neuroblastoma SH-SY5Y cell lines stably transfected with either WT, or mutant R42P or G328E parkin.|WT parkin expression significantly reduced the levels of PLCgamma1 in human neuroblastoma." SIGNOR-278592 TSH complex SIGNOR-C412 SIGNOR TSHR protein P16473 UNIPROT "up-regulates activity" binding 9606 BTO:0001379 25905363 t scontino "The thyroid-stimulating hormone (TSH) receptor (TSHR) is a member of the glycoprotein hormone receptors (GPHRs), a sub-group of class A G protein-coupled receptors (GPCRs). TSHR and its ligand thyrotropin are of essential importance for growth and function of the thyroid gland." SIGNOR-267048 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser102 GGFPPLNsVSPSPLM 9606 16076840 t gcesareni "The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex." SIGNOR-139312 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1619 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248804 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser750 RRKMKKTsTSTETRS 9606 15568999 t lperfetto "Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known." SIGNOR-131399 MDM2 protein Q00987 UNIPROT NFATC2 protein Q13469 UNIPROT "down-regulates quantity" ubiquitination 9606 24777531 t miannu "MDM2 negatively regulates NFATc2 and T cell activation.|The E3 ubiquitin ligase MDM2 is known to induce NFATc2 ubiquitination in a breast cancer cell line 24." SIGNOR-278657 "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI "up-regulates quantity" relocalization 9606 18790874 t brain lperfetto "GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)" SIGNOR-263817 EPB42 protein P16452 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266014 ACAT1 protein P24752 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI "down-regulates quantity" "chemical modification" 9606 31268215 t miannu "The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2 " SIGNOR-280430 FGF11 protein Q92914 UNIPROT SCN3A protein Q9NY46 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253446 selumetinib chemical CHEBI:90227 ChEBI MAP2K1 protein Q02750 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258280 YWHAE protein P62258 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 17202468 t miannu "14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. 14-3-3ε binds to NUDEL phosphorylated by cyclin-dependent kinase (cdk5) and maintains NUDEL phosphorylation. Deficiency of 14-3-3ε causes mislocalization of the NUDEL/LIS1 complex from axons, suggesting that 14-3-3ε regulates the axonal targeting of the NUDEL/LIS1 complex by sustaining NUDEL phosphorylation" SIGNOR-252160 TRAF6 protein Q9Y4K3 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates ubiquitination 9606 BTO:0000782 17948050 t gcesareni "Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract)" SIGNOR-158554 LCK protein P06239 UNIPROT DAPP1 protein Q9UN19 UNIPROT "up-regulates activity" phosphorylation Tyr139 KVEEPSIyESVRVHT 10880360 t lperfetto "Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins." SIGNOR-249373 CCN2 protein P29279 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 33358571 f miannu "As a matricellular protein, connective tissue growth factor (CTGF) functions beyond its classical role in extracellular matrix (ECM) remolding. Increasing evidence emphasizes the notion that CTGF is pivotal in cancer initiation and progression." SIGNOR-277683 MRE11 protein P49959 UNIPROT PIH1D1 protein Q9NWS0 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Ser688;Ser689;Ser561;Ser558 SKGVDFEsSEDDDDD;KGVDFESsEDDDDDP;MANDSDDsISAATNK;AEQMANDsDDSISAA 28436950 t miannu "Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689." SIGNOR-265898 exemestane chemical CHEBI:4953 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191520 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser150 PELCGPGsPPVLTPG 9606 15952796 t lperfetto "We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling." SIGNOR-138163 ACAT1 protein P24752 UNIPROT acetoacetyl-CoA(4-) smallmolecule CHEBI:57286 ChEBI "up-regulates quantity" "precursor of" 9606 31268215 t miannu "The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2 " SIGNOR-280431 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Tyr141 AITSPFKyQSLLTKN 10029 BTO:0000246 8557631 t "Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors." SIGNOR-251300 RARA protein P10276 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 t "inferred from family member" gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-270293 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 BTO:0000150;BTO:0000782 SIGNOR-C13 16046471 t lperfetto "Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k). We now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. Ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536." SIGNOR-138903 MRPS5 protein P82675 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261441 AXIN2 protein Q9Y2T1 UNIPROT APC protein P25054 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 t gcesareni "It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains." SIGNOR-79944 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr425 KKCLELFtELAEDKE 9606 24117238 t lperfetto "Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity." SIGNOR-202816 PRKACA protein P17612 UNIPROT THOP1 protein P52888 UNIPROT "up-regulates activity" phosphorylation Ser643 KVGMDYRsCILRPGG -1 10969067 t miannu "PKA phosphorylation is suggested to play a regulatory role in EP24.15 enzyme activity. Mutation analysis of each putative PKA site, in vitro phosphorylation, and phosphopeptide mapping indicated serine 644 as the phosphorylation site. The most dramatic change upon PKA phosphorylation was a substrate-specific, 7-fold increase in both K(m) and k(cat) for GnRH." SIGNOR-250060 GSK3B protein P49841 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates activity" phosphorylation Thr226 HLQPGHPtPPPTPVP 10090 BTO:0000944 10567568 t "Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes." SIGNOR-251231 A2M protein P01023 UNIPROT MMP9 protein P14780 UNIPROT "down-regulates activity" binding -1 9344465 t lperfetto "Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261801 SMARCD2 protein Q92925 UNIPROT "Muscle cell-specific SWI/SNF ARID1A variant" complex SIGNOR-C481 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270693 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257923 IPO5 protein O00410 UNIPROT DSCAM protein O60469 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 30745319 t miannu "DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs." SIGNOR-264273 motesanib chemical CHEBI:51098 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258253 MYC protein P01106 UNIPROT DHODH protein Q02127 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003291 18628958 t miannu "PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria." SIGNOR-267382 "GABA-A (a5-b1-g2) receptor" complex SIGNOR-C335 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268606 IL15RA protein Q13261 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates 9606 30029643 f areggio "Since recent study demonstrated desert Hedgehog (DHH) signaling can repressed FAP-derived adipocyte differentiation through Timp3 [30], we tested the mRNA expression of DHH and Timp3 in injured muscle with injection of IL-15. As expected, mRNA levels of DHH and Timp3 were both upregulated (Fig. 2f)." SIGNOR-256232 MTFP1 protein Q9UDX5 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" relocalization 10090 BTO:0002572 28918902 f Barakat "Regardless of the precise mechanism, our data establish MTFP1 as an essential regulator of mitochondrial fission through the modulation of DRP1 phosphorylation and recruitment to the mitochondrion." SIGNOR-275449 FBXW7 protein Q969H0 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243766 GNA13 protein Q14344 UNIPROT ARHGEF28 protein Q8N1W1 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 25922072 t "Marta Tosoni" "Taken together, the results suggest that active G13 and Gq form a complex with Rgnef and that G13 and Gq are upstream activators of Rgnef." SIGNOR-278064 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265920 imatinib chemical CHEBI:45783 ChEBI PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" 9606 22045730 t "Recently, imatinib, an inhibitor of several tyrosine kinases, including c-abl, c-kit and PDGFRs, was demonstrated to ameliorate dystrophic phenotypes in mdx mice by suppressing the phosphorylation of PDGFRa" SIGNOR-254378 PRKCD protein Q05655 UNIPROT APC protein P25054 UNIPROT "down-regulates activity" phosphorylation 9606 23520519 t miannu "APC is Phosphorylated by PKCdelta in Intact RKO Cells." SIGNOR-279650 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT down-regulates relocalization 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t gcesareni "Su(fu) is a negative regulator of shh that interacts with all three gli proteins to retain them in the cytosol." SIGNOR-72308 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 19115199 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-182996 GTF2H2 protein Q13888 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR "form complex" binding 9606 30860024 t lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits" SIGNOR-269311 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser420 KHPTPGSsDPLIQPS -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273931 mTORC2 complex SIGNOR-C2 SIGNOR AMOTL2 protein Q9Y2J4 UNIPROT "down-regulates activity" phosphorylation Ser759 SSSQRAAsLDSVATS 25998128 t lperfetto "AMOTL2 is phosphorylated at serine 760 by mTORC2. Mutation of AMOTL2 mimicking constitutive Ser(760) phosphorylation blocks its ability to bind and repress YAP leading to increased relative expression of known YAP gene targets." SIGNOR-272085 SREBF1 protein P36956 UNIPROT VLDL_assembly phenotype SIGNOR-PH62 SIGNOR up-regulates 9606 11111091 f miannu "SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. SREBP1 induced the expression of the genes regulating the synthesis of all VLDL lipids" SIGNOR-252112 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM FLT1 protein P17948 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258287 "Av/b1 integrin" complex SIGNOR-C175 SIGNOR POU5F1 protein Q01860 UNIPROT "up-regulates quantity by expression" 10090 18757303 f lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253272 PLIN3 protein O60664 UNIPROT M6PR protein P20645 UNIPROT "up-regulates activity" relocalization 9534 BTO:0004055 9590177 t lperfetto "TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi." SIGNOR-253093 SMO protein Q99835 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-199174 PRKCA protein P17252 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates phosphorylation Ser25 KDEPQRRsARLSAKP 9606 10739259 t lperfetto "Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools." SIGNOR-76320 APEX1 protein P27695 UNIPROT TG protein P01266 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9813166 t lperfetto "In co-transfection experiments, Ref-1 increases the Pax-8 activating effect on thyroglobulin promoter." SIGNOR-271694 PPP4C protein P60510 UNIPROT PLK1 protein P53350 UNIPROT "down-regulates activity" dephosphorylation Ser137 LELCRRRsLLELHKR 9606 35546066 t miannu "PPP4C dephosphorylated PLK1 at the S137 site, negatively regulating its activity in the DSB response in early embryonic cells." SIGNOR-277076 PPAT protein Q06203 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "down-regulates quantity" "chemical modification" 9606 8106516 t "Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù" SIGNOR-267187 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr653 RDIHHIDyYKKTTNG 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto "In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses." SIGNOR-236195 CYCS protein P99999 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR "form complex" binding -1 10206961 t lperfetto " APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9. " SIGNOR-256430 SMARCA2 protein P51531 UNIPROT "Brain-specific SWI/SNF SMARCA2 variant" complex SIGNOR-C485 SIGNOR "form complex" binding 9606 BTO:0000142 11790558 t miannu " Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core." SIGNOR-270742 PRKN protein O60260 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys477 LNQEVALkLEPNPES 9606 29180628 t miannu "These results indicate that Parkin inhibits HIF-1alpha transcriptional activity.|Ubiquitination of HIF-1alpha at lysine 477 by Parkin." SIGNOR-278542 ACAT1 protein P24752 UNIPROT "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "precursor of" 9606 31268215 t miannu "The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2 " SIGNOR-280432 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273911 SRC protein P12931 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" phosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 25157176 t "Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis" SIGNOR-252093 MAPK1 protein P28482 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser62 SYTPTPRsPRFIGRR 9606 7901013 t "The effect has been demonstrated using P07101-2" gcesareni "Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylase in vitro at comparable rates to other proteins thought to be physiological substrates of these protein kinases.The effect on activity of phosphorylating both ser31 and ser40 was not additive. The possible roles of mapkap kinase-1, mapkap kinase-2 and map kinase in the regulation of tyrosine hydroxylase in vivo are discussed." SIGNOR-34674 NUP62 protein P37198 UNIPROT TUBG1 protein P23258 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 24107630 t Simone "Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles." SIGNOR-261257 PELI3 protein Q8N2H9 UNIPROT IRF4 protein Q15306 UNIPROT "down-regulates activity" ubiquitination Lys48 LVWENEEkSIFRIPW 9606 BTO:0005025 37341064 t Tiberia "Peli3 induces the degradation of IRF4 through K48‐mediated ubiquitination |To detect the direct interaction of Peli3 and IRF4, Peli3 and IRF4 DNA constructs were transfected into HEK293 cells." SIGNOR-280453 IRF4 protein Q15306 UNIPROT RIPK2 protein O43353 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 24670424 t Tiberia "These studies demonstrate that inhibition of RICK (RIPK2) polyubiquitination by IRF4 involves polyubiquitination of the kinase domain of RICK and this inhibition is facilitated by binding of IRF4 to the kinase and/or intermediate domains of RICK." SIGNOR-280454 VPS13B protein Q7Z7G8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 f miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons" SIGNOR-266872 PRKD3 protein O94806 UNIPROT MFF protein Q9GZY8 UNIPROT "up-regulates activity" phosphorylation Ser275 DNVRYGIsNIDTTIE 34010649 t lperfetto "The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275" SIGNOR-275946 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 11062529 t gcesareni "Mckinsey et al. report that calcium/calmodulin-dependent kinase (camk), stimulates myogenesis and prevents formation of mef2/hdac complexes by inducing phosphorylation and nuclear export of hdacs 4 and 5." SIGNOR-83837 "Integrator complex" complex SIGNOR-C265 SIGNOR H4C1 protein P62805 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 25675981 f lperfetto "Integrator-dependent function at promoter proximal sites that is unrelated to NELF-regulated pausing. Given its termination function at both the U2 snRNA and Histone H4 genes, we favor a model in which Integrator also has a termination function at promoter proximal sites." SIGNOR-261481 FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT "down-regulates activity" binding 10090 24627466 t lperfetto "Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. FST315-deltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function." SIGNOR-251717 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 9679146 t gcesareni "Pkc phosphorylation of native and recombinant adducin inhibited actin capping measured using pyrene-actin polymerization and abolished activity of adducin in recruiting spectrin to ends and sides of actin filaments" SIGNOR-59299 CHEK2 protein O96017 UNIPROT DNA2 protein P51530 UNIPROT "up-regulates activity" phosphorylation 9606 22682245 t miannuccelli "We later observed that Dna2 phosphorylation by Cds1 is necessary for Dna2 association with chromatin in HU treated cells." SIGNOR-279729 MTOR protein P42345 UNIPROT TFEB protein P19484 UNIPROT "down-regulates activity" phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 22343943 t "Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity." SIGNOR-255310 EGFR protein P00533 UNIPROT GPRC5A protein Q8NFJ5 UNIPROT "down-regulates activity" phosphorylation Tyr317 EETGDTLyAPYSTHF 9606 25311788 t miannu "EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells." SIGNOR-278333 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT "down-regulates activity" binding 9606 12244043 t areggio "Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes" SIGNOR-254986 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000567 9687510 t gcesareni "Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha" SIGNOR-59443 TLN1 protein Q9Y490 UNIPROT "A11/b1 integrin" complex SIGNOR-C168 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257617 CTDP1 protein Q9Y5B0 UNIPROT MASTL protein Q96GX5 UNIPROT "down-regulates activity" dephosphorylation Ser453 NFELVDSsPCKKIIQ 9606 26653855 t lperfetto "Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl." SIGNOR-276971 FOXO proteinfamily SIGNOR-PF27 SIGNOR FASLG protein P48023 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10102273 f gcesareni "Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene." SIGNOR-252942 PRKCD protein Q05655 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser60 VVGARRSsWRVISSI 9606 16024783 t gcesareni "We provide a mechanism for these observations through the phosphorylation of 14-3-3 by ikk and pkc on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm." SIGNOR-138612 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT "down-regulates activity" phosphorylation Ser33 LRRSQRKsGSELPSI -1 23901111 t miannu "Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. " SIGNOR-276124 SIRT7 protein Q9NRC8 UNIPROT DDX21 protein Q9NR30 UNIPROT "up-regulates activity" deacetylation Lys600 HFKQSAEkLIEEKGA 28790157 t lperfetto "Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21." SIGNOR-275905 ANO6 protein Q4KMQ2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 24663380 f miannu "Using a shRNA KD approach, we show that Ano6-KD C2C12 myoblasts exhibit reduced proliferation capacity. Our data demonstrate that Ano6 is required to maintain the proliferative status of myoblasts." SIGNOR-261213 MIPOL1 protein Q8TD10 UNIPROT RELA protein Q04206 UNIPROT "down-regulates activity" 9606 31609475 f miannu "In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9" SIGNOR-261136 ARHGAP11A protein Q6P4F7 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260466 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr191 LDGSREyVNVSQE 9606 29915297 t "Isoform O43561-2" Barakat "In the presence of the catalytically inactive LckK273R, the phosphorylation of LAT Y132 and Y191 residues by Zap70K362E were considerably increased" SIGNOR-274562 PAK3 protein O75914 UNIPROT PAK3 protein O75914 UNIPROT "up-regulates activity" phosphorylation Ser154 VNNQKYMsFTSGDKS -1 11278486 t miannu "Both in vivo and in vitro analyses demonstrate that, although most phosphorylation events in the PAK N-terminal regulatory domain play no direct role in activation, a phosphorylation of alphaPAK serine 144 or betaPAK serine 139, which lie in the kinase inhibitory domain, significantly contribute to activation. " SIGNOR-250245 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-251591 BIRC5 protein O15392 UNIPROT XIAP protein P98170 UNIPROT up-regulates binding 9606 15218035 t gcesareni "Formation of a survivin-xiap complex promotes increased xiap stability against ubiquitination/proteasomal destruction and synergistic apoptosis" SIGNOR-126367 RIPK2 protein O43353 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000633 33935757 t Tiberia "Binding of bacterial MDP or viral RNA to NOD2 results in the association of RIPK2 with TRAF6 and subsequent activation of TRAF6." SIGNOR-280456 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM25 protein Q14258 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271155 NFATC1 protein O95644 UNIPROT PLAUR protein Q03405 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23015147 t "Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays." SIGNOR-253336 PTBP2 protein Q9UKA9 UNIPROT KHSRP protein Q92945 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 11003644 t lperfetto "Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA." SIGNOR-261268 Galanin smallmolecule CHEBI:80161 ChEBI GALR3 protein O60755 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257496 ATG16L1 protein Q676U5 UNIPROT RIPK2 protein O43353 UNIPROT "down-regulates activity" binding 9606 BTO:0005096 33935757 t Tiberia "In human monocyte-derived dendritic cells, NOD2 activation by MDP induced physical interaction between ATG16L1 and RIPK2 and negatively regulated NF-κB activation. It is important to note that ATG16L1 acts synergistically with IRF4 to inhibit RIPK2 polyubiquitination." SIGNOR-280457 PTEN protein P60484 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000356 10400703 t "The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN dephosphorylates phosphatidylinositol 3,4, 5-trisphosphate (PIP3) and focal adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and focal adhesions. We investigated molecular interactions of PTEN and FAK in glioblastoma and breast cancer cells lacking PTEN. The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr397" SIGNOR-248547 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 10669763 t gcesareni "The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-Œ± or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro." SIGNOR-74943 PPP2CA protein P67775 UNIPROT STK4 protein Q13043 UNIPROT down-regulates dephosphorylation Thr183 DTMAKRNtVIGTPFW 9606 23431053 t gcesareni "Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively." SIGNOR-201270 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0000680 16039586 t "inferred from 70% family members" lperfetto "Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin." SIGNOR-270059 WEE1 protein P30291 UNIPROT PLRG1 protein O43660 UNIPROT "down-regulates activity" phosphorylation 9606 33450002 t miannu "These results indicate that WEE1 promotes PRL1 phosphorylation.|WEE1 promotes PRL1 degradation ." SIGNOR-279579 RIMS2 protein Q9UQ26 UNIPROT UNC13B protein O14795 UNIPROT "up-regulates activity" relocalization 9606 31679900 t miannu "N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle" SIGNOR-264383 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t lperfetto "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-137175 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT "up-regulates activity" binding 9606 12629049 t "Activation of PKC depends on the availability of DAG,a signaling lipid that is tightly and dynamically regulated." SIGNOR-251559 MAPK1 protein P28482 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates phosphorylation 9606 12359725 t lperfetto "In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e." SIGNOR-217499 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 t "The effect has been demonstrated using Q08499-2" gcesareni "These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro." SIGNOR-270069 MYO5A protein Q9Y4I1 UNIPROT ACTB protein P60709 UNIPROT "up-regulates activity" binding 9606 21077886 t miannu "Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis" SIGNOR-269280 192927-92-7 chemical CID:11957576 PUBCHEM HTR1D protein P28221 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193814 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1387 GRCPSDPyKHSLPSQ -1 10195142 t lperfetto "To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain." SIGNOR-247171 TLR4 protein O00206 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates binding 9606 18221795 t fstefani "Mappit analysis of early toll-like receptor signalling events." SIGNOR-160424 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT "down-regulates activity" acetylation Lys206 DLINLAKkRTNIIPV 30540930 t lperfetto "Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206)" SIGNOR-275897 EGFR protein P00533 UNIPROT GPRC5A protein Q8NFJ5 UNIPROT "down-regulates activity" phosphorylation Tyr347 AHAWPSPyKDYEVKK 9606 25311788 t miannu "EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells." SIGNOR-278335 PHF2 protein O75151 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 BTO:0000007 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-264518 ITCH protein Q96J02 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates activity" binding 9606 BTO:0001109 40185717 t Tiberia "ITCH preferentially binds to RIPK2, promoting its K63-linked ubiquitination while simultaneously protecting YAP protein levels and maintaining its nuclear localization in CRC cells." SIGNOR-280458 NFKB1 protein P19838 UNIPROT CTCF protein P49711 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21912613 f miannu "In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription." SIGNOR-254788 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser27 DRHLRSEsQRQRREI 9606 BTO:0000671 9166747 t gcesareni "Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling." SIGNOR-48681 NUP35 protein Q8NFH5 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262080 TBX2 protein Q13207 UNIPROT MYOG protein P15173 UNIPROT "down-regulates activity" binding 9606 24470334 t "We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity." SIGNOR-251561 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259792 BRCC3 protein P46736 UNIPROT "BRCA1-A complex" complex SIGNOR-C296 SIGNOR "form complex" binding 9606 BTO:0000007 20656690 t lperfetto "We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. " SIGNOR-263213 SMG1 protein Q96Q15 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 15175154 t gcesareni "Hsmg-1 is a stress-activated kinase that phosphorylates p53 and hupf1 in vitrothe observation that hsmg-1 exhibits p53 (ser-15) kinase activity in vitro suggested that this pikk might be involved in genotoxic stress-induced p53 phosphorylation and stabilization in intact cells." SIGNOR-125135 RUNX2 protein Q13950 UNIPROT ALPL protein P05186 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast" SIGNOR-107123 ARHGEF3 protein Q9NR81 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260530 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Ser27 PFRDSPLsSRLLDDG 9606 22721717 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-197932 SRC protein P12931 UNIPROT NELFCD protein Q8IXH7 UNIPROT "down-regulates activity" phosphorylation Tyr14 GAIMDEDyYGSAAEW 9534 22238675 t miannu " Here we show that c-Src interacts with TH1 by GST-pull down assay, coimmunoprecipitation and confocal microscopy assay. The interaction leads to phosphorylation of TH1 at Tyr-6 in vivo and in vitro. Phosphorylation of TH1 decreases its association with A-Raf and PAK1." SIGNOR-276402 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates 10090 BTO:0001103 24003218 f lperfetto "SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3" SIGNOR-252997 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 9677429 t "MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade." lperfetto "The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells." SIGNOR-244802 CDK1 protein P06493 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates phosphorylation Ser668 IGEETDSsPGRKKFP 9606 19881501 t gcesareni "Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce." SIGNOR-189017 FLT3 protein P36888 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 10090 18192505 f "Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity" SIGNOR-261536 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Val72 GLTEYRLvSINKSSP -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263567 AKT proteinfamily SIGNOR-PF24 SIGNOR S1PR1 protein P21453 UNIPROT "up-regulates activity" phosphorylation Thr236 RTRSRRLtFRKNISK 9606 11583630 t lperfetto "Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis" SIGNOR-110845 EP300 protein Q09472 UNIPROT PLAGL2 protein Q9UPG8 UNIPROT up-regulates acetylation 9606 16207715 t miannu "Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7." SIGNOR-140947 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" phosphorylation Tyr368 CGGARICyIFHETFG 9606 BTO:0000793 29022905 t miannu "In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation." SIGNOR-277329 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT "down-regulates quantity" binding 9606 BTO:0000567 14960576 t amattioni "Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells." SIGNOR-121883 TIRAP protein P58753 UNIPROT AGER protein Q15109 UNIPROT "up-regulates activity" binding 9606 BTO:0005548 21829704 t Tiberia "These results indicate that TIRAP functions as an essential adaptor protein for RAGE, binding to ligand-activated phosphorylated RAGE and transducing a signal from it." SIGNOR-280459 TIRAP protein P58753 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0006328 19592497 t Tiberia "Mal interaction with TRAF6 is required for NF-κB transactivation" SIGNOR-280461 PML protein P29590 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 15356634 t lperfetto "Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome." SIGNOR-232090 SH3PXD2A protein Q5TCZ1 UNIPROT NOXA1 protein Q86UR1 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20943948 t lperfetto "Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation" SIGNOR-264708 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 9606 BTO:0000567 9398320 t lperfetto "Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)]." SIGNOR-53739 ANXA3 protein P12429 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 9606 27995049 f miannu "We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells." SIGNOR-262212 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT "up-regulates activity" phosphorylation Ser825 GGGQAKTsPKPAVVE 9606 BTO:0000567 25097229 t miannu "Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins." SIGNOR-277833 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1724 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248776 mTORC1 complex SIGNOR-C3 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 19593385 f lperfetto "Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation." SIGNOR-235349 F2RL1 protein P55085 UNIPROT DUSP6 protein Q16828 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254853 conivaptan chemical CHEBI:681850 ChEBI AVPR2 protein P30518 UNIPROT "down-regulates activity" "chemical inhibition" -1 20471258 t Luana "One of the targets, 13d, demonstrated improved V2-receptor binding and was further profiled for comparison with conivaptan, the program’s mixed V1a/V2 standard (Table 4). Compound 13d displayed similar V1a-receptor affinity, albeit with a 30-fold weaker V2-receptor affinity when compared to conivaptan." SIGNOR-257844 MRGPRX2 protein Q96LB1 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256930 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000785 18467333 t gcesareni "Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt." SIGNOR-178619 NOTCH1 protein P46531 UNIPROT BCL11B protein Q9C0K0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r." SIGNOR-197449 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR IGF1 protein P05019 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269258 IL6ST protein P40189 UNIPROT YES1 protein P07947 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000584 31296870 t miannu "Binding of LIF to the LIFR-gp130 receptor complex has been previously shown to activate YES and YAP/TAZ-TEAD -dependent transcription, which is required to maintain self-renewal in embryonic stem cells" SIGNOR-278033 GDP smallmolecule CHEBI:17552 ChEBI GNAS protein P63092 UNIPROT down-regulates "chemical inhibition" 9606 17095603 t gcesareni "Galfa subunits cycle between inactive (GDP-bound) and active (GTP-bound) states, and the lifetime of the active state is limited by GTP hydrolysis." SIGNOR-253072 PFDN2 protein Q9UHV9 UNIPROT "Prefoldin co-chaperone" complex SIGNOR-C513 SIGNOR "form complex" binding 9606 32699605 t miannu "The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)" SIGNOR-270931 EPHB6 protein O15197 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates activity" binding 9606 BTO:0000093 25239188 t miannu "EphB6 is frequently silenced in invasive and metastatic cancers; however, its role in cancer progression is poorly understood. Here we show that EphB6 interacts with EphA2 and suppresses EphA2-mediated promotion of anoikis resistance in MCF7 breast cancer cells. " SIGNOR-273853 WNT9B protein O14905 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni "We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles." SIGNOR-195978 "prostaglandin H2(1-)" smallmolecule CHEBI:57405 ChEBI "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI "up-regulates quantity" "precursor of" -1 10922363 t Luana "Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently." SIGNOR-269765 CCL2 protein P13500 UNIPROT Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 f miannu "The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages." SIGNOR-260849 PRKAA1 protein Q13131 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 SIGNOR-C15 15866171 t gcesareni "Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest" SIGNOR-135960 MAPK14 protein Q16539 UNIPROT NFATC4 protein Q14934 UNIPROT "down-regulates activity" phosphorylation Ser168 QGGGAFFsPSPGSSS 10029 BTO:0001131 11997522 t miannu "P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity." SIGNOR-250107 everolimus chemical CHEBI:68478 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 20689758 t gcesareni "M14, m288, and skmel28 (sensitive and resistant) were exposed to rad001, an mtor inhibitor, and to ly294002, a pi3k inhibitor." SIGNOR-167402 GATA1 protein P15976 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" binding 9606 17725493 t miannu "We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation." SIGNOR-254194 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 12869565 t gcesareni "Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols." SIGNOR-103721 MKNK1 protein Q9BUB5 UNIPROT PLA2G4A protein P47712 UNIPROT "up-regulates activity" phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007 10978317 t lperfetto "The results suggest that MNK1 or a closely related kinase is responsible for in vivo phosphorylation of cPLA2 on Ser-727." SIGNOR-226633 RBM38 protein Q9H0Z9 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 9606 17050675 t Luana "Here, we found that RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript." SIGNOR-275391 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr315 TFCGTPEyLAPEVLE 9534 BTO:0004055 11445557 t lperfetto "Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity." SIGNOR-246368 ROS stimulus SIGNOR-ST2 SIGNOR Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 32454942 f miannu "Next to their interaction with adaptive immune cells, activated microglia can secrete cytotoxic cytokines and oxidative products, such as ROS and NO radicals in MS lesions thereby promoting oxidative stress and contributing to myelin destruction" SIGNOR-263828 WDR45 protein Q9Y484 UNIPROT ATG2B protein Q96BY7 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 28561066 t miannu "WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation." SIGNOR-268484 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr740 TGESDGGyMDMSKDE -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248413 CREBBP protein Q92793 UNIPROT DDX21 protein Q9NR30 UNIPROT "down-regulates activity" acetylation Lys137 PKKMKKEkEMNGETR 28790157 t lperfetto "Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21." SIGNOR-275904 HDAC2 protein Q92769 UNIPROT "MECP2/SIN3A/HDAC complex" complex SIGNOR-C360 SIGNOR "form complex" binding 9606 BTO:0000567 9620804 t Luana "We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases." SIGNOR-267736 S protein P0DTC2 UNIPROT ACE2 protein Q9BYF1 UNIPROT "down-regulates activity" binding 9606 32125455 t miannu "SARS-CoV and likely SARS-CoV-2 lead to downregulation of the ACE2 receptor, but not ACE, through binding of the spike protein with ACE2. This leads to viral entry and replication, as well as severe lung injury." SIGNOR-260742 S protein P59594 UNIPROT ACE2 protein Q9BYF1 UNIPROT "down-regulates activity" binding 9534 18554741 t miannu "Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells." SIGNOR-260283 PIM2 protein Q9P1W9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 16146838 f lperfetto "The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells." SIGNOR-256575 S protein P59594 UNIPROT ACE2 protein Q9BYF1 UNIPROT "down-regulates activity" binding 9606 14670965 t miannu "The coronavirus spike (S) protein mediates infection of receptor-expressing host cells and is a critical target for antiviral neutralizing antibodies. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for the coronavirus (severe acute respiratory syndrome (SARS)-CoV) that causes SARS. Here we demonstrate that a 193-amino acid fragment of the S protein (residues 318-510) bound ACE2 more efficiently than did the full S1 domain (residues 12-672). Smaller S protein fragments, expressing residues 327-510 or 318-490, did not detectably bind ACE2." SIGNOR-260216 S protein P59594 UNIPROT ACE2 protein Q9BYF1 UNIPROT "down-regulates activity" binding 9606 16988814 t miannu "In acute lung injury, such as acid aspiration, pneumonia, or sepsis, the generation of ANG II from ANG I is enhanced by ACE, and ANG II induces acute lung failure through stimulation of the AT1 receptor, while ACE2 and ANG II type 2 receptor negatively regulate this pathway and protect from acute lung failure. On the other hand, SARS-CoV infection is mediated through binding of the SARS-Spike protein to ACE2 or L-SIGN and down-regulates the protective molecule ACE2, and thus leads to severe lung injury and acute lung failure" SIGNOR-260291 RAD50 protein Q92878 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni "One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase." SIGNOR-181634 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna" SIGNOR-171030 KLHL42 protein Q9P2K6 UNIPROT PPP2R5E protein Q16537 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys84 MDTLSDLkMKEYKRS 9606 BTO:0000764 32071084 t miannu "PPP2R5ϵ is a KLHL42 substrate and affects TGF-β signaling in SSc. Lys-84 is a candidate ubiquitin acceptor site within PPP2R5ϵ." SIGNOR-272205 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 10197981 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3" SIGNOR-66738 DNA_damage stimulus SIGNOR-ST1 SIGNOR ERCC6 protein Q03468 UNIPROT up-regulates 24086043 f lperfetto "TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2." SIGNOR-275691 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT "down-regulates activity" phosphorylation Thr198 DEEEEIAtPPPPPPP 10090 BTO:0000944 14754904 t miannu "Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. A lower level of phosphorylation was observed for the double mutant, suggesting that T332 might also be phosphorylated by cdc2 kinase." SIGNOR-262727 ZFP36 protein P26651 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 25815583 t "The TTP binding site in the 3′ UTR of MyoD would permit TTP-mediated mRNA decay" SIGNOR-253597 TLN1 protein Q9Y490 UNIPROT "Av/b8 integrin" complex SIGNOR-C185 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257637 SMAD1/4 complex SIGNOR-C85 SIGNOR RUNX2 protein Q13950 UNIPROT "up-regulates activity" binding 9606 15573378 t ggiuliani "The Runx2 WT and deletion constructs (1 –495, 1–464, and 1–432) all physically interact with the BMP2 responsive Smad 1" SIGNOR-255782 PTK6 protein Q13882 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 26247733 t miannu "29 PTK6 promotes activating phosphorylation of STAT3 at tyrosine residue 705.|STAT3 has been shown to promote tumor initiation of different tumor types, including those of the gastrointestinal tract and skin, and PTK6 was previously shown to promote STAT3 activation and tumorigenesis in mouse models of colon and skin cancer." SIGNOR-278346 AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 f "Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation" SIGNOR-254353 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176821 ATF4 protein P18848 UNIPROT NARS1 protein O43776 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269422 Laminin-8 complex SIGNOR-C181 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253220 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205743 FOXO proteinfamily SIGNOR-PF27 SIGNOR RBL2 protein Q08999 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0000944 11884591 t gcesareni "Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression." SIGNOR-252934 CSNK2A1 protein P68400 UNIPROT HOXB7 protein P09629 UNIPROT "down-regulates activity" phosphorylation Thr204 KTAGPGTtGQDRAEA 10090 BTO:0002882 11290787 t llicata "Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation." SIGNOR-250897 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR LAMP2 protein P13473 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 28743755 t miannu "Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment.We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy." SIGNOR-272324 HOXD3 protein P31249 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002828 14610084 t Luana "The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis." SIGNOR-261650 BRCA1 protein P38398 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0002572 19074868 t gcesareni "The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation" SIGNOR-252458 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001544 19261608 t "The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells." SIGNOR-248327 PGM2 protein Q96G03 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "chemical modification" 9606 32898648 t miannu "Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P)." SIGNOR-268116 carbachol chemical CHEBI:3385 ChEBI CHRM3 protein P20309 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258618 ZNHIT1 protein O43257 UNIPROT H2AZ1 protein P0C0S5 UNIPROT unknown 9606 BTO:0000887 20473270 f gcesareni "The chromatin-remodelling complex snf2-related cbp activator protein (srcap) regulates chromatin structure in yeast by modulating the exchange of histone h2a for the h2a.z variant. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation." SIGNOR-165610 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000661 15870263 t gianni "In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits." SIGNOR-266436 EEF1A1P5 protein Q5VTE0 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269550 HMOX1 protein P09601 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000356 26722274 f irozzo "Heme oxygenase-1 (HO-1) protects endothelial cells (EC) from undergoing apoptosis. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy." SIGNOR-256559 PTK2B protein Q14289 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 9606 26084289 t miannu "These results imply that following EGF stimulation, PYK2 enhances a STAT3-dependent IL8 expression, thus creating a positive feedback loop between ErbB receptors, PYK2, and IL8.|These results suggest that PYK2-induced STAT3 phosphorylation is crucial for IL8 secretion, while IL8 is crucial for EGF-induced MMP9 transcription (Figure xref ) and for SKBR3 invasion (Figure xref )." SIGNOR-279429 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "carbamoyl phosphate(2-)" smallmolecule CHEBI:58228 ChEBI "up-regulates quantity" "precursor of" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267416 ULK2 protein Q8IYT8 UNIPROT PFKM protein P08237 UNIPROT "down-regulates activity" phosphorylation Ser74 EATWESVsMMLQLGG 9606 BTO:0000007 27153534 t done miannu "Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown)." SIGNOR-274043 CAPN1 protein P07384 UNIPROT GSK3A protein P49840 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase" SIGNOR-251585 MIB2 protein Q96AX9 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates activity" polyubiquitination Lys634 KVYQMLQkWVMREGI 9606 BTO:0000815 29642005 t miannu "Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation.  We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. MIB2 Ubiquitylates RIPK1 at Lysines K377 and K634" SIGNOR-272663 "Uridylate-specific endoribonuclease" protein P0C6X7-PRO_0000037321 UNIPROT IFIH1 protein Q9BYX4 UNIPROT "down-regulates activity" 9606 28158275 f miannu "Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation." SIGNOR-260245 MDM2 protein Q00987 UNIPROT HEXIM1 protein O94992 UNIPROT "up-regulates activity" ubiquitination 9606 19617712 t miannu "Here we report that human double minute-2 protein (HDM2), a p53-specific E3 ubiquitin ligase, specifically ubiquitinates HEXIM1 through the lysine residues located within the basic region of HEXIM1.|However, the HDM2-induced HEXIM1 ubiquitination does not lead to proteasome-mediated protein degradation." SIGNOR-278701 CEBPB protein P17676 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12493739 f miannu "The C/EBP5 motif, which is located between the TATA-box and the translation start point, is essential for the C/EBP-mediated constitutive and most of the cAMP-stimulated expression as its mutation nearly abolished IL-10 promoter activity. Our results suggest a dominant role of C/EBP transcription factors relative to CREB/ATF in tissue-specific and differentiation-dependent IL-10 transcription" SIGNOR-254523 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 21779440 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-89818 EML4-ALK "fusion protein" SIGNOR-FP8 SIGNOR STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 21415216 t irozzo "We also found that phosphorylation of both the mitogen-activated proteinkinase (MAPK) ERK and STAT3 was markedly increased inthe cells expressing either variant of EML4-ALK[.]. Oncogenic EML4-ALK tyrosine kinase activates ERKand STAT3 signaling pathways" SIGNOR-259203 RPL22 protein P35268 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262499 RIPK2 protein O43353 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser435 EMFSGELsWSADSIR 9606 22412986 t lperfetto "Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay" SIGNOR-196520 LRRK2 protein Q5S007 UNIPROT SNAPIN protein O95295 UNIPROT down-regulates phosphorylation Thr117 NHSVAKEtARRRAML 9606 BTO:0000938 BTO:0000142 23949442 t lperfetto "Lrrk2 phosphorylates snapin and inhibits interaction of snapin with snap-25. these data suggest that lrrk2 may regulate neurotransmitter release via control of snapin function by inhibitory phosphorylation. hreonine 117 of snapin is one of the sites phosphorylated by lrrk2" SIGNOR-202436 MDM2 protein Q00987 UNIPROT SIRT6 protein Q8N6T7 UNIPROT "down-regulates quantity" ubiquitination 9606 25074979 t miannu "These results suggest that MDM2 degrades SIRT6 in a proteasome dependent manner.|USP10 has been shown to deubiquitinate and stabilize p53, a well-known substrate of MDM2, suggesting a mechanism whereby SIRT6 is ubiquitinated and destabilized by MDM2, which could be reversed by USP10 mediated deubiquitination." SIGNOR-278702 ATF4 protein P18848 UNIPROT AARS2 protein Q5JTZ9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269415 AKT proteinfamily SIGNOR-PF24 SIGNOR RPS3 protein P23396 UNIPROT "up-regulates activity" phosphorylation Thr70 GRRIRELtAVVQKRF 10116 BTO:0003060 20605787 t miannu "Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage." SIGNOR-259816 DVL2 protein O14641 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" binding 9606 17529994 t amattioni "Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex." SIGNOR-155221 PLK1 protein P53350 UNIPROT CCNT1 protein O60563 UNIPROT "down-regulates activity" phosphorylation Ser564 KTYSLSSsFSSSSST 9606 BTO:0002181 23977272 t miannu " Further analysis indicated that Plk1 could phosphorylate cyclin T1 at Ser564 and inhibit the kinase activity of cyclin T1/Cdk9 complex on phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. " SIGNOR-276501 FOXJ1 protein Q92949 UNIPROT CETN2 protein P41208 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000939 23822649 t miannu "FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1)." SIGNOR-266930 HNF1A protein P20823 UNIPROT UGT1A8 protein Q9HAW9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 15044625 t "Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter." SIGNOR-253972 ATP7A protein Q04656 UNIPROT copper(1+) smallmolecule CHEBI:49552 ChEBI "up-regulates quantity" relocalization 28389643 t lperfetto "Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper- transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations. " SIGNOR-272298 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257746 RBL2 protein Q08999 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 10090 BTO:0000165 10801445 f gcesareni "Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program." SIGNOR-241946 CSNK1E protein P49674 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 12000790 t gcesareni "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms." SIGNOR-87444 MAPK10 protein P53779 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 14699954 t amattioni "The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53" SIGNOR-120552 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 11581251 t "inferred from 70% family members" lperfetto "Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL." SIGNOR-270119 TP73 protein O15350 UNIPROT PMAIP1 protein Q13794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17700533 f miannu "Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis." SIGNOR-255469 SMURF2 protein Q9HAU4 UNIPROT UBE2D1 protein P51668 UNIPROT "up-regulates activity" ubiquitination Lys144 HAREWTQkYAM 9606 24709419 t miannu "Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS family E3, beta transducing repeat containing protein 1 (beta-TrCP1)." SIGNOR-278718 SMAD6 protein O43541 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates binding 9606 11737269 t lpetrilli "Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads." SIGNOR-112642 "cyclosporin A" chemical CHEBI:4031 ChEBI PPP3CB protein P16298 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127228 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89205 VCP protein P55072 UNIPROT NGLY1 protein Q96IV0 UNIPROT "up-regulates activity" binding 9606 15362974 t simone "PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome." SIGNOR-261058 PPM1B protein O75688 UNIPROT MPRIP protein Q6WCQ1 UNIPROT "down-regulates activity" dephosphorylation 9606 25751141 t lperfetto "Ppm1b prevents Rip3 auto-activation in resting cells.|Together, these data demonstrate that Ppm1b dephosphorylates Rip3 and thus negatively regulates TNF induced necroptosis in L929 cells." SIGNOR-277019 MYC protein P01106 UNIPROT PFKM protein P08237 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 10823814 t "C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway." SIGNOR-259988 GSK3B protein P49841 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 20331603 t lperfetto "Phosphorylation of the residue Tyrosine in 216 position results in the constitutive activity of GSK-3beta and believed to be important target for signal transduction." SIGNOR-217865 BRAF protein P15056 UNIPROT EEF1A1 protein P68104 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu "Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf. " SIGNOR-276404 PTK2B protein Q14289 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" phosphorylation Tyr486 YPAEDSTyDEYENDL 9606 29133485 t miannu "In conclusion, these data suggest that Pyk2 phosphorylates cortactin on tyrosine residues Y421, Y466, and Y482.|To confirm the direct and indirect effects of Pyk2 on cortactin phosphorylation, we used cells overexpressing Arg YFP and treated with Pyk2 siRNA or a nonsilencing siRNA." SIGNOR-278345 SP1 protein P08047 UNIPROT SCNN1A protein P37088 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004299 12684058 f "Regulation of expression" miannu "Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression." SIGNOR-251950 SRC protein P12931 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 11483655 t lperfetto "We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases" SIGNOR-247180 ERG protein P11308 UNIPROT ENG protein P17813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22235125 f miannu "It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1." SIGNOR-253916 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr133 EMPSEEGyQDYEPEA 9606 BTO:0000975;BTO:0000142 11744621 t llicata "Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers." SIGNOR-113065 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val48 KVDGTSHvTGKGVTV -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263598 MUL1 protein Q969V5 UNIPROT STING1 protein Q86WV6 UNIPROT "up-regulates activity" ubiquitination Lys224 PNIRFLDkLPQQTGD 9606 28763789 t miannu "Identification of MUL1 as an essential activator of dsDNA mediated STING dependent pathway.|We further report that the mitochondrial E3 ubiquitin protein ligase 1 (MUL1, also known as GIDE/MAPL/MULAN/RNF218) ubiquitinates STING on K224 via K63-linked polyubiquitination, which facilitates optimal STING trafficking and the transcription of host defense genes." SIGNOR-278634 CSNK1A1 protein P48729 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity." SIGNOR-183667 PTAFR protein P25105 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257329 USP22 protein Q9UPT9 UNIPROT "SAGA complex" complex SIGNOR-C465 SIGNOR "form complex" binding 9606 34811519 t lperfetto "Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module" SIGNOR-269578 BLOC1S2 protein Q6QNY1 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265937 SGK1 protein O00141 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates activity" phosphorylation Ser274 LERERPLsLLQLLGS 8355 BTO:0000887 17382906 t lperfetto "We evaluated the putative role of sgk1 in the modulation of glut4. Coexpression of the kinase along with glut4 in xenopus oocytes stimulated glucose transport. The enhanced glut4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the sgk1 phosphorylation site on glut4 ((s274a)glut4) abrogated the stimulating effect of sgk1. In summary, sgk1 promotes glucose transporter membrane abundance via glut4 phosphorylation at ser274." SIGNOR-236653 SNCA protein P37840 UNIPROT CADPS2 protein Q86UW7 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 28647363 f gianni "This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells." SIGNOR-268929 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "up-regulates activity" phosphorylation Ser441 GHSPLSLsAQSVMEE 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204708 NVP-BEP800 chemical CID:25210273 PUBCHEM HSP90AB1 protein P08238 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194904 CSKMT protein A8MUP2 UNIPROT CS protein O75390 UNIPROT "down-regulates activity" methylation Lys395 LLEQGKAkNPWPNVD 34929314 t lperfetto "A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate." SIGNOR-267637 ADORA2A protein P29274 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256909 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr651 ALGGKAAyRTSPRLK -1 10210201 t llicata "Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624." SIGNOR-250783 CDX2 protein Q99626 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR "form complex" binding 9606 10506141 t lperfetto "In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300." SIGNOR-70954 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser5 sSQKRHWT 9606 10993082 t gcesareni "Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth." SIGNOR-82037 KCNS1 protein Q96KK3 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 10029 BTO:0000246 10484328 t miannu "We describe the cloning and characterization of the first human members, hKv9.1 and hKv9.3, of the electrically silent delayed-rectifying-like K+ channel subfamily." SIGNOR-269449 FABP5 protein Q01469 UNIPROT "Fatty acid" stimulus SIGNOR-ST19 SIGNOR "up-regulates quantity" relocalization 9606 28457600 t miannu "Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs)." SIGNOR-264459 SKIL protein P12757 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 SIGNOR-C85 12419246 t gcesareni "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7" SIGNOR-195636 ESRRA protein P11474 UNIPROT SNAI1 protein O95863 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000159 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253799 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257988 PPP2R1A protein P30153 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR "form complex" binding 9606 23454242 t gcesareni "[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity." SIGNOR-243445 POU5F1 protein Q01860 UNIPROT RARG protein P13631 UNIPROT "up-regulates quantity" 27499297 f SimoneGraziosi "OCT4 positively controls the level of RARgamma" SIGNOR-269222 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2S protein Q16763 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271309 PRKCE protein Q02156 UNIPROT GSTP1 protein P09211 UNIPROT "up-regulates activity" phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu "Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently" SIGNOR-276020 sorafenib chemical CHEBI:50924 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258284 PRKCQ protein Q04759 UNIPROT CARD11 protein Q9BXL7 UNIPROT "up-regulates activity" phosphorylation Ser644 NLMFRKFsLERPFRP 9606 BTO:0000782 21157432 t lperfetto "NF-kappaB activation is triggered by PKCteta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCteta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCteta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation." SIGNOR-249193 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR RIPK1 protein Q13546 UNIPROT "down-regulates activity" cleavage Asp324 RMQSLQLdCVAVPSS 9606 BTO:0000007;BTO:0000093;BTO:0000567 10521396 t amattioni "These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability." SIGNOR-256442 NELFA protein Q9H3P2 UNIPROT NELF complex SIGNOR-C521 SIGNOR "form complex" binding 9606 18628398 t miannu "The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E." SIGNOR-271401 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120200 KLK2 protein P20151 UNIPROT NCOA4 protein Q13772 UNIPROT up-regulates 9606 BTO:0001130 24122203 f miannu "Klk2may cooperate with the ar coregulator, ara70, to enhance ar transactivation" SIGNOR-202885 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX10 protein P56693 UNIPROT "down-regulates activity" phosphorylation Thr244 GPPTPPTtPKTELQS 9606 BTO:0002806 29295999 t miannu "Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity.ERK2 directly phosphorylates SOX10 at T240 and T244." SIGNOR-277820 NEDD4L protein Q96PU5 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253459 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." SIGNOR-250762 AMFR protein Q9UKV5 UNIPROT GPI protein P06744 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 24810856 t miannu "Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF." SIGNOR-272177 barium(2+) chemical CHEBI:37136 ChEBI KCNJ13 protein O60928 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9620703 t miannu "Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations" SIGNOR-258925 LUBAC complex SIGNOR-C527 SIGNOR DDX58 protein O95786 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21292167 t miannu "HOIL-1L/HOIP LUBAC induces TRIM25 ubiquitination and degradation Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner." SIGNOR-271860 E2F1 protein Q01094 UNIPROT BBC3 protein Q96PG8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003476 17263886 f miannu "Up-regulation of the PUMA gene and protein by E2F-1 overexpression was detected by real-time PCR and Western blot analysis in the SK-MEL-2 melanoma cell line" SIGNOR-253843 NEDD4L protein Q96PU5 UNIPROT SLC1A2 protein P43004 UNIPROT "down-regulates quantity" ubiquitination 9606 28151476 t miannu "Our results confirm that Nedd4-2 knockdown in MPTP treated mice increased GLT-1 expression at the membrane protein level (XREF_FIG; P < 0.01).|These results suggest that Nedd4-2 mediates the ubiquitination of both GLT-1 and GLAST in the midbrain in MPTP treated mice, and Nedd4-2 maybe a potential target in regulating glutamate transporters in PD." SIGNOR-278706 CDK2 protein P24941 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 t gcesareni "We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5" SIGNOR-173681 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" dephosphorylation Tyr505 FTATEGQyQPQP 9606 11259588 t "Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity" SIGNOR-248350 GLI1 protein P08151 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni "Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin" SIGNOR-188875 PGAM5 protein Q96HS1 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000007 19590015 t miannu "PGAM5 Is a Protein Ser/Thr Phosphatase That Activates ASK1. PGAM5 Dephosphorylates ASK1. This dephosphorylation unleashes phosphorylation ofThr-838 in the kinase domain, with activation of ASK1." SIGNOR-277984 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 BTO:0001271 17318191 t lperfetto "Bcr_abl_mediated phosphorylation of y86 could induce a conformational change of __catenin impairing its binding to axin" SIGNOR-153435 S protein P59594 UNIPROT CLEC4M protein Q9H2X3 UNIPROT "up-regulates activity" binding 9606 15479853 t lperfetto "Here we show that DC-SIGN and DC-SIGNR enhance infection mediated by the glycoprotein (GP) of Marburg virus (MARV) and the S protein of severe acute respiratory syndrome coronavirus and might promote viral dissemination." SIGNOR-260269 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT "up-regulates activity" phosphorylation Ser14 PFSCHYPsRLRRDPF 9606 BTO:0000887 11342557 t lperfetto "Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation" SIGNOR-107684 TBXA2R protein P21731 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256744 PIM1 protein P11309 UNIPROT EPAS1 protein Q99814 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser435 GKAILPPsQPWATEL 9606 BTO:0002181 34211090 t miannu "PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits." SIGNOR-277310 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr1223 AEREGPGtPPTTLAR 9606 15125835 t lperfetto "Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis." SIGNOR-124646 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Thr393 DFVGHQGtVPSDNID -1 8662852 t "we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411)." SIGNOR-251200 PSMB7 protein Q99436 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263360 NUP62 protein P37198 UNIPROT SASS6 protein Q6UVJ0 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 24107630 t Simone "Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles." SIGNOR-261256 F7 protein P08709 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" binding 9606 BTO:0000131 SIGNOR-C319 29880919 t lperfetto "TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively." SIGNOR-263544 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15677482 t gcesareni "Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of enac. Sgk1 catalyzed phosphorylation of hnedd4-2 at ser-468 maintaining hnedd4-2 in an inactive phosphorylated state." SIGNOR-133438 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT "down-regulates activity" phosphorylation Ser29 QRRSARLsAKPAPPK 9606 BTO:0000567 11438671 t lperfetto "We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets." SIGNOR-249103 SMARCA2 protein P51531 UNIPROT CERF complex SIGNOR-C340 SIGNOR "form complex" binding 9606 BTO:0000227 15640247 t miannu "Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation." SIGNOR-263890 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159381 RPS6 protein P62753 UNIPROT "Ribosome biogenesis" phenotype SIGNOR-PH164 SIGNOR up-regulates -1 19812304 f Luana "The stimulation of S6K1 activity by mTORC1 leads to increases in mRNA biogenesis, cap-dependent translation and elongation, and the translation of ribosomal proteins through regulation of the activity of many proteins, such as S6K1 aly/REF-like target (SKAR), programmed cell death 4 (PDCD4), eukaryotic elongation factor 2 kinase (eEF2K) and ribosomal protein S6 " SIGNOR-264617 ADP chemical CHEBI:16761 ChEBI AMPK complex SIGNOR-C15 SIGNOR up-regulates "chemical activation" 9606 21399626 t lperfetto "Amp binding to the gamma-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation.Adp also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive." SIGNOR-217475 MARK4 protein Q96L34 UNIPROT MAPT protein P10636-4 UNIPROT "down-regulates activity" phosphorylation Ser353 RHLSNVSsTGSIDMV -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273934 GRPEL1 protein Q9HAV7 UNIPROT HSPA8 protein P11142 UNIPROT "down-regulates activity" binding 9606 BTO:0000793 11311562 t miannu "As we had observed earlier,HMGE bound avidly to DnaK (Fig. 5A). In addition, bothMt-Hsp70 and Hsc70 bound to GST-HMGE, but Hsc70 appeared to bind with lower affinity. HMGE inhibitedthe co-chaperone enhancement of Hsc70 ATPase activity byapproximately 50% (Table 1)." SIGNOR-261241 BLVRB protein P30043 UNIPROT biliverdin(2-) smallmolecule CHEBI:57991 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000759 7929092 t lperfetto "This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions." SIGNOR-275524 SPI1 protein P17947 UNIPROT TAL2 protein Q16559 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24086757 f irozzo "We show that Tal2 is a direct target gene of the myeloid transcription factor PU.1, which is a key transcription factor for osteoclast gene expression" SIGNOR-259086 AKT proteinfamily SIGNOR-PF24 SIGNOR PHF20 protein Q9BVI0 UNIPROT down-regulates phosphorylation Ser291 ELRRRKIsKGCEVPL 9606 22334668 t llicata "Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function." SIGNOR-196112 ADD2 protein P35612 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266039 PRRX1 protein P54821 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000567 9334314 t miannu "The human homeodomain proteinphox1interacts functionally with serum response factor (srf) to impart serum responsive transcriptional activity to srf-binding sites in a hela cell cotransfection assay." SIGNOR-52657 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI "up-regulates quantity" "precursor of" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267900 GATA2 protein P23769 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR "up-regulates activity" 10090 21605981 f "GATA1 and GATA2 are expressed principally in hematopoietic lineages, and have essential roles in the development of multiple hematopoietic cells, including erythrocytes and megakaryocytes." SIGNOR-259960 PLK1 protein P53350 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 27003818 t miannu "An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (Figure 8C).|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation." SIGNOR-278191 ERAP1 protein Q9NZ08 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI "down-regulates quantity" "chemical modification" 9606 31810556 t scontino "While peptides loaded onto MHC class I molecules are 8‚Äì11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1." SIGNOR-267771 TBK1 protein Q9UHD2 UNIPROT HTT protein P42858 UNIPROT "up-regulates activity" phosphorylation Ser13 KLMKAFEsLKSFQQQ 9606 BTO:0000007 32757223 t "Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity." SIGNOR-270350 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT "up-regulates activity" phosphorylation Tyr722 EEDDEENyENVPRVL -1 12051764 t miannu "Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2." SIGNOR-274009 hsa-miR-146a mirna URS00005E1F00_9606 RNAcentral CXCR4 protein P61073 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001412 26045293 t "MiR-146a overexpression in U937 cells induces a decrease of CXCR4 protein" SIGNOR-277939 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 BTO:0000887;BTO:0001103 11500363 t lperfetto "Sapk4/p38delta phosphorylated eef2k at ser359 in vitro, causing its inactivation." SIGNOR-109703 TNF protein P01375 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32446778 f "doi: 10.1016/j.cytogfr.2020.05.003" miannu "Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α)" SIGNOR-260856 CHRM1 protein P11229 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256878 TIMM29 protein Q9BSF4 UNIPROT "TIM22 complex" complex SIGNOR-C424 SIGNOR "form complex" binding 9606 BTO:0000007 32901109 t lperfetto "Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK)." SIGNOR-267707 AURKA protein O14965 UNIPROT AURKAIP1 protein Q9NWT8 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser70 MLVPRKMsVSPLESW 9606 BTO:0000567 17957726 t miannu "AIP is phosphorylated on Serine 70 by Aurora‐A but not Aurora‐B and expression of phosphorylation mimic mutant of AIP results in prolonged protein stability compared to unphosphorylatable mutant. Phosphorylation of AIP Prolongs its Protein Stability" SIGNOR-262648 GSK3A protein P49840 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Thr254 RQVAIVFRtPPYADPS 10090 BTO:0000249 22761446 t "Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation" SIGNOR-255827 CAPN2 protein P17655 UNIPROT CDK5R1 protein Q15078 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251610 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t esanto "Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89248 "Rix1 complex" complex SIGNOR-C373 SIGNOR "Ribosome biogenesis" phenotype SIGNOR-PH164 SIGNOR up-regulates 9606 BTO:0000007 22190736 f miannu "In this study, we show that LAS1L forms a protein complex with PELP1, TEX10, NOL9, SENP3, and WDR18. Our data demonstrate that all the components of the LAS1L complex cosediment with the pre-60S ribosomal particle and are required for proper processing of the 32S rRNA intermediate.These findings demonstrate that the LAS1L complex is critical for ribosome biogenesis and cell proliferation and provide additional evidence that multiple protein complexes have distinct functions in the synthesis of eukaryotic ribosomes." SIGNOR-265473 CAMTA1 protein Q9Y6Y1 UNIPROT NPPA protein P01160 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002004 21857646 t Luana "CAMTA1 itself stimulates the expression of the anti-proliferative peptide NPPA." SIGNOR-261570 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto "Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1" SIGNOR-245428 PRKCQ protein Q04759 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr354 RKPANDItSQLEINF 9606 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249250 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD2 protein Q9BZL6 UNIPROT "up-regulates activity" phosphorylation Ser876 QGLAERIsVL 12058027 t lperfetto "Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead." SIGNOR-275950 GSK3B protein P49841 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates activity" phosphorylation Thr1966 TPEKTDMtPSTTSPP 9606 BTO:0000938 32599005 t lperfetto "Glycogen synthase kinase 3β (GSK3beta) phosphorylates the Nav1.2C-terminal tail at T1966, suppressing Na+ currents and channel trafficking to the plasma membrane" SIGNOR-275748 TAGAP protein Q8N103 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260524 CDK3 protein Q00526 UNIPROT MECOM protein Q03112 UNIPROT "up-regulates activity" phosphorylation Ser624 KMFKDKVsPLQNLAS 33082307 t lperfetto "The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A." SIGNOR-273431 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 9606 19365405 t gcesareni "B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1." SIGNOR-185274 ABL1 protein P00519 UNIPROT YAP1 protein P46937 UNIPROT up-regulates phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 18280240 t llicata "In this study, we show that c-abl directly phosphorylates yap1 at position y357 in response to dna damage. Tyrosine-phosphorylated yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes." SIGNOR-160860 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC14 protein Q99879 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271994 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT up-regulates 9606 BTO:0000934 23939472 f lperfetto "We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. " SIGNOR-261488 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-252568 STK33 protein Q9BYT3 UNIPROT HPD protein P32754 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr382 QNLRGNLtNMETNGV 10090 BTO:0003036 31537781 t lperfetto "Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation." SIGNOR-272958 midostaurin chemical CHEBI:63452 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 12124173 t "PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors." SIGNOR-256308 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248298 SMURF1 protein Q9HCE7 UNIPROT UVRAG protein Q9P2Y5 UNIPROT "down-regulates activity" ubiquitination Lys559 DTSLDFSkENKKKGE 9606 BTO:0000007 30686098 t miannu "Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux. " SIGNOR-273653 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258120 CTTNBP2 protein Q8WZ74 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" binding 10116 BTO:0000938 22262902 t miannu "Fluorescence recovery after photobleaching further suggested that CTTNBP2 modulates the mobility of cortactin in neurons. CTTNBP2 may thus help to immobilize cortactin in dendritic spines and control the density of dendritic spines." SIGNOR-269703 Avagacestat chemical CID:46883536 PUBCHEM APP protein P05067 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190479 ALPL protein P05186 UNIPROT SPP1 protein P10451 UNIPROT "down-regulates activity" dephosphorylation 10090 23427088 t miannu "This result suggests that endogenous mouse TNAP dephosphorylates OPN in osteoblasts and that overexpressed human TNAP dephosphorylates OPN, compensating for the lack of endogenous TNAP in [Col1a1-Tnap +/\u2212 ;Alpl \u2212/\u2212 ] cells." SIGNOR-277045 FOXD2 protein O60548 UNIPROT PRKAR1A protein P10644 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 12621056 t Luana "Elevating the amounts of FOXD2 expression vector up to 12-fold relative to the RIα1b reporter construct demonstrated that maximal induction of the RIα1b promoter by FOXD2 was at least 5.8-fold" SIGNOR-261605 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1B protein P35368 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257451 IL1R1 protein P14778 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 9625767 t lperfetto "Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab" SIGNOR-249513 ERCC6 protein Q03468 UNIPROT APEX1 protein P27695 UNIPROT "down-regulates activity" binding 9606 17567611 t Regulation miannu "CSB stimulates the AP site incision activity of APE1 on normal (i.e. fully paired) and bubble AP-DNA substrates, with the latter being more pronounced (up to 6-fold). This activation is ATP-independent, and specific for the human CSB and full-length APE1 protein. CSB and APE1 were also found in a common protein complex in human cell extracts, and recombinant CSB, when added back to CSB-deficient whole cell extracts, resulted in increased total AP site incision capacity." SIGNOR-251932 GSK3A protein P49840 UNIPROT BCL3 protein P20749 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser402 LSASPSSsPSQSPPR 9606 BTO:0000007 15469820 t miannu "In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway." SIGNOR-276011 APH1B protein Q8WW43 UNIPROT PSENEN protein Q9NZ42 UNIPROT up-regulates binding 9606 12522139 t gcesareni "Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex." SIGNOR-97110 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273066 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 t lperfetto "Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. " SIGNOR-249071 TAOK1 protein Q7L7X3 UNIPROT MARK2 protein Q7KZI7 UNIPROT "up-regulates activity" phosphorylation Thr208 TFGNKLDtFCGSPPY -1 18424437 t miannu "MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase." SIGNOR-276164 NOTCH3 protein Q9UM47 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 11404076 t gcesareni "Both notch 1 and notch 3 ics displace the co-repressor smrt from the dna-binding protein rbp-j kappa on the hes promoter. The latter observation suggests that both notch 3 ic and notch 1 ic can access rbp-j kappa in vivo, and that the difference in activation capacity instead stems from structural differences in the two ics when positioned on rbp-j kappa." SIGNOR-86128 FYN protein P06241 UNIPROT FCGR2C protein P31995 UNIPROT "up-regulates activity" phosphorylation Tyr294 YETADGGyMTLNPRA -1 8756631 t miannu "Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation" SIGNOR-262677 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPK3 protein P27361 UNIPROT "up-regulates activity" phosphorylation Thr207 FLTEYVAtRWYRAPE 9606 BTO:0000562 19060905 t lperfetto "Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy." SIGNOR-244565 PRKN protein O60260 UNIPROT SEPTIN5 protein Q99719 UNIPROT "down-regulates quantity" ubiquitination 9606 11078524 t miannu "Furthermore, Parkin ubiquitinates and promotes the degradation of CDCrel-1.|Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1." SIGNOR-278711 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Thr27 KFRFRKEtNNAAIIM -1 9030586 t lperfetto "Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively." SIGNOR-248961 LPCAT1 protein Q8NF37 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI "down-regulates quantity" "chemical modification" 9606 21498505 t miannu "Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. " SIGNOR-272763 PRKCQ protein Q04759 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251636 FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001103 19319192 t gcesareni "Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy." SIGNOR-184861 NatA complex SIGNOR-C415 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 f miannu "About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity." SIGNOR-267229 RAC2 protein P15153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 9705280 t gcesareni "This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2." SIGNOR-59546 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT "down-regulates activity" dephosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 16778204 t "The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels" SIGNOR-248701 GPR35 protein Q9HC97 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257283 PAF1 protein Q8N7H5 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR "form complex" binding 9606 BTO:0000567 20178742 t miannu "Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). " SIGNOR-269833 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR NFKBIA protein P25963 UNIPROT "up-regulates quantity by stabilization" cleavage -1 9367996 t lperfetto "The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues." SIGNOR-256456 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 11258706 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-105737 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 19864431 t lperfetto "Here we focus primarily although not exclusively on raptor Ser(863) phosphorylation. We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser(863) via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. mTORC1 activation by other stimuli (e.g. amino acids, epidermal growth factor/MAPK signaling, and cellular energy) also promote raptor Ser(863) phosphorylation." SIGNOR-217559 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Ser241 SKQARANsFVGTAQY 9606 10455013 t lperfetto "Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1" SIGNOR-236789 SLC24A3 protein Q9HC58 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 30173760 t miannu "K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+)" SIGNOR-264396 GEMIN5 protein Q8TEQ6 UNIPROT "SMN complex" complex SIGNOR-C158 SIGNOR "form complex" binding 12065586 t lperfetto "SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry." SIGNOR-253119 EVL protein Q9UI08 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 f miannu "Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance." SIGNOR-268394 MAPK9 protein P45984 UNIPROT ATN1 protein P54259 UNIPROT "down-regulates activity" phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 t lperfetto "Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment," SIGNOR-102402 DAPT chemical CHEBI:86193 ChEBI APP protein P05067 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191292 CAMK2A protein Q9UQM7 UNIPROT NOS1 protein P29475 UNIPROT "down-regulates activity" phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 t llicata "It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation." SIGNOR-250635 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates activity" dephosphorylation Tyr960 GHQKRIAySLLGLKD -1 21538645 t gcesareni "The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates" SIGNOR-246023 CDK1 protein P06493 UNIPROT RAB5B protein P61020 UNIPROT unknown phosphorylation Ser123 KELQRQAsPSIVIAL 9606 10403367 t lperfetto "Cdc2 kinase preferentially phosphorylates ser-123 of rab5b. More work will be required to establish how phosphorylation of the three rab5 isoforms influences their function in the endocytic pathway" SIGNOR-69233 "1-acyl-sn-glycerol 3-phosphate(2-)" smallmolecule CHEBI:57970 ChEBI "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "up-regulates quantity" "precursor of" 9606 21173190 t lperfetto "The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬†" SIGNOR-267010 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 10090 BTO:0002295 31063459 f lperfetto "Mitochondrial fission is governed primarily by the cytoplasmic dynamin-related protein 1 (Drp1). Drp1 is a conserved dynamin GTPase superfamily protein that is translocated from its cytoplasmic pool to the outer mitochondrial membrane, where Drp1 then assembles into constrictive ring-like multimeric structures, ultimately driving mitochondrial fragmentation through a GTP-dependent mechanism|We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes" SIGNOR-262553 HCK protein P08631 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249364 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 21798082 t gcesareni "Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 (pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation." SIGNOR-175675 PAK3 protein O75914 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser150 TLRRVRIsADAMMQA 9606 BTO:0000887 15769444 t lperfetto "In vitro addition of pak3 to skinned rat cardiac fibres increased myofilament ca2+ sensitivity with no change in maximal ca2+-activated force [67]. These effects were associated with pak3-induced phosphorylation of myofilament proteins, including ctni which was phosphorylated at a novel site, ser149, located in the region forming a ca2+-sensitive interaction with the n-terminal regulatory domain of tnc." SIGNOR-134593 MS4A2 protein Q01362 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR "form complex" binding 9606 BTO:0000830 16470226 t "Alessandro Palma" "FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling." SIGNOR-254960 GABRD protein O14764 UNIPROT "GABA-A (a4-b3-d) receptor" complex SIGNOR-C327 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263749 GPR34 protein Q9UPC5 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256831 ASAP2 protein O43150 UNIPROT ARF1 protein P84077 UNIPROT "up-regulates activity" "gtpase-activating protein" -1 10022920 t miannu "Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro." SIGNOR-269705 TRAF3 protein Q13114 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 24622840 t miannu "MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1." SIGNOR-260156 JAK2 protein O60674 UNIPROT CCR2 protein P41597 UNIPROT "up-regulates activity" phosphorylation Tyr139 ILLTIDRyLAIVHAV 9606 9670957 t "JAK2 phosphorylates CCR2 at the Tyr139 position and promotes JAK2/STAT3 complex association to the receptor. " SIGNOR-251345 NRXN3 protein Q9Y4C0 UNIPROT DAG1 protein Q14118 UNIPROT "up-regulates activity" binding 9606 22626542 t miannu "The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM." SIGNOR-265463 TNF protein P01375 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253489 CSNK2B protein P67870 UNIPROT CSNK2B protein P67870 UNIPROT unknown phosphorylation Ser2 sSSEEVSW 9606 1939094 t llicata "Phosphorylation of the beta subunit of casein kinase II in human A431 cells. Identification of the autophosphorylation site | Cleavage of the beta subunit, that had been autophosphorylated in vitro, at tryptophan 9 and tryptophan 12 using N-chlorosuccinimide demonstrated that the autophosphorylation site is located near the amino terminus of the protein, most likely at serine 2 and serine 3." SIGNOR-251062 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1327 CCSPPPDyNSVVLYS 9606 9722576 t lperfetto "Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor." SIGNOR-59758 ZMYND8 protein Q9ULU4 UNIPROT ADORA1 protein P30542 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 21620140 t Luana "We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8. " SIGNOR-266208 PAX1 protein P15863 UNIPROT MEOX1 protein P50221 UNIPROT "up-regulates activity" binding -1 11423130 t miannu "We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family." SIGNOR-222193 ALK protein Q9UM73 UNIPROT STAT3 protein P40763 UNIPROT up-regulates binding 9606 BTO:0000785 16084951 t gcesareni "Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1." SIGNOR-139460 NOTCH1 protein P46531 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001253 12107827 f gcesareni "Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression." SIGNOR-90455 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192823 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation 9606 21880741 t miannu "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-255463 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser633 GISQCGYsSTIVHVP 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250818 AKT1 protein P31749 UNIPROT HMOX1 protein P09601 UNIPROT unknown phosphorylation Ser188 LYRSRMNsLEMTPAV 9606 BTO:0000007 15581622 t llicata "We have identified a putative consensus sequence for phosphorylation by akt/pkb of ho-1 at ser188. although the changes in activity are small, this study provides the first evidence for a role of the survival kinase akt in the regulation of ho-1." SIGNOR-252506 letrozole chemical CHEBI:6413 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193651 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1672 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248784 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 18372406 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-178145 S protein P59594 UNIPROT CD209 protein Q9NNX6 UNIPROT "up-regulates activity" binding 9606 15479853 t lperfetto "Here we show that DC-SIGN and DC-SIGNR enhance infection mediated by the glycoprotein (GP) of Marburg virus (MARV) and the S protein of severe acute respiratory syndrome coronavirus and might promote viral dissemination." SIGNOR-260270 STK24 protein Q9Y6E0 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 9606 BTO:0000007 16314523 t lperfetto "Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity." SIGNOR-142467 NFKB1 protein P19838 UNIPROT MAP3K8 protein P41279 UNIPROT down-regulates binding 9606 SIGNOR-C13 22435554 t gcesareni "Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek" SIGNOR-196747 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser539 GLITINSsQEHLTVQ 9606 22123827 t lperfetto "Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication." SIGNOR-177809 Oxytocin protein P01178-PRO_0000020495 UNIPROT "GABA-A (a3-b1-g2) receptor" complex SIGNOR-C332 SIGNOR up-regulates 9606 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268581 PTPN2 protein P17706 UNIPROT JAK3 protein P52333 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-133078 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" phosphorylation Ser29 ATKAARKsAPATGGV 9606 11856369 t "Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription." gcesareni "Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation" SIGNOR-114852 regorafenib chemical CHEBI:68647 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206412 POLE3 protein Q9NRF9 UNIPROT "DNA polymerase epsilon" complex SIGNOR-C377 SIGNOR "form complex" binding 9606 BTO:0000567 10801849 t lperfetto "Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon." SIGNOR-265522 PRKD1 protein Q15139 UNIPROT ARFIP1 protein P53367 UNIPROT up-regulates phosphorylation Ser132 LELVRKWsLNTYKCT 9606 23695357 t lperfetto "We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway." SIGNOR-202101 AMPK complex SIGNOR-C15 SIGNOR AMPK complex SIGNOR-C15 SIGNOR unknown phosphorylation 9606 BTO:0000007 11171104 t lperfetto "In contrast, the phosphorylation site mutations, ss24, 25aa and s182a, while having no effects on enzyme activity, are associated with nuclear redistribution of the subunit." SIGNOR-216415 CSNK2A1 protein P68400 UNIPROT IP6K2 protein Q9UHH9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser347 RPEVVLDsDAEDLED 9606 BTO:0000007 21262846 t miannu "CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation." SIGNOR-273624 SRC protein P12931 UNIPROT DGKA protein P23743 UNIPROT up-regulates phosphorylation Tyr335 ILPPSSIyPSVLASG 9606 17700527 t llicata "Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility." SIGNOR-157365 PTK2 protein Q05397 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9416004 t gcesareni "Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors." SIGNOR-252726 SGCG protein Q13326 UNIPROT DGC complex SIGNOR-C217 SIGNOR "form complex" binding 9606 15117830 t apalma "The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink)." SIGNOR-255987 Ub:E2 complex SIGNOR-C497 SIGNOR RNF212B protein A8MTL3 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271257 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser213 SGAPVKPsPQAAAVE 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-84984 DAB2IP protein Q5VWQ8 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates quantity by destabilization" 9606 27476001 f miannu "DAB2IP destabilizes HIF1Œ± protein to inhibit EMT in PCa cells. DAB2IP may destabilize HIF1Œ± protein in PCa cells via an ubiquitin-proteasome system." SIGNOR-254765 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-251590 Ub:E2 complex SIGNOR-C497 SIGNOR RNF103 protein O00237 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271093 SIRT5 protein Q9NXA8 UNIPROT SIRT3 protein Q9NTG7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31608237 f Monia "In U2OS cells, SIRT5 silencing resulted in downregulation of SIRT1 and SIRT3 protein levels (Figures 4Ai,ii, compare bars 1 to 5)." SIGNOR-261209 3-N-Me-Phe-morphiceptin chemical CID:115335 PUBCHEM OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258417 PKA proteinfamily SIGNOR-PF17 SIGNOR PIK3CG protein P48736 UNIPROT "down-regulates activity" phosphorylation Thr1024 YLALRHHtNLLIILF 9606 BTO:0002181 21474070 t miannu "Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP(3) production. " SIGNOR-276321 MKRN1 protein Q9UHC7 UNIPROT RPS10 protein P46783 UNIPROT "up-regulates activity" ubiquitination Lys107 ETGRPRPkGLEGERP 9606 BTO:0000007 31640799 t miannu "We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1.Our data show that MKRN1 associates with polysomes and ubiquitylates RPS10, indicating a role in translational control. We hypothesize that ribosomes encountering the MKRN1-PABPC1 complex are stalled, possibly via ubiquitylation of RPS10 on K107 and other MKRN1 substrates." SIGNOR-272216 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207603 OXTR protein P30559 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257332 SMAD6 protein O43541 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 20663871 t lperfetto "The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation." SIGNOR-167160 F2RL1 protein P55085 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257144 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser310 LDVQRVPsFESFEDD 9606 19182667 t lperfetto "Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters" SIGNOR-183600 MOAP1 protein Q96BY2 UNIPROT RASSF1 protein Q9NS23 UNIPROT "up-regulates activity" binding 9606 26269600 t miannu "Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax. " SIGNOR-272914 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 SIGNOR-C83 10428798 t gcesareni "Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity." SIGNOR-69710 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 10090 BTO:0000944 10698938 t "Protein tyrosine phosphatase alpha (PTPalpha) is believed to dephosphorylate physiologically the Src proto-oncogene at phosphotyrosine (pTyr)527, a critical negative-regulatory residue. It thereby activates Src, and PTPalpha overexpression neoplastically transforms NIH 3T3 cells." SIGNOR-248438 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR EP300 protein Q09472 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 28630438 t miannu "NUP98-HOXA9 has an activator-repressor role in transcriptional regulation driven by p300 and HDAC1 interactions. The chromosomal translocation t(7;11)(p15, p15), encoding the fusion protein NUP98-HOXA9 (NHA9), is a rare poor risk cytogenetic event in AML associated with a particularly poor prognosis.In summary, NHA9 deregulates the expression of key leukemic genes, including MEIS1-HOXA9-PBX3 complex, through the enhancer binding and the direct interaction of the fusion protein with HDAC and p300 transcriptional regulators." SIGNOR-261497 SERPINA5 protein P05154 UNIPROT FN1 protein P02751 UNIPROT "down-regulates activity" binding 9606 BTO:0000594 24388360 t miannu "SERPINA5 inhibits HCC cell migration by directly interacting with fibronectin. SERPINA5 disrupts the fibronectin–integrin β1 signaling pathway." SIGNOR-265881 SUN1 protein O94901 UNIPROT SPDYA protein Q5MJ70 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 SIGNOR-C305 33015044 t lperfetto "In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | Taken together, we speculate that speedy A is likely capable of interacting with both telomeres and the LINC complex and thus might function as the missing linkage between telomeres and the LINC complex during prophase I, stabilizing the telomere–NE connection" SIGNOR-263301 ATF4 protein P18848 UNIPROT EPRS1 protein P07814 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269419 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001412 8394219 f "We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death." SIGNOR-255722 DDB1 protein Q16531 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "form complex" binding 9606 22649780 t gcesareni "The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors" SIGNOR-234802 FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity" ubiquitination 9606 SIGNOR-C135 20852628 t gcesareni "We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it." SIGNOR-243545 hsa-miR-205-5p mirna URS0000446722_9606 RNAcentral LRP1 protein Q07954 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003765 24525843 t Parnian "Taken together, LRP-1 overexpression by the decreased miR-205 may promote the proliferation of DFSP cells.| LRP-1 is the direct target of miR-205." SIGNOR-278835 CSNK1A1 protein P48729 UNIPROT MDM4 protein O15151 UNIPROT up-regulates phosphorylation Ser289 DDLEDSKsLSDDTDV 9606 23028042 t lperfetto "Previous studies showed that casein kinase 1? (ck1?) Stably associates with mdmx, stimulates mdmx-p53 binding, and cooperates with mdmx to inactivate p53ck1? Binding to the mdmx central domain and phosphorylation of s289 disrupts the intramolecular interaction, allowing the n terminus to bind p53 with increased affinity. After dna damage, the mdmx-ck1? Complex is disrupted by chk2-mediated phosphorylation of mdmx at s367, leading to reduced mdmx-p53 binding." SIGNOR-199015 ATG4B protein Q9Y4P1 UNIPROT GABARAPL2 protein P60520 UNIPROT "up-regulates activity" cleavage -1 16303767 t lperfetto "In mammals, at least three atg8 homologs, lc3, gabarap, and gate-16, have been identified (fig. 1a), all of which have structural ubiquitin folds (1416). In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly" SIGNOR-141932 PP1 proteinfamily SIGNOR-PF54 SIGNOR PYGM protein P11217 UNIPROT "down-regulates activity" dephosphorylation Ser15 QEKRKQIsVRGLAGV 9606 BTO:0002049 22225877 t "GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation" SIGNOR-267402 cabozantinib chemical CHEBI:72317 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000184 26536165 t miannu "Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3." SIGNOR-262243 CSNK1D protein P48730 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Ser143 FHPNVSSsHENLEPE 9606 22609948 t lperfetto "Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle" SIGNOR-197547 PSMD12 protein O00232 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263352 UHMK1 protein Q8TAS1 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 19033656 t gcesareni "This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of kis-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation." SIGNOR-182489 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR VRK3 protein Q8IV63 UNIPROT "up-regulates activity" phosphorylation Ser108 RPPTPKSsPQKTRKS 27346674 t lperfetto "Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation|" SIGNOR-275545 PTPRK protein Q15262 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 25612622 t miannu "In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705)." SIGNOR-277060 KAT2A protein Q92830 UNIPROT H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269600 KIF11 protein P52732 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272521 MAPK8 protein P45983 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 t gcesareni "Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase." SIGNOR-196038 CLASP2 protein O75122 UNIPROT CLIP2 protein Q9UDT6 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15631994 t lperfetto "CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability." SIGNOR-265093 CTNNB1 protein P35222 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265813 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Thr119 PTCRGALtPSIRNLA 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198733 SATB1 protein Q01826 UNIPROT MYB protein P10242 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255135 MYLIP protein Q8WY64 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity" ubiquitination 9606 29707137 t miannu "MYLIP knockdown increased AR protein levels whereas CNPY2 knockdown increased MYLIP and reduced AR protein expression levels.|These results showed that the E3 ligase MYLIP could ubiquitinate lysine 845 and 847 residues of AR." SIGNOR-278766 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser153 SWTRVFQsWWDRNLG 9606 BTO:0000007 10837486 t lperfetto "We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites." SIGNOR-249045 WNT5A protein P41221 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" 9606 21078818 f lperfetto "We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3)" SIGNOR-227961 TAGAP protein Q8N103 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260523 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75914 CDK2 protein P24941 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser301 IQSNLDFsPVNSASS 9606 21765472 t lperfetto "Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency" SIGNOR-175083 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248737 PKA proteinfamily SIGNOR-PF17 SIGNOR V-ATPase complex SIGNOR-C560 SIGNOR "up-regulates activity" relocalization 9606 BTO:0000567 31827278 t miannu "It is worth noting that CA-PKA failed to rescue macropinocytosis in KRAS-knockdown cells, indicating that whereas PKA activation is necessary for mutant KRAS-dependent plasma membrane translocation of V-ATPase and induction of macropinocytosis, it is not sufficient (Extended Data Fig. 6e)." SIGNOR-277763 CSNK2B protein P67870 UNIPROT RNF7 protein Q9UBF6 UNIPROT "up-regulates activity" phosphorylation Thr10 DVEDGEEtCALASHS 9606 BTO:0000567 12748192 t llicata "In the present study, we show the evidence that CKBBP1 is phosphorylated on threonine residue at position 10 by CKII in vitro and in vivo. Most importantly, disruption of this phosphorylation in CKBBP1 results in accumulation of IκBα and p27Kip1 in HeLa cells and inhibits cell proliferation that appears to be linked to defects in G1/S transition." SIGNOR-251081 ARHGEF19 protein Q8IW93 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260543 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT "up-regulates activity" phosphorylation Tyr175 EITTNRFyGPQVNNI -1 16199863 t "Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation." SIGNOR-251436 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT "up-regulates activity" phosphorylation Ser627 KKRVRRPsESDKEDE -1 14657015 t lperfetto "Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin." SIGNOR-271841 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-244723 PTPN11 protein Q06124 UNIPROT SYK protein P43405 UNIPROT "down-regulates activity" dephosphorylation 9606 23182168 t miannu "Another SHP isoform, SHP-2, has been linked to negative regulation of Syk.|Syk and LAT are differentially dephosphorylated by SHP-2 and SHP-1, respectively." SIGNOR-277085 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270428 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates binding 9606 14718519 t gcesareni "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate tbetari." SIGNOR-120471 TFE3 protein P19532 UNIPROT GLA protein P06280 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 24448649 f lperfetto "Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A)." SIGNOR-276823 MAPK8 protein P45983 UNIPROT ATN1 protein P54259 UNIPROT "down-regulates activity" phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 t lperfetto "Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment," SIGNOR-102398 E2F5 protein Q15329 UNIPROT CBX5 protein P45973 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000815 21374739 t Luana "We identified for E2F5 a repressor function for HP1a expression." SIGNOR-261591 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser464 QAIHQLRsVKMEQRK 9606 16513649 t llicata "Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization" SIGNOR-145028 IL1R1 protein P14778 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 9606 BTO:0003432 10217414 t lperfetto "Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88." SIGNOR-67140 ATM protein Q13315 UNIPROT KAT8 protein Q9H7Z6 UNIPROT "up-regulates activity" phosphorylation Thr392 LSQMTSItQNDIIST 9606 24953651 t miannu "In this study we present evidence that MOF is phosphorylated at the threonine 392 residue (pT392-MOF) by ATM subsequent to IR induced DNA damage.|Interestingly, ATM dependent-MOF phosphorylation increases MOF retention on DNA post-irradiation in S/G2-phase cells." SIGNOR-278350 AURKA protein O14965 UNIPROT RALA protein P11233 UNIPROT "up-regulates activity" phosphorylation Ser194 NGKKKRKsLAKRIRE 9606 21822277 t miannu "Specifically, the mitotic kinase Aurora A phosphorylates Ser 194 of RALA, relocalizing it to the mitochondria, where it concentrates RALBP1 and DRP1.|These data suggest that Aurora A promotes mitochondrial fission at mitosis through RalA and RalBP1." SIGNOR-278351 SOD2 protein P04179 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "down-regulates quantity" "chemical modification" 9606 29301787 t lperfetto "Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD)." SIGNOR-272281 CHEK1 protein O14757 UNIPROT CHEK1 protein O14757 UNIPROT "up-regulates activity" phosphorylation Ser296 GFSKHIQsNLDFSPV 9606 BTO:0001938 23068608 t lperfetto "TheSer296autophosphorylation ofCHK1is mainly regulated by an intramolecular mechanism in response to DNA damage." SIGNOR-217904 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr735 KYLANMNyVHRDLAA 9606 18387945 t lperfetto "The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells." SIGNOR-178177 DOT1L protein Q8TEK3 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20854876 f irozzo "Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented." SIGNOR-256141 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7322 RAGSRAGsRASSRRG 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264433 BGLF5 protein P03217 UNIPROT TLR9 protein Q9NR96 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 9606 21191071 t scontino "The EBV lytic-phase protein BGLF5 reduces TLR9 expression through mRNA degradation. We established that the EBV early protein BGLF5 degrades TLR9 mRNA in vitro, providing a mechanism for its contribution to TLR9 downregulation." SIGNOR-266633 LMP1 protein P03230 UNIPROT TLR9 protein Q9NR96 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000726 20980631 f scontino "We determined that the EBV oncoprotein latent membrane protein 1 (LMP1) is a strong inhibitor of TLR9 transcription. These data show that the oncoprotein LMP1 downregulates TLR9 promoter activity in B cells." SIGNOR-266804 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250791 P-TEFb complex SIGNOR-C238 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation 9606 32048991 t miannu "Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. To perform this task, Pol II needs to be activated by a complex of proteins called P-TEFb; however, P-TEFb is usually found in an inactive form held by another group of proteins. Yet, it is unclear how P-TEFb is released and allowed to activate Pol II." SIGNOR-261039 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "precursor of" 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267124 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT "up-regulates activity" phosphorylation Ser138 NNLSRSNsDESNFSE 9606 BTO:0000007 16818229 t miannu "Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling." SIGNOR-276292 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT "down-regulates activity" phosphorylation Ser97 TIAESEDsQESVDSV 9606 15073328 t lperfetto "Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivophosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp)" SIGNOR-124043 SMO protein Q99835 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 9606 18455992 t gcesareni "Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion." SIGNOR-178607 2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol chemical CHEBI:93235 ChEBI DRD3 protein P35462 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258728 MAPK3 protein P27361 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 10828059 t "The effect has been demonstrated using Q08499-2" gcesareni "These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro." SIGNOR-77578 EIF1 protein P41567 UNIPROT 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR "form complex" binding 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269161 AKT1 protein P31749 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t gcesareni "Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no." SIGNOR-112363 TLE1 protein Q04724 UNIPROT SIX6 protein O95475 UNIPROT "up-regulates activity" binding -1 12441302 t lperfetto "Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation" SIGNOR-234592 HERC5 protein Q9UII4 UNIPROT NME2 protein P22392 UNIPROT "up-regulates quantity by stabilization" ubiquitination 9606 BTO:0000007 18535780 t miannu "HERC5 is required for ubiquitination of Nm23B. In summary, Nm23B ubiquitination is mediated by HERC5. Stable Nm23B protein in presence of HERC5 as well as proteasome-independent ubiquitination suggest that ubiquitination of Nm23B serves a different purpose than marking it for degradation." SIGNOR-271778 ABL1 protein P00519 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Tyr28 AVHSLSRiGDELYLE 9606 11971963 t Manara "The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. | c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL |these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress." SIGNOR-260843 FLT3 protein P36888 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18559972 f apalma "In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors." SIGNOR-255698 "Hair cells mechanotransduction channel" complex SIGNOR-C290 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 10090 23217710 t lperfetto "Despite this progress, it is not known which genes encode subunits of the mechanotransduction channel of hair cells. Ca2+ enters stereocilia upon mechanical stimulation near the lower tip-link insertion site, indicating that transduction channels are present in proximity to PCDH15" SIGNOR-262573 SPI1 protein P17947 UNIPROT GATA1 protein P15976 UNIPROT "down-regulates activity" binding 10090 10364157 t irozzo "We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation." SIGNOR-256049 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser1466 YSRASINsLLSDKRS 10090 29301787 t lperfetto "Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466" SIGNOR-272270 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ECT2 protein Q9H8V3 UNIPROT down-regulates phosphorylation Thr373 VSMLSLNtPNSNRKR 9606 16170345 t lperfetto "We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341" SIGNOR-216864 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr5 yLDPNLNH 9606 20802513 t llicata "In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases." SIGNOR-167662 ASIP protein P42127 UNIPROT MC2R protein Q01718 UNIPROT "down-regulates activity" binding 9606 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268695 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding 23729744 t apalma "The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes" SIGNOR-255378 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 t "JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity" SIGNOR-251359 MOV10 protein Q9HCE1 UNIPROT UPF1 protein Q92900 UNIPROT "up-regulates activity" binding 9606 27016603 t miannu "MOV10 has been shown to promote mRNA degradation by associating with UPF1, this activity requires the helicase activity of MOV10." SIGNOR-261139 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 18039567 t gcesareni "Ly2157299, a new type i receptor tgf-beta kinase antagonist, was" SIGNOR-159354 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Ser271 ISGRLVDsKAKTRSA 9606 9312068 t lperfetto "Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1" SIGNOR-51207 TRIM25 protein Q14258 UNIPROT KLF5 protein Q13887 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0001538 21542805 t miannu " The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked. " SIGNOR-271908 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000567 16120644 t irozzo "Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells." SIGNOR-259103 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT "up-regulates activity" phosphorylation Ser196 RKEDRSAsSGAEGDV -1 25258324 t done miannu " Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D)." SIGNOR-273971 POMC protein P01189 UNIPROT MC2R protein Q01718 UNIPROT "up-regulates activity" binding 10029 BTO:0000047 20371771 t lperfetto "Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP)." SIGNOR-268615 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120048 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14701735 f irozzo "Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function." SIGNOR-255863 venetoclax chemical CHEBI:133021 ChEBI BCL2 protein P10415 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23291630 t miannu "Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers." SIGNOR-261938 Nalorphine chemical CHEBI:7458 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258815 metaproterenol chemical CHEBI:6792 ChEBI ADRB3 protein P13945 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" SIGNOR-257874 KLHL9 protein Q9P2J3 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 17543862 t miannu "Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis." SIGNOR-271660 CALM1 protein P0DP23 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t lperfetto "The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases" SIGNOR-232178 SUV39H1 protein O43463 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002267 23435416 f lperfetto "The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation" SIGNOR-249600 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Tyr529 TITKTVEyLHAQGVV 9606 BTO:0000007 18156174 t llicata "Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway." SIGNOR-160052 ESR1 protein P03372 UNIPROT PGR protein P06401 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11000528 f gcesareni "We observed the transcriptional inhibition of the progesterone and glucocorticoid receptors when eralpha was cotransfected" SIGNOR-82161 LPAR5 protein Q9H1C0 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256861 etorphine chemical CHEBI:4912 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258802 GFI1 protein Q99684 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 10090 BTO:0000725 17197705 t miannu "Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line." SIGNOR-256043 Isoetharine chemical CHEBI:6005 ChEBI DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" -1 7576010 t miannu "The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1." SIGNOR-258432 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr500 WDGVTTKtFCGTPDY 9606 17115692 t lperfetto "The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif" SIGNOR-150857 AKT1 protein P31749 UNIPROT DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 21619873 t gcesareni "Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5." SIGNOR-252513 UBQLN2 protein Q9UHD9 UNIPROT TARDBP protein Q13148 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0003704 23541532 t lperfetto "Here, we describe a high affinity interaction between UBQLN2 and TDP-43 and demonstrate that overexpression of both UBQLN2 and TDP-43 reduces levels of both exogenous and endogenous TDP-43 in human H4 cells.|Consequently, these data suggest that UBQLN2 enhances the clearance of TDP-43" SIGNOR-262112 CDK1 protein P06493 UNIPROT PSRC1 protein Q6PGN9 UNIPROT "down-regulates activity" phosphorylation 9606 21473853 t miannu "MT-polymerizing activity was decreased from samples with DDA3 phosphorylated by Cdk1 ( xref , lanes 4 vs 6) and Aurora A ( xref , lanes 14 vs 16).|Taken together, the mitotic Cdk1 and Aurora A kinases inhibit MT polymerization activities and MT bundling activities of DDA3." SIGNOR-279601 AMPK complex SIGNOR-C15 SIGNOR GBF1 protein Q92538 UNIPROT down-regulates phosphorylation Thr1337 GKIHRSAtDADVVNS 9606 18063581 t lperfetto "These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration." SIGNOR-216588 GABRB2 protein P47870 UNIPROT "GABA-A (a6-b2-d) receptor" complex SIGNOR-C328 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263769 PDP1 protein Q9P0J1 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16510868 t lpetrilli "We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1." SIGNOR-144876 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16611981 t gcesareni "Gli2 can also be phosphorylated directly by ck-1 at the non-optimal sites" SIGNOR-146112 KDR protein P35968 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 10090 22264731 t "VEGF pathway" Gianni "Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation" SIGNOR-261945 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR2 protein Q92731 UNIPROT "up-regulates activity" "chemical activation" -1 9048584 t miannu "In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes." SIGNOR-258592 WNT3 protein P56703 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131820 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRB4 protein P13762 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 t miannu "Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination." SIGNOR-271409 HNF4A protein P41235 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes." SIGNOR-254451 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR KIF23 protein Q02241 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 30224758 f lperfetto "By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ." SIGNOR-276579 NCBP1 protein Q09161 UNIPROT mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 26382858 f lperfetto "The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization." SIGNOR-268361 MYC protein P01106 UNIPROT NFE2L2 protein Q16236 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29731393 f miannu "Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2" SIGNOR-267363 RBPJ protein Q06330 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 23729744 f apalma "In the absence of NICD, CSL forms complexes with a variety of co-repressors to suppress the transcription of Notch target genes" SIGNOR-255373 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR4 protein Q99677 UNIPROT "up-regulates activity" "chemical activation" 9606 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257531 ATM protein Q13315 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation 9606 12607003 t fstefani "We show that, in response to ionizing radiation, mdc1 is hyperphosphorylated in an atm-dependent manner, and rapidly relocalizes to nuclear foci that also contain the mre11 complex, phosphorylated histone h2ax and 53bp1." SIGNOR-98798 MAP3K7 protein O43318 UNIPROT MAP2K7 protein O14733 UNIPROT "up-regulates activity" phosphorylation 9606 21552290 t miannu "TAK1 also phosphorylates and activates MKK6 and MKK7, leading to the activation of p38 and JNK kinase pathways, which may also contribute to disease pathogenesis (" SIGNOR-279214 JAK2 protein O60674 UNIPROT IFNGR2 protein P38484 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 23898330 t lperfetto "In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation" SIGNOR-249489 ITGB7 protein P26010 UNIPROT "A4/b7 integrin" complex SIGNOR-C187 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253294 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TDGF1 protein P13385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269244 RHOQ protein P17081 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 12242347 f gcesareni "Tc10 is activated afte rinsulin stimulation, and its activation is required for insulin-stimulated glucose uptake and glut4 translocation" SIGNOR-93117 EGFR protein P00533 UNIPROT BECN1 protein Q14457 UNIPROT "down-regulates activity" phosphorylation Tyr233 EAQYQREySEFKRQQ 9606 24034250 t miannu "The mechanism by which EGFR suppresses Beclin 1 function involves EGFR interaction with two domains (BH3 and ECD) of Beclin 1; EGFR mediated multisite tyrosine phosphorylation of Beclin 1 on residues Y229, Y233 and Y352; and EGFR mediated alterations in the Beclin 1 interactome (increased binding to the negative regulators, Bcl-2 and Rubicon, and decreased binding to the VPS34 lipid kinase).|Thus, EGFR signaling suppresses autophagy via its interaction with Beclin 1 during normal mitogenic signaling as well as during aberrant cell proliferation in cancer cells." SIGNOR-278357 RNF11 protein Q9Y3C5 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" binding 9606 BTO:0000150 19131965 t lperfetto "Rnf11, together with tax1bp1 and itch, is an essential component of an a20 ubiquitin-editing protein complex; rnf11 is required for a20 to interact with and inactivate rip1 to inhibit tnf-mediated nf-_kb activation." SIGNOR-183188 TRIM23 protein P36406 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by stabilization" ubiquitination 9606 25905670 t miannu "In this study, we showed that TRIM23 mediates atypical polyubiquitin conjugation including M1- and K27 linked ubiquitin chains to PPARgamma and that ubiquitination of PPARgamma by TRIM23 causes reduced recognition of PPARgamma by 26S proteasome." SIGNOR-278577 PAMPs stimulus SIGNOR-ST11 SIGNOR Pr3-ANCA complex SIGNOR-C475 SIGNOR "up-regulates quantity" 9606 BTO:0000133 15972951 f lperfetto "In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. |using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus." SIGNOR-270587 KAT2B protein Q92831 UNIPROT H3C15 protein Q71DI3 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269626 PTK2 protein Q05397 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 15688067 t miannu "Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade." SIGNOR-257733 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-A (a6-b1-g2) receptor" complex SIGNOR-C334 SIGNOR "up-regulates activity" "chemical activation" 9606 18790874 t brain lperfetto "Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS)." SIGNOR-263790 belinostat chemical CHEBI:61076 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257954 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129418 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LIFR protein P42702 UNIPROT down-regulates phosphorylation 9606 7777512 t "inferred from 70% family members" gcesareni "Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044." SIGNOR-270001 "cyclosporin A" chemical CHEBI:4031 ChEBI TTN protein Q8WZ42 UNIPROT up-regulates 9606 17636278 f "Regulation of transcription" "Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells." SIGNOR-251975 TBK1 protein Q9UHD2 UNIPROT IRF7 protein Q92985 UNIPROT "up-regulates activity" phosphorylation Ser479 SLDSSSLsLCLSSAN 9606 22787218 t miannu "In most cell types, IRF7 is phosphorylated and activated by IKK\u03b5 and TBK1 after viral infection.|We found that phosphorylation of IRF7 on Ser477 and Ser479 by IKK\u03b5 or TBK1 is inhibited by ORF45." SIGNOR-278216 MAPK1 protein P28482 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser291 TYVNNSPsPGFNSSH 9606 19237534 t lperfetto "We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309." SIGNOR-184168 TEC protein P42680 UNIPROT STAP1 protein Q9ULZ2 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10518561 t miannu "In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling." SIGNOR-261817 SYN1 protein P17600 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 f miannu "Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet." SIGNOR-264105 cabozantinib chemical CHEBI:72317 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000184 26536165 t miannu "Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3." SIGNOR-262242 hsa-miR-338-3p mirna URS00000254A6_9606 RNAcentral SMO protein Q99835 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004169 29069716 t Parnian "MiR-338-3p suppresses the invasiveness and metastasis of HCC cells by directly targeting the Smoothened (SMO) protein" SIGNOR-277973 YAP1 protein P46937 UNIPROT TOP2A protein P11388 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001939 30224758 f lperfetto "By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ." SIGNOR-276570 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" phosphorylation 10090 11730323 t "Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs" SIGNOR-258994 NELF complex SIGNOR-C521 SIGNOR "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "down-regulates activity" binding 9606 18628398 t miannu "The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E." SIGNOR-271403 GGCX protein P38435 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261230 PRKCA protein P17252 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 16574739 t flangone "We show that pkcalpha is likely to be directly involved in ser24 phosphorylation...These observations are entirely consistent with a recent independent study demonstrating that the IRS1-S24D mutant shows impaired insulin-stimulated IR-IRS-1 interactions, tyrosine phosphorylation of IRS-1, recruitment/activation of PI 3-Kinase, and insulin-stimulated Glut4 translocation" SIGNOR-145398 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT "up-regulates activity" phosphorylation Thr564 LEEADNQtLDSYRNE -1 26119734 t miannu "Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro" SIGNOR-276214 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr295 AEALNQVtQRASRRS 9606 19366211 t gcesareni "These results implicate pkcdelta-thr(295) autophosphorylation as a lipid-dependent modification that links pkcdelta-thr(505) phosphorylation to src-dependent regulation of pkcdelta catalytic function." SIGNOR-185283 5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine chemical CHEBI:91338 ChEBI ALK protein Q9UM73 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207132 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-235929 RHOA protein P61586 UNIPROT PFN1 protein P07737 UNIPROT "up-regulates activity" 9606 BTO:0000815 22820501 t lperfetto "We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells." SIGNOR-253109 DTNBP1 protein Q96EV8 UNIPROT WASF2 protein Q9Y6W5 UNIPROT "up-regulates activity" binding 10116 BTO:0000601 20531346 t miannu "Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1." SIGNOR-265659 ZNF365 protein Q70YC5 UNIPROT PARP1 protein P09874 UNIPROT "up-regulates activity" binding 9606 23966166 t "We identified ZNF365 as a necessary component of the HR repair pathway. ZNF365 interacts with PARP1 and tethers MRE11 to the nucleolytic resection sites for replication fork recovery" SIGNOR-272477 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr453 PEALHYDyIDVEMSA 9534 9655255 t lperfetto "In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110." SIGNOR-246355 ERO1B protein Q86YB8 UNIPROT ERP44 protein Q9BS26 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 11847130 t Simone "Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits." SIGNOR-261048 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000150 12167717 f lperfetto "PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473," SIGNOR-236353 GDNF protein P39905 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni "A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling" SIGNOR-49091 GLI1 protein P08151 UNIPROT HHIP protein Q96QV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209623 DAD1 protein P61803 UNIPROT "OST-A complex" complex SIGNOR-C535 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272059 KAT6A protein Q92794 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates binding 9606 SIGNOR-C54 11742995 t miannu "The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription" SIGNOR-113056 PTPN2 protein P17706 UNIPROT FKBP4 protein Q02790 UNIPROT down-regulates dephosphorylation 9606 BTO:0000567 12552015 t tpavlidou "We have documented that a cellular protein that binds the immunosuppressant drug fk506, termed the fk506-binding protein (fkbp52), interacts with the single-stranded d sequence within the aav inverted terminal repeats, inhibits viral second-strand dna synthesis, and consequently limits high-efficiency transgene expression. Deliberate overexpression of the murine wild-type (wt) tc-ptp gene, but not that of a cysteine-to-serine (c-s) mutant, caused tyrosine dephosphorylation of fkbp52, leading to efficient viral second-strand dna synthesis and resulting in a significant increase in aav-mediated transduction efficiency in hela cells in vitro." SIGNOR-97794 POLG protein P54098 UNIPROT "DNA polymerase gamma" complex SIGNOR-C378 SIGNOR "form complex" binding -1 19837034 t lperfetto "Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit." SIGNOR-265719 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9136927 t fspada "Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro" SIGNOR-249649 MYCBP2 protein O75592 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 18308511 t miannu "We show that Pam associates with E2 ubiquitin conjugating enzymes, and tuberin can be ubiquitinated by Pam through its RING finger domain." SIGNOR-278704 KIF2B protein Q8N4N8 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 22535524 f lperfetto "The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation." SIGNOR-252051 resiquimod chemical CHEBI:36706 ChEBI TLR7 protein Q9NYK1 UNIPROT "up-regulates activity" "chemical activation" 9606 15661881 t miannu "Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively." SIGNOR-259246 SMARCA1 protein P28370 UNIPROT ST7 protein Q9NRC1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 15485929 t lperfetto "Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes." SIGNOR-268991 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 16495336 t gcesareni "We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell" SIGNOR-144783 APC2 protein O95996 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" relocalization 9606 BTO:0000038 10980707 t lperfetto "The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation." SIGNOR-81545 PINK1 protein Q9BXM7 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" phosphorylation 9606 22643835 t miannu "PINK1 also enhances the association between TRAF6 and TAK1, phosphorylates TAK1, and stimulates polyubiquitination of TAK1." SIGNOR-279644 GABRG2 protein P18507 UNIPROT "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263761 ID2 protein Q02363 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR "down-regulates activity" binding 10090 BTO:0004058 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241143 LATS2 protein Q9NRM7 UNIPROT YWHAG protein P61981 UNIPROT up-regulates phosphorylation Ser59 VVGARRSsWRVISSI 9606 21118956 t lperfetto "Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions," SIGNOR-170139 DLL1 protein O00548 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 16140393 t lperfetto "Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate." SIGNOR-209732 WNK3 protein Q9BYP7 UNIPROT SLC12A5 protein Q9H2X9 UNIPROT "down-regulates activity" phosphorylation 21613606 t lperfetto "We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs" SIGNOR-264628 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr760 TVTSTDEyLDLSAPF 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation." SIGNOR-106742 CEBPA protein P49715 UNIPROT Basophil_diff phenotype SIGNOR-PH116 SIGNOR "up-regulates activity" 10090 BTO:0000725 23990620 f "Notably, enforced overexpression of C/EBP-α in BMCPs results in exclusive differentiation into basophils, whereas conditional deletion of C/EBP-α in these same cells promotes mast cell differentiation,1 suggesting that C/EBP-α is an essential “switch factor” for basophil lineage choice" SIGNOR-259968 PRPS2 protein P11908 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 BTO:0006038 29074724 f lperfetto "We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production." SIGNOR-265734 CARD11 protein Q9BXL7 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates binding 9606 BTO:0000785 20685844 t gcesareni "The carboxy-terminal part of the bcl10 card and a short stretch of 13 amino acids following the card are required for constitutive binding to malt1." SIGNOR-167393 MAGEA3 protein P43357 UNIPROT TRIM28 protein Q13263 UNIPROT "up-regulates activity" binding 9606 BTO:0000594 28394358 t lperfetto "In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28." SIGNOR-267592 PRKCA protein P17252 UNIPROT TOP1 protein P11387 UNIPROT "up-regulates activity" phosphorylation Ser21 ADFRLNDsHKHKDKH -1 18408216 t miannu "In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells." SIGNOR-276154 CSNK2A1 protein P68400 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr350 PEVKKEEtLLDLDFD 9606 BTO:0000567 16945112 t lperfetto "Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin." SIGNOR-149314 RABEPK protein Q7Z6M1 UNIPROT M6PR protein P20645 UNIPROT "up-regulates activity" relocalization 9230071 t lperfetto "P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking." SIGNOR-253091 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 16151013 t "Cytosolic p53" amattioni "P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization." SIGNOR-140242 PRKCZ protein Q05513 UNIPROT AKT3 protein Q9Y243 UNIPROT "up-regulates activity" phosphorylation Ser472 RPHFPQFsYSASGRE 9534 BTO:0001538 12162751 t lperfetto "Full activation of the PKB enzyme requires phosphorylation of a threonine in the activation" SIGNOR-249153 IL7R protein P16871 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000776 18445337 t milica "For instance, jak1 is associated with the ? Subunits of ?c Cytokines such as il-7r? And IL-4R. jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation." SIGNOR-178494 AURKB protein Q96GD4 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser265 QKVAERRsSPLLRRK 9606 22865920 t lperfetto "We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions" SIGNOR-198646 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser77 PGPFATRsPLFIFMR 10090 12818176 t miannu "JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity." SIGNOR-250131 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 19115199 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-217613 levomethadone chemical CHEBI:136003 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258807 SHC1 protein P29353 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR "up-regulates activity" 10090 BTO:0000944 17673906 f "inferred from 70% of family members" lperfetto "We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-269903 NAA38 protein Q9BRA0 UNIPROT NatC complex SIGNOR-C417 SIGNOR "form complex" binding 9606 19398576 t miannu "We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation." SIGNOR-267235 PRKACA protein P17612 UNIPROT MYOM2 protein P54296 UNIPROT down-regulates phosphorylation Ser76 RVCAKRVsTQEDEEQ 9606 BTO:0000887 9529381 t llicata "This binding is regulated in vitro by phosphorylation of a single serine residue (ser76) in the immediately adjacent amino-terminal domain mp1. M-protein phosphorylation by camp-dependent kinase a inhibits binding to myosin lmm." SIGNOR-56395 DDX20 protein Q9UHI6 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates binding 9606 BTO:0000975 16153597 t miannu "Dp103 further increased the cell killing effect induced by foxl2 probably due to the direct association of dp103 with foxl2 protein." SIGNOR-140388 UDP-N-acetyl-alpha-D-glucosamine smallmolecule CHEBI:16264 ChEBI "N-acyl-D-mannosamine 6-phosphate(2-)" smallmolecule CHEBI:57666 ChEBI "up-regulates quantity" "precursor of" 10745088 t lperfetto "UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate." SIGNOR-266075 GADD45B protein O75293 UNIPROT CDK11A protein Q9UQ88 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 26885618 t lperfetto "Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58." SIGNOR-273024 PTPN11 protein Q06124 UNIPROT NTRK2 protein Q16620 UNIPROT "down-regulates activity" dephosphorylation 9606 28947394 t miannu "Conversely, PTPN11 knockdown lead to increased Y 515 phosphorylation of TrkB compared to the scramble control in the neuronal cells.|This study established that TrkB activation as demonstrated by receptor phosphorylation at Tyr 515 in the SH-SY5Y cells is negatively regulated by PTPN11 actions." SIGNOR-277123 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA8 protein Q9Y5G5 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265702 BDP1 protein A6H8Y1 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR "form complex" binding 29378333 t lperfetto "Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1)." SIGNOR-266189 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249326 zinc(2+) chemical CHEBI:29105 ChEBI "BRCA1-C complex" complex SIGNOR-C299 SIGNOR "form complex" binding 25400280 t lperfetto "The BRCA1‚ÄìC complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2" SIGNOR-269478 KLF2 protein Q9Y5W3 UNIPROT PPARG protein P37231 UNIPROT down-regulates "transcriptional regulation" 9606 12426306 f fspada "Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta." SIGNOR-210019 CDX2 protein Q99626 UNIPROT INS protein P01308 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000120 12783165 f miannu "In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3." SIGNOR-254906 FZR1 protein Q9UM11 UNIPROT PFKFB3 protein Q16875 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000793 20080744 t miannu "We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. Cdh1 promotes PFKFB3 degradation in the nucleus." SIGNOR-271436 MAPK1 protein P28482 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Thr185 HDHTGFLtEYVATRW 1712480 t lperfetto "Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|" SIGNOR-249414 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" phosphorylation Thr813 GDNVLINtYSGVLKI 9606 17937911 t lperfetto "Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling." SIGNOR-158423 PRKAA1 protein Q13131 UNIPROT ACSS2 protein Q9NR19 UNIPROT "up-regulates activity" phosphorylation Ser659 PGLPKTRsGKIMRRV 28820290 t lperfetto "This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin α5 for binding. In the nucleus, ACSS2 forms a complex with TFEB (transcription factor EB) and utilizes the acetate generated from histone deacetylation to locally produce acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes." SIGNOR-271822 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 21205641 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-170859 PSMA6 protein P60900 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263368 hsa-miR-124-5p mirna URS00003AA409_9606 RNAcentral FZD5 protein Q13467 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0006204 25861751 t Parnian "The current study showed that miR-124 was downregulated in vinblastine- and doxorubicin-resistant renal cancer cells, accompanied by increased levels of FZD5 and P-gp. | Meanwhile, miR-124 targeted FZD5 and abolished its presentation" SIGNOR-277969 OGT protein O15294 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates activity" glycosylation Ser109 KSHSRQAsTDAGTAG 34155345 t lperfetto "Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation." SIGNOR-276942 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr766 ALTSNQEyLDLSMPL 10116 19224897 t lperfetto "This second-stage autophosphorylation occurs on y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of y463 in the juxtamembrane region, y766 in the c-terminal tail, and y585 in the kinase insert region (1). The third-stage autophosphorylation takes place on the second tyrosine in the activation loop (y654), resulting in an additional 10-fold increase in the intrinsic tyrosine kinase activity of fgfr1." SIGNOR-236203 CCR3 protein P51677 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 11591790 f "We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation" SIGNOR-254357 EIF2AK2 protein P19525 UNIPROT "NLRP3 inflammasome" complex SIGNOR-C225 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22801494 t miannu "Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation." SIGNOR-263119 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF10 protein Q8NA82 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271047 RHOA protein P61586 UNIPROT MSN protein P26038 UNIPROT "up-regulates activity" phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0000132 35267019 t miannu "Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies." SIGNOR-268431 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT "up-regulates activity" phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 BTO:0004553 24614225 t gianni "NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity." SIGNOR-266442 PRKAA1 protein Q13131 UNIPROT MCU protein Q8NE86 UNIPROT "up-regulates activity" phosphorylation Ser57 TVHQRIAsWQNLGAV -1 30858581 t lperfetto "Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57" SIGNOR-275547 NCAPD2 protein Q15021 UNIPROT "Condensin I" complex SIGNOR-C341 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263905 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" deacetylation 9606 14976264 t lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-122405 MAML3 protein Q96JK9 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 12370315 t gcesareni "We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors." SIGNOR-94097 SMAD5 protein Q99717 UNIPROT SATB2 protein Q9UPW6 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268939 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193615 FBXO2 protein Q9UK22 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 10090 BTO:0000938 20854419 t miannu "SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production." SIGNOR-271902 NEDD4L protein Q96PU5 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys933 LCLSSTVkQVVRRLN 9606 27932573 t miannu "NEDD4L ubiquitylates ULK1 at lysine 925 and lysine 933.|Next, we found that down-regulation of the ULK1 protein by NEDD4L is blocked by proteasome inhibitors (MG132 and lactacystin), but not by lysosomal inhibitors (leupeptin and Clq; XREF_FIG and S2 C), indicating that NEDD4L triggers ULK1 degradation exclusively through the proteasome pathway." SIGNOR-278523 DLGAP1 protein O14490 UNIPROT SHANK3 protein Q9BYB0 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264588 PTPN3 protein P26045 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248459 UBA52 protein P62987 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262459 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000552 14744793 t gcesareni "We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription." SIGNOR-248062 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT "down-regulates activity" phosphorylation Ser337 EAPERASsVYTRSTG 9534 BTO:0000298 10085131 t "Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism" SIGNOR-251464 TCL1A protein P56279 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto "Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation" SIGNOR-244449 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser314 RAREKRDsRNMEVQV 9606 15767678 t gcesareni "Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis." SIGNOR-134580 FBXL5 protein Q9UKA1 UNIPROT NABP2 protein Q9BQ15 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000018 25249620 t miannu "Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation." SIGNOR-271655 TLN1 protein Q9Y490 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257608 FBXL14 protein Q8N1E6 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0006155 27923907 t done miannu " In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation." SIGNOR-274125 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 t amattioni "Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation." SIGNOR-85179 UBE2E1 protein P51965 UNIPROT ZSWIM2 protein Q8NEG5 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16522193 t miannu "MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin. " SIGNOR-271555 Phenelzine chemical CHEBI:8060 ChEBI SLC6A3 protein Q01959 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter." SIGNOR-258745 UFD1 protein Q92890 UNIPROT AMFR protein Q9UKV5 UNIPROT "up-regulates activity" binding 17681147 t miannu "Here we show that Ufd1 directly interacts with gp78 and functions as a cofactor. Ufd1 enhances the E3 activity of gp78, accelerates the ubiquitination and degradation of reductase, and eventually promotes receptor-mediated uptake of low-density lipoprotein." SIGNOR-252425 CDK1 protein P06493 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Thr19 GSRRGRAtPAQTPRS 9606 BTO:0000567 12714602 t lperfetto "We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex." SIGNOR-100877 STUB1 protein Q9UNE7 UNIPROT CIB1 protein Q99828 UNIPROT "down-regulates quantity" ubiquitination 9606 33082516 t miannu "All those were suggesting that CHIP promotes CIB1 ubiquitination via the Lys 48 residue of ubiquitin.|K10 and K65 were the Lysine (K) residues for CHIP mediated CIB1 degradation." SIGNOR-278721 FLT3 protein P36888 UNIPROT IDH2 protein P48735 UNIPROT "down-regulates activity" phosphorylation Tyr107 SALATQKySVAVKCA 9606 BTO:0001545 34289383 t lperfetto "FLT3 promotes mIDH2 acetylation through Y107 phosphorylation of mIDH2 that enhances ACAT1 recruitment," SIGNOR-267632 PRKCZ protein Q05513 UNIPROT MYH10 protein P35580 UNIPROT down-regulates phosphorylation Ser1937 RGGPISFsSSRSGRR 9606 16611744 t lperfetto "After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell" SIGNOR-146100 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR INCA1 protein Q0VD86 UNIPROT unknown phosphorylation Ser23 CSRVVSRsPPPRLPS -1 15159402 t miannu " GST-INCA1 was phosphorylated in vitro by cyclin A2-CDK2 but not by CDK2 or either cyclin alone.  Mutation of Ser23, Thr167, and Ser176 strongly reduced in vitro phosphorylation of INCA1.Cyclin A1 and Cyclin A2 in Complex with CDK2 Phosphorylated INCA1 in Vitro Predominantly at Ser176" SIGNOR-273593 PLK1 protein P53350 UNIPROT CEP85 protein Q6P2H3 UNIPROT "up-regulates activity" phosphorylation 9606 30611117 t miannu "In summary, our results identify Cep85 as a platform to directly relay the activities of Plk1 and Mst2 to Nek2A activation at centrosomes through phospho-Nek2A-assistant Cep85 phosphorylation by Plk1 at the onset of mitosis.|Plk1 Heavily Phosphorylates the Nek2A-Binding Domain in Cep85 at Centrosomes in Late G2." SIGNOR-278367 HOXB2 protein P14652 UNIPROT OTX2 protein P32243 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000946 9556594 t Luana "Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively" SIGNOR-261634 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 t "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis." SIGNOR-248384 CTH protein P32929 UNIPROT "L-selenocystathionine zwitterion" smallmolecule CHEBI:62226 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275823 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219316 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT "up-regulates activity" phosphorylation Thr142 DSVTKLLtDVQLMKG 9606 35080342 t miannu "AKT1 and AKT2 phosphorylate HSF1 at S326 but only AKT1 activates HSF1.|Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not." SIGNOR-278372 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr205 IMLNSKGyTKSIDIW 9606 BTO:0000007 19494114 t lperfetto "In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo." SIGNOR-101276 H4C1 protein P62805 UNIPROT "Nucleosome_H2A.Z.1 variant" complex SIGNOR-C322 SIGNOR "form complex" binding -1 24311584 t miannu "In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined." SIGNOR-263718 TSC complex SIGNOR-C101 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto "These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor" SIGNOR-251527 PRKAA1 protein Q13131 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 SIGNOR-C15 9636039 t gcesareni "Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase." SIGNOR-58255 CCNY protein Q8ND76 UNIPROT CDK14 protein O94921 UNIPROT up-regulates binding 9606 20059949 t gcesareni "L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6." SIGNOR-162920 PRKCE protein Q02156 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 21251911 t lperfetto "We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation" SIGNOR-171712 pembrolizumab antibody DB09037 DRUGBANK PDCD1 protein Q15116 UNIPROT "down-regulates activity" binding 9606 "BTO:0000848; BTO:0002058" 25685857 t miannu "Preclinical studies described PD-1 blockade resulting in tumor growth suppression and even decreased metastasis. This has led to the development of pembrolizumab (MK-3475), a highly selective, humanized monoclonal IgG4-kappa isotype antibody against PD-1. Early clinical trials have shown high tumor response rates and long duration of effect in previously treated advanced melanoma resulting in accelerated FDA approval for the drug in this situation. Pembrolizumab has also had success in non-small cell lung cancer and is being tested in multiple other tumor types." SIGNOR-259899 GATA1 protein P15976 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR "up-regulates activity" 10090 BTO:0004911 12032775 f "The zinc finger transcription factor GATA-1, a central mediator of erythroid gene expression, interacts with multiple proteins including FOG-1, EKLF, SP1, CBP/p300 and PU.1." SIGNOR-259962 RalGAP1 complex SIGNOR-C468 SIGNOR RALA protein P11233 UNIPROT "down-regulates activity" "guanine nucleotide exchange factor" 10090 BTO:0000011 21148297 t miannu "Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA." SIGNOR-269795 CDK1 protein P06493 UNIPROT PTTG2 protein Q9NZH5 UNIPROT "up-regulates activity" phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 BTO:0000567 10656688 t miannu "HPTTG is phosphorylated by Cdc2 at Ser165. we show that hPTTG is phosphorylated during mitosis. The direct phosphorylation of hPTTG by Cdc2 is interesting in itself since the substrates of this master mitotic kinase are supposed to play important roles in the initiation and progression of mitosis." SIGNOR-262700 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT "up-regulates quantity" binding 9606 BTO:0000567 25296192 t miannu "In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16." SIGNOR-266312 ERCC4 protein Q92889 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR "form complex" binding 9606 16338413 t miannu "Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair." SIGNOR-142992 MYC protein P01106 UNIPROT CDC25A protein P30304 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11154267 t lperfetto "Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen" SIGNOR-245465 ORF4b protein K9N643 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 26631542 t miannu "Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm" SIGNOR-260593 GABRA6 protein Q16445 UNIPROT "GABA-A (a6-b1-g2) receptor" complex SIGNOR-C334 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263762 TEX12 protein Q9BXU0 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR "form complex" binding 9606 22394509 t miannu "The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region." SIGNOR-264203 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide chemical CHEBI:95008 ChEBI MCL1 protein Q07820 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207465 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "precursor of" 9606 26003525 t miannu "Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer." SIGNOR-267507 CDK1 protein P06493 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates phosphorylation Thr286 VEGDAAEtPPRPRTP 9606 8114697 t gcesareni "P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well" SIGNOR-36112 H2AC11 protein P0C0S8 UNIPROT RNF168 protein Q8IYW5 UNIPROT up-regulates binding 9606 19203578 t gcesareni "Rnf168 is recruited to sites of dna damage by binding to ubiquitylated histone h2a." SIGNOR-183890 AKT proteinfamily SIGNOR-PF24 SIGNOR EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 18836482 t gcesareni "Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b." SIGNOR-181536 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7566092 t lperfetto "Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter." SIGNOR-209590 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" phosphorylation Tyr762 SDIQRSLyDRPASYK 9823 9546424 t miannu "Tyr-762 is an autophosphorylation site in the human platelet-derived growth factor (PDGF) alpha-receptor. Crk proteins associate with phosphorylated Tyr-762 in the PDGF a-receptor in vivo" SIGNOR-249716 quetiapine chemical CHEBI:8707 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258534 PRKAA1 protein Q13131 UNIPROT CYCS protein P99999 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni "Severalin vivostudies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochromec, uncoupling protein 3 (ucp-3)] (1518) and proteins involved in glucose uptake (glut4) (1820) are increased at the transcriptional level in skeletal muscle." SIGNOR-156772 FYN protein P06241 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000776 32323266 t scontino "The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases." SIGNOR-268210 PIH1D2 protein Q8WWB5 UNIPROT "R2SP co-chaperone" complex SIGNOR-C517 SIGNOR "form complex" binding 9606 29844425 t miannu "Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes." SIGNOR-270937 CLN8 protein Q9UBY8 UNIPROT SET protein Q01105 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 30453012 t miannu "CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8." SIGNOR-265584 KDM3A protein Q9Y4C1 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu "Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. " SIGNOR-276846 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser6 sKKRKPKV 9606 BTO:0000801;BTO:0000876 15221008 t llicata "We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling." SIGNOR-126572 E2F1 protein Q01094 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR "form complex" binding 9606 23213415 t gcesareni "Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes" SIGNOR-199955 CAMK2D protein Q13557 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates phosphorylation Ser210 YGKTQHSsLDQSSPP 9606 17179159 t lperfetto "These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2" SIGNOR-151418 CCND1 protein P24385 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates binding 9606 15713663 t gcesareni "Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5." SIGNOR-134053 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189933 GLI2 protein P10070 UNIPROT PPARG protein P37231 UNIPROT down-regulates BTO:0004300 29205155 f areggio "Molecularly, Gli2 is the principle transcription factor in the Gli family to mediate the anti-adipogenic and anti-lipogenic effects of Hh signaling" SIGNOR-256224 EPC2 protein Q52LR7 UNIPROT "NuA4 complex" complex SIGNOR-C459 SIGNOR "form complex" binding 9606 14966270 t miannu "NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails." SIGNOR-269306 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser486 RPLSRAQsSPAAPAS -1 15738054 t lperfetto "We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro." SIGNOR-249276 STAT3 protein P40763 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25194572 f miannu "Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. IL-6 stimulation promoted an increase in the mRNA levels of both Stat3 and Myod1. Stat3 mediated this effect, as IL-6‚Äìdependent Myod1 upregulation was impaired after infection with the shStat3 lentivirus." SIGNOR-255416 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR TSC2 protein P49815 UNIPROT "up-regulates activity" phosphorylation Ser1452 LPSSSPRsPSGLRPR 9606 BTO:0000007 32294430 t done miannu "We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. " SIGNOR-274100 histamine smallmolecule CHEBI:18295 ChEBI HRH3 protein Q9Y5N1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257514 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 14732063 t miannu "Tumour necrosis factor (TNF) exerts two main effects: a beneficial one as an anti-infection, anti-tumour cytokine, and a detrimental one in the systemic inflammatory response syndrome (SIRS). Two receptors (TNF-R) mediate these effects. two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b)" SIGNOR-253593 hsa-mir-126-5p mirna URS00001D69F6_9606 RNAcentral SPRED1 protein Q7Z699 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0001949 18694565 t Parnian "MiR-126 strongly repressed expression of the Spred-1 3’ UTR luciferase reporter" SIGNOR-278011 ITCH protein Q96J02 UNIPROT TNIP2 protein Q8NFZ5 UNIPROT down-regulates ubiquitination 9606 16469705 t gcesareni "Here we show that tnfa-mediated jnk activation accelerates turnover of the NF-kappaBinduced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activationof the e3ubiquitin ligaseitch, which speci?cally Ubiquitinates c-flip and induces its proteasomal degradation." SIGNOR-144453 "Set1-Ash2 HMT complex" complex SIGNOR-C352 SIGNOR "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "form complex" binding 9606 24680668 t miannu "Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation." SIGNOR-204744 lofexidine chemical CHEBI:51368 ChEBI ADRA2C protein P18825 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 22341244 t Luana "Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism. " SIGNOR-258330 MRPS14 protein O60783 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 BTO:0000934 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261456 PPP3CB protein P16298 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t "When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis." SIGNOR-248361 PRKCQ protein Q04759 UNIPROT CARD11 protein Q9BXL7 UNIPROT "down-regulates activity" phosphorylation Ser893 SPRLSRAsFLFGQLL -1 35230873 t miannu "PKCθ-catalyzed CARD11 Ser893 phosphorylation impairs CBM complex formation" SIGNOR-276298 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 t "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-248569 FCN2 protein Q15485 UNIPROT MASP2 protein O00187 UNIPROT "up-regulates activity" binding 17204478 t lperfetto "In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2)" SIGNOR-263413 MAPK1 protein P28482 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser432 NQNVLLMsPPASDSG 9606 14988395 t lperfetto "Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity." SIGNOR-123041 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 18570871 t gcesareni "Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex." SIGNOR-179088 Kallidin smallmolecule CHEBI:6102 ChEBI BDKRB2 protein P30411 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257465 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2B protein P29275 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257448 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR HDAC5 protein Q9UQL6 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 12058061 t gcesareni "In the cytoplasm, 14-3-3 proteins bind the phosphorylated hdac5 and retain it in the cytosol." SIGNOR-89444 PAM16 protein Q9Y3D7 UNIPROT "TIM23 complex" complex SIGNOR-C423 SIGNOR "form complex" binding 32074073 t lperfetto "The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE." SIGNOR-267699 GSK3B protein P49841 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates quantity" phosphorylation 9606 21554241 t miannu "GSK-3beta phosphorylates PTP1B at serine residues, and activation of GSK-3beta reduces the mRNA level of PTP1B." SIGNOR-279724 BLOC1S4 protein Q9NUP1 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265932 POLR2E protein P19388 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266147 TRIM27 protein P14373 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102025 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser376 PPAPAYLsSPLALPS 9606 SIGNOR-C14 12657630 t lperfetto "Phosphopeptide-mapping experiments with metabolically radiolabeled cells indicate that ikkbeta phosphorylates human ikkgamma at ser-31, ser-43, and ser-376" SIGNOR-209792 TLN1 protein Q9Y490 UNIPROT ITGB5 protein P18084 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257629 NKX3-1 protein Q99801 UNIPROT ACTG2 protein P63267 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19797053 f miannu "These results demonstrate the ability of MYOCD to discriminate among several juxtaposed CArG elements, presumably through its novel partnership with NKX3.1, to optimally transactivate the human ACTG2 promoter." SIGNOR-254619 axitinib chemical CHEBI:66910 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150 21297102 t gcesareni "The inhibitory effect of four tkis (axitinib, imatinib, masitinib, and vatalanib) for proliferation and phosphorylation of c-kit receptor as well as the expression and function of abcb1 were investigated in three cmct cell lines (hrmc, vimc1, and cmmc1)." SIGNOR-171866 VRK3 protein Q8IV63 UNIPROT BANF1 protein O75531 UNIPROT "down-regulates activity" phosphorylation Ser4 sQKHRDFV -1 25899223 t lperfetto "Although VRK3 has been regarded as a genuine pseudokinase from structural and biochemical studies, recent reports suggest that VRK3 acts as an active kinase as well as a signaling scaffold in cells. Here, we demonstrate that VRK3 phosphorylates the nuclear envelope protein barrier-to-autointegration factor (BAF) on Ser4.|Ectopic expression of VRK3 induces the translocation of BAF from the nucleus to the cytoplasm. I" SIGNOR-264564 RNF168 protein Q8IYW5 UNIPROT BLM protein P54132 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0001938 23708797 t miannu "Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of RAP80. " SIGNOR-272114 ACP1 protein P24666 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 10090 17353188 t "Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3" SIGNOR-248456 CSNK2A1 protein P68400 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates phosphorylation Ser1479 HVYEKLSsIESDV 9606 BTO:0000938 15537897 t gcesareni "Here we show that casein kinase ii (ck2) phosphorylates the serine residue (ser1480) within the c-terminal pdz ligand (iesdv) of the nr2b subunit of nmdar in vitro and in vivo. Phosphorylation of ser1480 disrupts the interaction of nr2b with the pdz domains of psd-95 and sap102 and decreases surface nr2b expression in neurons." SIGNOR-130336 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 14556242 t gcesareni "Two genes were newly identified to be shh responsive in neuroepithelial cell line mns-70: the metal-binding protein ceruloplasmin (cp) and the serine protease inhibitor inter-alpha-trypsine inhibitor heavy chain h3 (itih3). cp appeared to be regulated by gli-independent pathways." SIGNOR-118612 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1795 VASPRRLsNVSSSGS -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250166 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258538 NEDD4L protein Q96PU5 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" ubiquitination 9606 19917253 t lperfetto "Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation" SIGNOR-217622 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Thr161 ASRFHNHtTHMSLVG 9606 15342622 t gcesareni "Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation." SIGNOR-128577 dactolisib chemical CHEBI:71952 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21803746 t "ATP-competitive inhibitor of PI3K and mTOR" gcesareni "The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific" SIGNOR-175715 PRKCA protein P17252 UNIPROT KCNJ4 protein P48050 UNIPROT "down-regulates activity" phosphorylation Thr53 IFTTCVDtRWRYMLM -1 10206975 t miannu "These results therefore indicate that Kir2.3 is directly modulated by PKC phosphorylation of its channel protein and threonine 53 is the PKC phosphorylation site in Kir2.3." SIGNOR-275965 AT9283 chemical CID:11696609 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190011 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 14565864 f lperfetto "Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner." SIGNOR-268993 RAP1GDS1 protein P52306 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171421 FGFR1 protein P11362 UNIPROT PDP1 protein Q9P0J1 UNIPROT "down-regulates activity" phosphorylation Tyr94 SILKANEySFKVPEF 10090 BTO:0000944 24962578 t miannu "Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients. " SIGNOR-276640 S1PR2 protein O95136 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257349 SRC protein P12931 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "down-regulates activity" phosphorylation 9606 30889378 t miannu "SRC can directly phosphorylate and inhibit LATS" SIGNOR-259056 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 10090 14981546 f "These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation." SIGNOR-261521 AKT1 protein P31749 UNIPROT BAX protein Q07812 UNIPROT "down-regulates activity" phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 BTO:0003473 14766748 t lperfetto "Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members" SIGNOR-252538 LEPR protein P48357 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001282 18718905 t miannu "These observations indicate that leptin stimulates tyrosine phosphorylation of STAT3 via LEPRb but independent of JAK2." SIGNOR-263492 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Phe64 TVFSVDEfSASVLTG -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263586 PER2 protein O15055 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR "down-regulates activity" binding 9606 20817722 t miannu "The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop." SIGNOR-267973 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0001130 1010227 t gcesareni "Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner." SIGNOR-252819 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1330 QMRHQSEsQGVGLSD 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks" SIGNOR-72048 GRIK4 protein Q16099 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI "up-regulates quantity" relocalization 9606 BTO:0002609 12393813 t lperfetto "Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine" SIGNOR-268275 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 t gcesareni "Regulation of mammalian pdc activity is accomplished in large part by phosphorylation (resulting in inactivation) of the e1 component by a family of pyruvate dehydrogenase kinases (pdk 14 isozymes) and dephosphorylation (leading to activation) of phosphorylated e1 by a set of specific phosphatases (phosphopyruvate dehydrogenase phosphatase 12 isozymes) (1, 3-6). The subunit of the e1 component has three phosphorylation sites, named site 1 (ser-264), site 2 (ser-271), and site 3 (ser-203), and phosphorylation of any one of these three sites results in inactivation" SIGNOR-154640 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159398 MAPK9 protein P45984 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Thr320 SKYNAEStERESQDT 9606 18667537 t llicata "This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity." SIGNOR-179680 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 16046550 t "The effect has been demonstrated using Q01196-8" gcesareni "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-138928 SIRT5 protein Q9NXA8 UNIPROT LDHB protein P07195 UNIPROT "up-regulates activity" deacetylation Lys329 DTLWDIQkDLKDL 9606 BTO:0001615 34929314 t lperfetto "In colorectal cancer, SIRT5 binds to lactate dehydrogenase B (LDHB) to deacetylate it at Lysine 329, thereby increasing its enzymatic activity." SIGNOR-267645 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val53 SHVTGKGvTVETVFS -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263590 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 16679294 t gcesareni "Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action" SIGNOR-146680 NMDA proteinfamily SIGNOR-PF56 SIGNOR CTTN protein Q14247 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000142 14684878 t miannu "Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors." SIGNOR-266598 PRKCG protein P05129 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto "Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication." SIGNOR-249050 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser390 KEAEEESsGGEEEDE 9606 16227438 t gcesareni "We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2." SIGNOR-141159 YES1 protein P07947 UNIPROT WWTR1 protein Q9GZV5 UNIPROT "up-regulates activity" phosphorylation Tyr305 PFLNGGPyHSREQST 9606 BTO:0000578 35041461 t miannu "Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C)." SIGNOR-277654 CADPS2 protein Q86UW7 UNIPROT STX1A protein Q16623 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu "CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1" SIGNOR-264337 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000017;BTO:0000195 10753475 t "Canertinib is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC50 0.8 nM), HER-2 (IC50 19 nM) and ErbB-4 (IC50 7 nM)." gcesareni "Quinazoline analogues with 7-alkoxyamine solubilizing s were potent irreversible inhibitors of the isolated egfr enzyme, with ic(50[app]) values from 2 to 4 nm, and potently inhibited both egfr and erbb2 autophosphorylation in cells." SIGNOR-76554 POLR2L protein P62875 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266142 "SEC61 complex" complex SIGNOR-C368 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 33925740 t lperfetto "The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol. " SIGNOR-265284 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 t gcesareni "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" SIGNOR-183644 PP121 chemical CHEBI:50915 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206292 OPTN protein Q96CV9 UNIPROT BDNF protein P23560 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259878 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257970 CNOT1 protein A5YKK6 UNIPROT "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR "form complex" binding 9606 19558367 t lperfetto "In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules." SIGNOR-268300 USP13 protein Q92995 UNIPROT ATG5 protein Q9H1Y0 UNIPROT "up-regulates quantity by stabilization" deubiquitination 36528756 t lperfetto "Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells." SIGNOR-275838 Gbeta proteinfamily SIGNOR-PF4 SIGNOR IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation 9606 12510059 t "inferred from 70% family members" gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-269997 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT "down-regulates activity" dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0000298 16291744 t "down-regulates binding to src" lperfetto "Here we report that protein-tyrosine phosphatase 1B (PTP 1B) is an alpha-actinin phosphatase. PTP 1B-dependent dephosphorylation of alpha-actinin was seen in COS-7 cells|No dephosphorylation was observed in cells coexpressing the alpha-actinin phosphorylation mutant Y12F and PTP 1B. |A reversible interaction between alpha-actinin and Src enables the dephosphorylation of alpha-actinin by PTP 1B, releasing Src" SIGNOR-270539 P2RY1 protein P47900 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257185 PP2B proteinfamily SIGNOR-PF18 SIGNOR FLNA protein P21333 UNIPROT "down-regulates quantity by destabilization" dephosphorylation 9606 16442073 t "inferred from 70% family members" "Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation." SIGNOR-269986 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257940 MAF1 protein Q9H063 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "down-regulates activity" binding 29378333 t lperfetto "The synthesis of transfer RNA (tRNA) is directed by RNA polymerase III (Pol III) specialized in high-level transcription of short DNA templates. Pol III recruitment to tRNA genes is controlled by two general initiation factors, TFIIIB and TFIIIC. |Under stress conditions, tRNA synthesis is negatively regulated by the MAF1 protein, which interacts directly with Pol III." SIGNOR-266198 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10116 BTO:0000575 15738637 t "In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver." SIGNOR-248446 STK38 protein Q15208 UNIPROT RAB11FIP5 protein Q9BXF6 UNIPROT "up-regulates activity" phosphorylation Ser307 FTHKRTYsDEANQMR 10090 BTO:0000142 22445341 t miannu "We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation." SIGNOR-263035 STK11 protein Q15831 UNIPROT BRSK2 protein Q8IWQ3 UNIPROT up-regulates phosphorylation Thr174 VGDSLLEtSCGSPHY 9606 14976552 t lperfetto "Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold" SIGNOR-122485 "Shelterin complex" complex SIGNOR-C306 SIGNOR ATM protein Q13315 UNIPROT "down-regulates activity" binding 18680434 t lperfetto "It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex" SIGNOR-263322 "perfluorononanoic acid" chemical CHEBI:38397 ChEBI PPARD protein Q03181 UNIPROT "up-regulates activity" "chemical activation" -1 31332417 t miannu "In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group." SIGNOR-268756 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" phosphorylation Ser161 IADLGLAsFKMWSKL -1 18408713 t miannu "These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1)" SIGNOR-276158 CDK2 protein P24941 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 17361108 t gcesareni "Our results demonstrate that cdk2 is capable of autophosphorylation at thr160." SIGNOR-153636 ANAPC13 protein Q9BS18 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252012 TLR4 protein O00206 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 20596954 f fstefani "Regulation of toll-like receptor signaling in the innate immunity." SIGNOR-166485 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates "transcriptional regulation" 9606 23332504 f fspada "Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. " SIGNOR-210111 PRKACA protein P17612 UNIPROT PPARG protein P37231 UNIPROT "up-regulates activity" 10090 BTO:0000011 20638365 f "Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-gamma" SIGNOR-253019 ETS1 protein P14921 UNIPROT TBX22 protein Q9Y458 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 25373698 t miannu "TBX22 is an X-linked gene, which encodes a T-box-containing transcription factor. Loss-of-function mutation in the X-linked TBX22 promoter disrupts an ETS-1 binding site and leads to cleft palate. We first link the transcription factor ETS-1 to TBX22 pathway during embryonic palatogenesis." SIGNOR-265565 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262978 SOD1 protein P00441 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 10090 BTO:0004488 18519638 f "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)" "To investigate the role of ASK1 in the motor neurotoxicity by SOD1mut, we examined whether SOD1mut activates ASK1 as assessed by in vitro kinase assay. Expression of SOD1mut, but not SOD1wt, activated endogenous ASK1 (Fig. 4A, top panel). We next examined whether SOD1mut-induced ASK1 activation is mediated by ER stress." SIGNOR-262789 WAC protein Q9BTA9 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 30021153 t lperfetto "Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. " SIGNOR-265036 CERS4 protein Q9HA82 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI "up-regulates quantity" "chemical modification" 9606 26887952 t done miannu " Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. " SIGNOR-273998 SIAH1 protein Q8IUQ4 UNIPROT SCF(TBL1) complex SIGNOR-C533 SIGNOR "form complex" binding 9606 BTO:0000007 20181957 t miannu "Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC). " SIGNOR-271952 PLK1 protein P53350 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser739 SKILLDIsFPGLDED 9606 19737929 t lperfetto "It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression" SIGNOR-187892 USP7 protein Q93009 UNIPROT TP53 protein P04637 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni "Hausp counteracts the destabilizing effect of mdm2 by direct deubiquitination of p53." SIGNOR-139456 "JNJ-28312141 free base" chemical CID:11676971 PUBCHEM CSF1R protein P07333 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258228 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Thr388 VYFKPSLtPSGEFRK 9606 19767751 t llicata "These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport." SIGNOR-188127 CSNK1G1 protein Q9HCP0 UNIPROT LYN protein P07948 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser13 SKGKDSLsDDGVDLK 9606 BTO:0000007 33004926 t miannu "Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane." SIGNOR-275396 SRSF2 protein Q01130 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27524244 t miannu "Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2." SIGNOR-260076 ID1 protein P41134 UNIPROT TCF4 protein P15884 UNIPROT "down-regulates activity" binding 10090 BTO:0004058 SIGNOR-C129 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241385 RXRB protein P28702 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11237216 t gcesareni "Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology" SIGNOR-105448 ACSL5 protein Q9ULC5 UNIPROT "long-chain fatty acid anion" smallmolecule CHEBI:57560 ChEBI "down-regulates quantity" "chemical modification" 9606 24269233 t "ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity" SIGNOR-267713 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity." SIGNOR-129284 SLC9A3 protein P48764 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265593 KANSL3 protein Q9P2N6 UNIPROT "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR "form complex" binding 9606 BTO:0000007 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex." SIGNOR-267162 PTPRG protein P23470 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 BTO:0000876 25624455 t miannu "Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG." SIGNOR-254690 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273038 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 phosphorylation:Tyr177 8402896 t gcesareni "BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation" SIGNOR-248199 PAWR protein Q96IZ0 UNIPROT WT1 protein P19544 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 8943350 t 2 miannu "We identified par-4 (for prostate apoptosis response) as a WT1-interacting protein that itself functions as a transcriptional repressor. Functionally, par-4 inhibited transcription activated by WT1" SIGNOR-240596 SGK1 protein O00141 UNIPROT WNK4 protein Q96J92 UNIPROT "down-regulates activity" phosphorylation Ser1190 SSRQRRLsKGSFPTS 9606 27517916 t miannu "Constitutively active SGK1 S422D phosphorylates WNK4 at Ser-1169 [ xref ] and Ser-1196 [ xref ], relieving the inhibitory effect of WNK4 on NCC\u2019s activity [ xref , xref ].|SGK1 is thought to modulate NCC activity by inhibiting WNK4 , , ]." SIGNOR-278454 haloperidol chemical CHEBI:5613 ChEBI HTR2B protein P41595 UNIPROT "down-regulates activity" "chemical inhibition" 10036 BTO:0000452 9459568 t miannu "The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-" SIGNOR-258680 FUS protein P35637 UNIPROT PA2G4 protein Q9UQ80 UNIPROT "up-regulates activity" sumoylation Lys93 VCHFSPLkSDQDYIL 9606 BTO:0000007 19946338 t gcesareni "Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity." SIGNOR-236904 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A3-B2 complex SIGNOR-C139 SIGNOR "up-regulates activity" "chemical activation" 9606 15036565 t gcesareni "One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)" SIGNOR-244113 PRKAA1 protein Q13131 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr198 PGLRRRQt 10090 30033086 t Luana "P27Kip1-Mediated Cell Survival Is Dependent on AMPK-Specific Thr198 Phosphorylation|AMPK-dependent phosphorylation of p27Kip1 on Thr198 promotes p27Kip1 protein stability, resulting in more autophagy and less apoptosis." SIGNOR-259859 XCL1 protein P47992 UNIPROT XCR1 protein P46094 UNIPROT up-regulates binding 9606 BTO:0000763 10518929 t gcesareni "Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells." SIGNOR-71164 CEBPB protein P17676 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003697 18583320 t "Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells." SIGNOR-254046 hsa-miR-101-5p mirna URS000017D10B_9606 RNAcentral CXCL12 protein P48061 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000018 26349988 t Parnian "MiR-101 suppressed the transcription activity of the CXCL12 gene by targeting the binding site in the 3'UTR of CXCL12 mRNA independently. | We observed that upon transfection with miR-101, the expression of CXCL12 protein and mRNA were both decreased. Collectively, these findings suggest that miR-101 regulates the expression of CXCL12 post-transcriptionally." SIGNOR-278008 AHSP protein Q9NZD4 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by stabilization" binding 9606 18179859 t Regulation miannu "α-Hemoglobin stabilizing protein (AHSP) binds α-hemoglobin (Hb), avoiding its precipitation and its pro-oxidant activity." SIGNOR-251770 HNuRF complex SIGNOR-C448 SIGNOR EN1 protein Q05925 UNIPROT "up-regulates quantity by expression" 9606 14609955 f miannu "Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. ) ChIP assays localize hNURF specifically to engrailed-1 (en-1) and engrailed-2 (en-2) promoters." SIGNOR-268839 KPNA6 protein O60684 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 t gcesareni "Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling." SIGNOR-165343 PRKCZ protein Q05513 UNIPROT PLA2G4A protein P47712 UNIPROT "up-regulates activity" phosphorylation Thr376 GSKFFMGtVVKKYEE 9606 BTO:0006398 32559461 t miannu "To further evaluate cPLA2 as a candidate substrate for PKCζ, we developed a custom antibody recognizing the cPLA2 T376 phosphorylation site. Specificity was validated in both serum starved/stimulated samples" SIGNOR-277518 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr89 QSSNGHItTTPTPTQ 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170772 SPRY4 protein Q9C004 UNIPROT Cell_invasion phenotype SIGNOR-PH226 SIGNOR down-regulates 9606 BTO:0002283 20501643 f "Re-expression of Spry4 inhibits migration and invasion in NSCLC cells." SIGNOR-278112 CIB1 protein Q99828 UNIPROT ITGA2B protein P08514 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 11756406 t Gianni "The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading" SIGNOR-269061 cinolazepam chemical CHEBI:59514 ChEBI "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t brain lperfetto "The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005)." SIGNOR-263801 MDM2 protein Q00987 UNIPROT RPL6 protein Q02878 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 24174547 t miannu "Furthermore, we also demonstrated that RPL6 is a substrate for HDM2-mediated ubiquitination and proteasomal degradation.|The interaction of RPL6 and HDM2 drives HDM2 mediated RPL6 polyubiquitination and proteasomal degradation." SIGNOR-278630 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser216 PSGSGAAsPTGSAVD 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262762 Ub:E2 complex SIGNOR-C497 SIGNOR PCGF6 protein Q9BYE7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271037 MAPK14 protein Q16539 UNIPROT SMARCD3 protein Q6STE5 UNIPROT "up-regulates activity" phosphorylation 9606 21902831 t lperfetto "P38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci." SIGNOR-176557 "NUP98 Fusion" "fusion protein" SIGNOR-FP16 SIGNOR CDK6 protein Q00534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32344427 f miannu "NUP98-fusion proteins directly regulate leukemia-associated gene expression programs in AML. CDK6 expression is under direct transcriptional control of NUP98-fusions and NUP98-fusion AML is particularly sensitive to CDK6 inhibition." SIGNOR-261505 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252441 PRKD1 protein Q15139 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 20179209 t lperfetto "Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated" SIGNOR-163924 "NMDA receptor_2B" complex SIGNOR-C348 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264133 EID3 protein Q8N140 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 23720823 f miannu "Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene." SIGNOR-266641 GSK3B protein P49841 UNIPROT WT1 protein P19544 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser208 GCHTPTDsCTGSQAL 9606 33184107 t miannu "Glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8." SIGNOR-277540 CAMK1 protein Q14012 UNIPROT CAMK1 protein Q14012 UNIPROT "up-regulates activity" phosphorylation Thr177 DPGSVLStACGTPGY -1 8253780 t llicata "CaM kinase I was autophosphorylated in a Ca2+/CaM-dependent manner at a threonyl residue (Thr-177) which is located at a position equivalent to that of the threonyl residue (Thr-197) autophosphorylated in cAMP-dependent protein kinase." SIGNOR-250612 AHR protein P35869 UNIPROT CYP1B1 protein Q16678 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 16115918 f miannu "Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1." SIGNOR-253733 SRC protein P12931 UNIPROT CASP7 protein P55210 UNIPROT "up-regulates activity" phosphorylation 9606 24407236 t miannu "Src enhances caspase-7 activity in vitro and in cells.|When all four sites were mutated to phenylalanine, the in vitro kinase assay results showed that phosphorylation of the Mut-caspase-7 protein by Src decreased dramatically compared with Wt-caspase-7, suggesting that these four sites, Tyr58, Tyr151, Tyr229 and Tyr230, are the most important sites of caspase-7 to be phosphorylated by Src (XREF_FIG)." SIGNOR-278455 SCF-FBW7 complex SIGNOR-C135 SIGNOR GATA2 protein P23769 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 25670854 t miannu "GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1). " SIGNOR-276885 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr875 GLITTLHyPAPKRNK 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260816 ITGB1BP1 protein O14713 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257655 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2B protein P18089 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257454 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr771 ADIESSNyMAPYDNY 10090 BTO:0002572 14966296 t "The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP." SIGNOR-248389 DUSP3 protein P51452 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR "down-regulates activity" dephosphorylation 9534 BTO:0004055 10224087 t "inferred from 70% of family members" "Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2" SIGNOR-269907 NHLRC1 protein Q6VVB1 UNIPROT PPP1R3C protein Q9UQK1 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 19171932 t miannu "We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity. " SIGNOR-276238 TRAF6 protein Q9Y4K3 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates quantity" ubiquitination 9606 27990298 t miannu "Consistently, TRAF6 reduced G6pase gene expression or reporter activity induced by wild-type CRTC1 and CRTC2 but not TRAF6-interaction-defective CRTC1 and CRTC2 (XREF_FIG and XREF_SUPPLEMENTARY).|Indeed, TRAF6, the E3 ubiquitin ligase activated by IL-1beta associates with and ubiquitinates CRTC2." SIGNOR-278725 LPAR6 protein P43657 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 15856019 t gcesareni "Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13." SIGNOR-135822 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT "down-regulates activity" phosphorylation 9606 28114302 t miannu "A secondary genome-wide screen revealed CSNK1A1 as the kinase that phosphorylates AGO2 on these sites." SIGNOR-279699 CLCN3 protein P51790 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "down-regulates quantity" relocalization 9606 29845874 t miannu "ClC-3 is a strongly outwardly rectifying, electrogenic 2Cl/H exchanger with biophysical properties that closely resemble those of its close homologues ClC-4 and ClC-5" SIGNOR-265422 PTH1R protein Q03431 UNIPROT SLC34A1 protein Q06495 UNIPROT "down-regulates quantity" 28363951 f lperfetto "PTH inhibits reabsorption of phosphate from the glomerular filtrate in RPT by decreasing the abundance of sodium-phosphate co-transporters NPT2a and NPT2c on the apical membrane, thus enhancing renal phosphate excretion" SIGNOR-270556 MC5R protein P33032 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257337 HIPK2 protein Q9H2X6 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser257 PGVVMASsPALPTQP 9606 20573984 t lperfetto "Ere we found that homeodomain-interacting protein kinase 2 (hipk2), a dna-damage responsive nuclear kinase, is a new creb kinase for phosphorylation at ser-271 but not ser-133, and activates creb transactivation function" SIGNOR-166338 AKT3 protein Q9Y243 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates activity" phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto "the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate" SIGNOR-249583 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 16076840 t gcesareni "The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex." SIGNOR-139320 HNF4A protein P41235 UNIPROT GK protein P32189 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18805788 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription" SIGNOR-181274 IRF3 protein Q14653 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 10090 20610653 f miannu "Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors." SIGNOR-260330 PPP2CA protein P67775 UNIPROT STK3 protein Q13188 UNIPROT down-regulates dephosphorylation Thr180 DTMAKRNtVIGTPFW 9606 23431053 t gcesareni "Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively." SIGNOR-201266 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 t gcesareni "Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression." SIGNOR-156891 TPO protein P07202 UNIPROT "L-tyrosine zwitterion" smallmolecule CHEBI:58315 ChEBI "down-regulates quantity" "chemical modification" 9606 16098474 t scontino "TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues." SIGNOR-266956 STX10 protein O60499 UNIPROT "LE-TGN SNARE" complex SIGNOR-C157 SIGNOR "form complex" binding 9606 BTO:0000567 18195106 t lperfetto "We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport" SIGNOR-253080 RUVBL2 protein Q9Y230 UNIPROT "R2TP core co-chaperone" complex SIGNOR-C515 SIGNOR "form complex" binding 9606 29662061 t miannu " Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. " SIGNOR-270929 RNF7 protein Q9UBF6 UNIPROT CASP3 protein P42574 UNIPROT "down-regulates activity" ubiquitination 9606 23136067 t miannu "SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes." SIGNOR-271448 GNAI3 protein P08754 UNIPROT ADCY6 protein O43306 UNIPROT "down-regulates activity" binding 7108 BTO:0001240 8119955 t "Marta Tosoni" "Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3" SIGNOR-278079 HACD proteinfamily SIGNOR-PF86 SIGNOR "very long-chain 2,3-trans-enoyl CoA(4-)" smallmolecule CHEBI:83728 ChEBI "up-regulates quantity" "chemical modification" 9606 18554507 t miannu "Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle." SIGNOR-267918 terbutaline chemical CHEBI:9449 ChEBI ADRB3 protein P13945 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" SIGNOR-257871 KDM3A protein Q9Y4C1 UNIPROT H3-2 protein Q5TEC6 UNIPROT "up-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu "Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. " SIGNOR-276843 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" phosphorylation Tyr326 KMETQSMyVSELKRT 9606 BTO:0002181 37977223 t miannu " To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation." SIGNOR-277863 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni "In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation" SIGNOR-154276 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI "up-regulates quantity" "precursor of" 9606 24786789 t miannu "Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle." SIGNOR-266508 SYVN1 protein Q86TM6 UNIPROT APP protein P05067 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 29083378 t miannu "Thus, HRD1 ubiquitinates and degrades denaturated APP as well as unfolded proteins, suggesting that HRD1 affects APP-A\u03b2 dynamics in the brains of AD patients." SIGNOR-278616 CUDC-101 chemical CID:24756910 PUBCHEM HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20143778 t miannu "By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively." SIGNOR-262259 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT unknown phosphorylation Tyr691 PKGTQADyAEVKFQ 9606 11733002 t lperfetto "These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691" SIGNOR-112499 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-160415 SIAH1 protein Q8IUQ4 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20940030 t gcesareni "The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation" SIGNOR-168460 methoxamine chemical CHEBI:6839 ChEBI ADRA1A protein P35348 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258455 PASK protein Q96RG2 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation 9606 23853095 t miannu "In vitro, PASK directly phosphorylates GSK3\u03b2 on its inactivating phosphorylation site Ser(9).|We conclude that PASK phosphorylates and inactivates GSK3\u03b2, thereby preventing PDX-1 serine phosphorylation and alleviating GSK3\u03b2-mediated PDX-1 protein degradation in pancreatic \u03b2-cells." SIGNOR-279639 2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine chemical CHEBI:95074 ChEBI EHMT2 protein Q96KQ7 UNIPROT "down-regulates activity" "chemical inhibition" -1 26320100 t miannu "Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression." SIGNOR-262240 NEDD4 protein P46934 UNIPROT PPARG protein P37231 UNIPROT "up-regulates activity" ubiquitination 9606 27917940 t miannu "First, NEDD4 interacts with and ubiquitinates PPARgamma.|NEDD4 increases PPARgamma stability through the inhibition of its proteasomal degradation." SIGNOR-278540 GRK5 protein P34947 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates phosphorylation 9606 32326036 t miannu "We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER." SIGNOR-278478 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Thr26 PPPQPQHtPSPAAPP 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198737 CEBPA protein P49715 UNIPROT HSD11B1 protein P28845 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19088256 t lperfetto "Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region." SIGNOR-268971 NOX4 protein Q9NPH5 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto "Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS)." SIGNOR-264717 PAX2 protein Q02962 UNIPROT Urogenital_tract phenotype SIGNOR-PH71 SIGNOR "up-regulates activity" 10090 8575306 f "Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases." SIGNOR-252301 cabazitaxel chemical CHEBI:63584 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" "chemical inhibition" 9606 21770474 t miannu "Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization" SIGNOR-259445 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr7 tQDQPMEE 9606 BTO:0000567 2507541 t lperfetto "Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha." SIGNOR-248888 CSNK2A1 protein P68400 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000527 19941816 t miannu "We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641." SIGNOR-265822 CSK protein P41240 UNIPROT CSK protein P41240 UNIPROT "up-regulates activity" phosphorylation Tyr304 DVCEAMEyLEGNNFV -1 9148770 t llicata "Taken together these results indicate that Csk can be phosphorylated in vivo at Tyr-184 by an as yet unknown tyrosine kinase, and that autophosphorylation of Tyr-304 occurs only at abnormally high Csk concentrations in vitro. Furthermore, Tyr-304 is required for the maintenance of the structure of the Csk kinase domain." SIGNOR-250778 FOXA2 protein Q9Y261 UNIPROT DLK1 protein P80370 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12865419 t "Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene." SIGNOR-254971 LUBAC complex SIGNOR-C527 SIGNOR TRIM25 protein Q14258 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21292167 t miannu "HOIL-1L/HOIP LUBAC induces TRIM25 ubiquitination and degradation.Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner." SIGNOR-271859 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-244588 EIF3G protein O75821 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266394 AGTR2 protein P50052 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptide gpcrs are coupled to the activation of phospholipase c, and therefore to calcium ele- vation and protein kinase c (pkc) activation, through g proteins of the alfaq family" SIGNOR-106995 PRKCA protein P17252 UNIPROT TTN protein Q8WZ42 UNIPROT "up-regulates activity" phosphorylation 9606 19679839 t miannu "In summary, titin is a PKC substrate with PKCalpha phosphorylating predominately the full-length titin molecule.|Mechanical experiments with skinned LV myocardium revealed that PKCalpha significantly increases titin based passive tension, an effect that is reversed by PP1." SIGNOR-278382 GNAI1 protein P63096 UNIPROT Cell_invasion phenotype SIGNOR-PH226 SIGNOR down-regulates 9606 BTO:0003191 23691483 t "Marta Tosoni" "Taken together, these observations indicate that GNAI1 is a negative regulator of HCC migration and invasion, similar to its family member GNAI2." SIGNOR-278879 MDM2 protein Q00987 UNIPROT IER3 protein P46695 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 26973248 t miannu "FHL2 stimulates MDM2 mediated ubiquitination of IER3 by forming a ternary complex.|Scaffold protein FHL2 facilitates MDM2 mediated degradation of IER3 to regulate proliferation of cervical cancer cells." SIGNOR-278824 AKT1 protein P31749 UNIPROT ATG4B protein Q9Y4P1 UNIPROT "up-regulates activity" phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000586 29165041 t lperfetto "In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity." SIGNOR-275834 BMS-554417 chemical CID:54754526 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190455 RAB1A protein P62820 UNIPROT C9orf72 protein Q96LT7 UNIPROT "up-regulates activity" binding 9606 27334615 t lperfetto "Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology." SIGNOR-261282 PTEN protein P60484 UNIPROT PIK3CB protein P42338 UNIPROT "down-regulates activity" 9606 18794881 f lperfetto "The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3))." SIGNOR-236663 MRPL13 protein Q9BYD1 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262380 RIMBP3C protein A6NJZ7 UNIPROT RIMS3 protein Q9UJD0 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264372 CITED2 protein Q99967 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003859 12960175 f miannu "CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway." SIGNOR-253777 BRCA1 protein P38398 UNIPROT "BRCA1-BARD1 complex" complex SIGNOR-C297 SIGNOR "form complex" binding 25400280 t lperfetto "Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks." SIGNOR-263224 RBM15 protein Q96T37 UNIPROT SON protein P18583 UNIPROT up-regulates binding 9606 19786495 t miannu "Here we report that the human nxf1-binding protein rbm15 binds specifically to human dbp5 and facilitates its direct contact with mrna in vivo." SIGNOR-188264 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178387 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" phosphorylation Ser60 ETNQNSSsDSEAERR -1 11711551 t llicata "We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4." SIGNOR-250964 canertinib chemical CHEBI:61399 ChEBI PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258094 AKT1 protein P31749 UNIPROT SLC2A1 protein P11166 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8940145 f gcesareni "The constitutively active akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3t3-l1 adipocytes directed lipid but not glycogen synthesis" SIGNOR-252579 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 t gcesareni "The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain." SIGNOR-111511 EIF3F protein O00303 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates deubiquitination Lys1759 CGVLLSRkRRRQHGQ 9606 21124883 t gcesareni "The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor." SIGNOR-170158 JUN protein P05412 UNIPROT KRT16 protein P08779 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000552 12954631 f miannu "these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter." SIGNOR-253905 HES1 protein Q14469 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19891787 f gcesareni "We earlier identified e2f-1 as a crucial transcription factor directly inhibited by hes-1." SIGNOR-189061 PCSK7 protein Q16549 UNIPROT ATF6 protein P18850 UNIPROT up-regulates phosphorylation 9606 12076252 t gcesareni "We discovered that azc, an agent that causes the formation of abnormal proteins, stimulates the stress-activated kinase p38 mapk, which phosphorylates atf6" SIGNOR-89813 MAPK7 protein Q13164 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 9384584 t lperfetto "Bmk1 dramatically enhances the transactivation activity of mef2c by phosphorylating a serine residue at amino acid position 387 in this transcription factor." SIGNOR-53545 PLEKHG6 protein Q3KR16 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260567 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000527 21419810 t lperfetto "In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer" SIGNOR-172894 GOT1 protein P17174 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "chemical modification" 9606 26003525 t miannu "Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer." SIGNOR-267509 CSNK2A1 protein P68400 UNIPROT KDM1A protein O60341 UNIPROT "up-regulates activity" phosphorylation Ser131 DESLANLsEDEYYSE 9606 BTO:0002181 25999347 t miannu "We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites." SIGNOR-276902 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser352 AATNRPNsIDPALRR 9606 BTO:0000150 16551632 t llicata "Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I" SIGNOR-145284 WNK4 protein Q96J92 UNIPROT OXSR1 protein O95747 UNIPROT "up-regulates activity" phosphorylation 9606 22342722 t miannu "In addition, WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1, which in turn phosphorylate and activate NCC [ xref ; xref ].|Later studies also indicate that WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1, which in turn phosphorylates and activates NCC ; ]." SIGNOR-278389 eletriptan chemical CHEBI:50922 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 10193663 t Luana "This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues " SIGNOR-258339 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 t "Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175" SIGNOR-248476 BLOC-1 complex SIGNOR-C381 SIGNOR histamine smallmolecule CHEBI:18295 ChEBI "up-regulates quantity" relocalization 9606 23805129 t lperfetto "The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules" SIGNOR-265998 TRIM65 protein Q6PJ69 UNIPROT TNRC6A protein Q8NDV7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 24778252 t miannu "Ubiquitination assays demonstrate that TRIM65 is an ubiquitin E3 ligase for TNRC6 proteins. The combination of overexpression and knockdown studies establishes that TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6." SIGNOR-272174 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR SALL4 protein Q9UJQ4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269252 PRKAA1 protein Q13131 UNIPROT CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21331044 t gcesareni "Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target." SIGNOR-172136 ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 11389842 t "Indirect_regulation of phosphorylation" miannu "Nodal Induces Smad Phosphorylation through ALK4 in a Cripto-Dependent Manner" SIGNOR-251943 MCU protein Q8NE86 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270869 GDNF protein P39905 UNIPROT GFRA2 protein O00451 UNIPROT up-regulates binding 9606 9192898 t gcesareni "Gdnf mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (gpi)-linked protein (designated gdnfr-alpha)." SIGNOR-49184 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation 9606 21419341 t "inferred from 70% family members" gcesareni "We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1." SIGNOR-270048 DOK7 protein Q18PE1 UNIPROT CRK protein P46108 UNIPROT "up-regulates activity" binding 10090 BTO:0000165 20603078 t miannu "Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7." SIGNOR-273847 MC1R protein Q01726 UNIPROT TNF protein P01375 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000552 19656324 f miannu "Constitutive expression of MC1R in HaCaT keratinocytes inhibits basal and UVB-induced TNF-alpha production. the constitutive activity of MC1R results in elevated intracellular cAMP level, reduced NF-kappaB activity and decreased TNF-alpha transcription" SIGNOR-252375 TP53INP1 protein Q96A56 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT up-regulates binding 9606 22421968 t gcesareni "These data indicate that cell death observed after tp53inp1-lc3 interaction depends on both autophagy and caspase activity. We conclude that tp53inp1 could act as a tumor suppressor by inducing cell death by caspase-dependent autophagy." SIGNOR-196676 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr26 SQPHGSVtQSQGSSS 9606 BTO:0000007 12024051 t gcesareni "We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr" SIGNOR-87850 chlorpromazine chemical CHEBI:3647 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258836 EFR3B protein Q9Y2G0 UNIPROT PI4KA protein P42356 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 34504076 t miannu "PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B" SIGNOR-269093 COLGALT1 protein Q8NBJ5 UNIPROT COL1A1 protein P02452 UNIPROT "up-regulates activity" glycosylation -1 19075007 t "Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues." SIGNOR-261152 HTR1E protein P28566 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256848 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 10649448 f gcesareni "The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells" SIGNOR-255753 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding -1 2467839 t irozzo "The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation." SIGNOR-256362 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1333 ARGGQVFyNSEYGEL 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165039 YWHAQ protein P27348 UNIPROT NEFL protein P07196 UNIPROT "down-regulates activity" binding 9606 23230147 t miannu "These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments." SIGNOR-252399 CCNE1 protein P24864 UNIPROT CDK2 protein P24941 UNIPROT up-regulates binding 9606 23437375 t gcesareni "Our results suggest that ad-induced cyclin e activates cdk2 that targets the transcriptional repressor prb/cyclin e activates the cdk2 kinase necessary for the actual initiation of dna replication" SIGNOR-201506 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr102 RAAMFPEtLDEGMQI -1 12432063 t miannu "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin. " SIGNOR-275993 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Thr530 YLSELPPtPLHVSED 9606 20027304 t "This phosphorylation increased sirt1 nuclear localization" gcesareni "Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53." SIGNOR-162322 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1710 HVTSKCGsLKNIRHR 9606 BTO:0000567 11029056 t miannu "CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA" SIGNOR-250002 CDK3 protein Q00526 UNIPROT CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR "form complex" binding 37104883 t lperfetto "Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively." SIGNOR-273185 FERMT3 protein Q86UX7 UNIPROT ITGB3 protein P05106 UNIPROT "up-regulates activity" binding 10090 BTO:0000132;BTO:0003292 18278053 t lperfetto "Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner" SIGNOR-266066 PRKCA protein P17252 UNIPROT VTN protein P04004 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto "Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin." SIGNOR-248962 PIK3C3 protein Q8NEB9 UNIPROT PTEN protein P60484 UNIPROT up-regulates binding 9606 BTO:0000567 20212113 t lperfetto "Direct positive regulation of pten by the p85 subunit of phosphatidylinositol 3-kinase.Thus p85 regulates both p110-pi3k and pten-phosphatase enzymes through direct interaction" SIGNOR-164075 PRDM2 protein Q13029 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8654390 f 2 miannu "We show that a portion of MTB-Zf, including an N-terminal zinc-finger domain, binds in vitro to MTE and that the transient coexpression of MTB-Zf cDNA leads to transativation of the heme-oxygenase-1 gene promoter." SIGNOR-241047 PAF1C complex SIGNOR-C471 SIGNOR "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 20178742 t miannu "HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription." SIGNOR-269837 CCL3 protein P10147 UNIPROT CCR5 protein P51681 UNIPROT "up-regulates activity" binding 10090 15075201 t lperfetto "The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days." SIGNOR-251724 SRC protein P12931 UNIPROT PTPRJ protein Q12913 UNIPROT "up-regulates activity" phosphorylation Tyr1320 NTTAMTIyENLAPVT 9606 BTO:0000007 22898603 t miannu " We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin." SIGNOR-276375 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser75 EIRSRHSsYPAGTED -1 10195903 t lperfetto "Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.| Bcl-xL did not coimmunoprecipitate with BAD(S75E, S99E) protein (Fig. 2A), regardless of whether it was coexpressed with DCnA/B¬†" SIGNOR-263739 BRAF protein P15056 UNIPROT EEF1A2 protein Q05639 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu "Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf. " SIGNOR-276406 CDK1 protein P06493 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Thr317 RGALVRGtPVRGAIT 9606 9315091 t lperfetto "Phosphorylation of sam68 by purified cdc2." SIGNOR-51275 CDC20 protein Q12834 UNIPROT MCC complex SIGNOR-C382 SIGNOR "form complex" binding 9606 BTO:0000567 25092294 t miannu "The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20." SIGNOR-265976 CSNK2A1 protein P68400 UNIPROT MYB protein P10242 UNIPROT "down-regulates activity" phosphorylation Ser12 PRHSIYSsDEDDEDF -1 7735324 t llicata "For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants. " SIGNOR-250919 Ub:E2 complex SIGNOR-C497 SIGNOR RNF125 protein Q96EQ8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271212 PRKCE protein Q02156 UNIPROT NREP protein Q16612 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser59 LGSSELRsPRISYLH 9606 BTO:0004605 16229809 t done miannu "Site-directed mutagenesis of S59A retarded P311 degradation and induced glioma cell motility. In contrast, S59D mutation resulted in the rapid degradation of P311 and reduced glioma cell migration.Taken together, our results show that the serine phosphorylation of P311 is dependent on the function of both PKCε and PKCz." SIGNOR-273830 SMURF2 protein Q9HAU4 UNIPROT KLF5 protein Q13887 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 34035464 t miannu "Consistent with these observations, another study documented that Smurf2 specifically destabilizes KLF5, that the degradation of KLF5 by Smurf2 is disrupted by the proteasome inhibitor MG132, and that Smurf2 ubiquitinates KLF5 ." SIGNOR-278781 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 20640476 t lperfetto "AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1" SIGNOR-209936 FANCG protein O15287 UNIPROT SPTAN1 protein Q13813 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000773 19102630 t lperfetto "In FA cells, deficiencies in FA proteins lead to decreased stability of alphaRIISp |These results demonstrate that one of the FA proteins, FANCG, contains a motif that interacts directly with the SH3 domain of alphaIISp. We propose that this binding of FANCG to alphaIISp may be important for the stability of alphaIISp in cells and the role alphaIISp plays in the DNA repair process.|" SIGNOR-263275 WHAMM protein Q8TF30 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 20498093 t lperfetto "Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes." SIGNOR-261004 TRIM10 protein Q9UDY6 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity" ubiquitination 9606 32343488 t miannu "Collectively, these results indicate that TRIM10 may lead to ubiquitination and degradation of PTEN, which could be an underlying reason for AKT signalling inhibition in cardiac hypertrophy processes (Figure\u00a05D).4\n\nDISCUSSION.|In addition, we found that the effect regulated by TRIM10 was mediated by interactions with phosphatase and tensin homolog (PTEN); specifically, TRIM10 promoted PTEN ubiquitination, thus leading to AKT signalling activation.|The results showed that TRIM10 overexpression decreased PTEN expression, and MG132 reversed the reduction in PTEN (Figure\u00a05C)." SIGNOR-278729 linifanib chemical CHEBI:91435 ChEBI PDGFRA protein P16234 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193663 MAPK1 protein P28482 UNIPROT SORBS3 protein O60504 UNIPROT unknown phosphorylation 9606 15184391 t "The effect has been demonstrated using O60504-2" llicata "Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _." SIGNOR-125224 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 22558186 t gcesareni "Among these effector proteins, chk1 phosphorylates tlk12 and rad51, while brca, pik3, pml and e2f1 are chk2 substrates." SIGNOR-197278 SOD1 protein P00441 UNIPROT dioxygen smallmolecule CHEBI:15379 ChEBI "up-regulates quantity" "chemical modification" 9606 29301787 t lperfetto "Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD)." SIGNOR-272286 PTPRG protein P23470 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254729 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" SIGNOR-244156 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 7888666 t apalma "We found that IL-5 induced two GAS-binding proteins in the nuclear extract from eosinophils. One of them was identified as STAT1 (p91)." SIGNOR-255071 SIRT1 protein Q96EB6 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity" deacetylation 10090 BTO:0002572 27776347 t "SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis." SIGNOR-256208 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI RAC1 protein P63000 UNIPROT up-regulates "chemical activation" 9606 18480413 t gcesareni "The c-terminal polybasic motif of rac1 is responsible for direct interaction with pa," SIGNOR-178632 GNAS protein P63092 UNIPROT ADCY9 protein O60503 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 29292367 t "Marta Tosoni" "Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The enzyme is weakly activated by forskolin, fully activated by the G protein Gαs subunit and is autoinhibited by the AC9 C-terminus." SIGNOR-278883 GSK3B protein P49841 UNIPROT ARNTL protein O00327 UNIPROT down-regulates phosphorylation Thr21 DFMSPGPtDLLSSSL 9606 20049328 t lperfetto "Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened." SIGNOR-162790 PRKCQ protein Q04759 UNIPROT ARHGEF6 protein Q15052 UNIPROT "up-regulates activity" phosphorylation Ser488 LSASPRMsGFIYQGK 25694429 t lperfetto "Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation.|More specifically, αPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway." SIGNOR-272168 PPARG protein P37231 UNIPROT NR1D1 protein P20393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 12821652 t miannu "Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation." SIGNOR-268022 FBXO9 protein Q9UK97 UNIPROT TELO2 protein Q9Y4R8 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23263282 t miannu "Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins." SIGNOR-271996 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 21749389 t "The effect has been demonstrated using O75030-9" gcesareni "The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert." SIGNOR-252795 NOTCH1 protein P46531 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f lperfetto "Other notch target genes identi?ed In the thymoma cell line were dtx1 (gene for deltex1), i?-202, i?-204, i?-D3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a)." SIGNOR-149777 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 11904305 t gcesareni "Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. sa-perk1/2 activates the transcription factor, sp1, via ser59 phosphorylation downstream of pkc_, leading to transcription of p21sdi1 and resulting in replicative senescence of hdf cells." SIGNOR-116174 CAMK4 protein Q16566 UNIPROT NOVA2 protein Q9UNW9 UNIPROT unknown phosphorylation Ser194 EQVHKAVsAIVQKVQ 9606 BTO:0000007 32492405 t miannu "CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. Conversely, Nova-2 with single or double mutations to alanine (2A and 1A2A) was predominantly nuclear, like the WT (Figures 5H and ​and5I).5I). In contrast, glutamate mutations at site 3 had no effect on Nova-2 localization (Figures 5H and ​and5I)5I) or on Nova-2 binding to RNA (Figure S5E). These results showed that active CaMKIV reduces Nova-2 nuclear localization by phosphorylating sites 1 and 2 (S25, T27)." SIGNOR-273519 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr348 LPMDTEVyESPYADP 9606 BTO:0000776 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246609 "lysophosphatidylserine 14:0(1-)" chemical CHEBI:72402 ChEBI GPR34 protein Q9UPC5 UNIPROT "up-regulates activity" "chemical activation" 9606 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257505 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 17998206 t lperfetto "The endoplasmic reticulum (er)-resident protein kinase perk attenuates protein synthesis in response to er stress through the phosphorylation of translation initiation factor eif2_ at serine 51 / a modification that blocks initiation" SIGNOR-159160 RPS10 protein P46783 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262442 ATM protein Q13315 UNIPROT IPO9 protein Q96P70 UNIPROT "up-regulates activity" phosphorylation 9606 26943034 t miannu "In line with our previous results, IR exposure induced the nuclear accumulation of RanBP9, which was prevented by ATM inhibition using KU-55933.|Taken together these data indicate that RanBP9 is a novel target of ATM and that ATM phosphorylates at least two different residues (S181 and S603) of RanBP9 following IR exposure." SIGNOR-278910 PCBP2 protein Q15366 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 19881509 t Giorgia "Only AIP4 associated with PCBP2 and caused MAVS degradation. The interaction between PCBP2 and AIP4 was abrogated when the linker region or WB2 of PCBP2 was deleted, which confirmed our previous data indicating that this region was critical for PCBP2-mediated degradation of MAVS" SIGNOR-260361 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser358 MHPYQGRsGCSSQSI -1 28130417 t lperfetto "Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3." SIGNOR-264868 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK10 protein P53779 UNIPROT down-regulates "chemical inhibition" 9606 18922779 t gcesareni "Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell." SIGNOR-181644 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 10090 18619954 f "We found that directed expression of MRFs in the neural tube of chicken embryos induced ectopic expression of miR-1 and miR-206. Conversely, the lack of Myf5 but not of MyoD resulted in a loss of miR-1 and miR-206 expression." SIGNOR-255920 "RZZ complex" complex SIGNOR-C357 SIGNOR DCTN2 protein Q13561 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 20462495 t lperfetto "ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores" SIGNOR-265017 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 10090 BTO:0000944 18042541 t gcesareni "Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B)." SIGNOR-243530 miR221 mirna URS0000245997_9606 RNAcentral MEOX2 protein P50222 UNIPROT "down-regulates quantity" 10090 20819939 t "We show that miR-1 and miR-206 facilitate satellite cell differentiation by restricting their proliferative potential. We identify Pax7 as one of the direct regulatory targets of miR-1 and miR-206. Inhibition of miR-1 and miR-206 substantially enhances satellite cell proliferation and increases Pax7 protein level in vivo" SIGNOR-255922 PRKCA protein P17252 UNIPROT PPP2R5A protein Q15172 UNIPROT "down-regulates activity" phosphorylation Ser41 RQKRSQGsSQFRSQG -1 24225947 t miannu " In this study, we identified a novel phosphorylation site at Ser(41) of B56α. This phosphoamino acid residue was efficiently phosphorylated in vitro by PKCα. " SIGNOR-276603 EGLN2 protein Q96KS0 UNIPROT ADSL protein P30566 UNIPROT "up-regulates activity" hydroxylation Pro24 LASRYASpEMCFVFS 9606 BTO:0000007 31729379 t miannu "ADSL is hydroxylated by EglN2 on Proline 24. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels" SIGNOR-266613 afatinib chemical CHEBI:61390 ChEBI ERBB4 protein Q15303 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 24643470 t miannu "This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively." SIGNOR-259295 HARS1 protein P12081 UNIPROT tRNA(His) smallmolecule CHEBI:29178 ChEBI "down-regulates quantity" "chemical modification" 9606 10430027 t miannu "Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes." SIGNOR-270485 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 7529876 t llicata "We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex." SIGNOR-27875 CSNK2A1 protein P68400 UNIPROT UBE2R2 protein Q712K3 UNIPROT "up-regulates activity" phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 t lperfetto "Ck2-dependent phosphorylation of the e2 ubiquitin conjugating enzyme ubc3b induces its interaction with beta-trcp and enhances beta-catenin degradation" SIGNOR-88050 PAMPs stimulus SIGNOR-ST11 SIGNOR "NLRP1 inflammasome" complex SIGNOR-C224 SIGNOR "up-regulates activity" 16037825 f miannu "Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage" SIGNOR-263125 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser569 SRRRRSSsTAPPTSS 9606 16513649 t llicata "Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization" SIGNOR-145044 G6PC1 protein P35575 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "chemical modification" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266568 NEDD1 protein Q8NHV4 UNIPROT "g-TuRC complex" complex SIGNOR-C282 SIGNOR "up-regulates activity" binding 9606 19029337 t miannu "It has been reported that NEDD1 directly interacts with and recruits the gamma-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly" SIGNOR-261422 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-249642 "hexadecanoic acid" smallmolecule CHEBI:15756 ChEBI FFAR1 protein O14842 UNIPROT "up-regulates activity" "chemical activation" 9606 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257488 ABL1 protein P00519 UNIPROT CRK protein P46108 UNIPROT "down-regulates activity" phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 21602891 t lperfetto "Abl induces phosphorylation at y251 in vivo, and that the kinetics of phosphorylation at y251 and the negative regulatory y221 site in vitro are similar." SIGNOR-173845 Motilin smallmolecule CHEBI:80269 ChEBI MLNR protein O43193 UNIPROT "up-regulates activity" "chemical activation" 9606 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257542 RAE1 protein P78406 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262095 FAM20C protein Q8IXL6 UNIPROT ERO1A protein Q96HE7 UNIPROT "up-regulates activity" phosphorylation Ser145 GAVDESLsEETQKAV 9606 BTO:0000567 29858230 t miannu "We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding." SIGNOR-277395 RNF168 protein Q8IYW5 UNIPROT H2AX protein P16104 UNIPROT unknown ubiquitination Lys14 TGGKARAkAKSRSSR 9606 22980979 t lperfetto "We find that K63 ubiquitin chains are conjugated to RNF168-dependent H2A/H2AX monoubiquitination at K13-15 and not on K118-119." SIGNOR-262063 PKC proteinfamily SIGNOR-PF53 SIGNOR SUN1 protein O94901 UNIPROT "down-regulates activity" phosphorylation Ser113 HVSRQVTsSGVSHGG 9606 BTO:0000567 28831067 t lperfetto "The SUN1-NXF1 association is at least partly regulated by a protein kinase C (PKC) which phosphorylates serine 113 (S113) in the N-terminal domain leading to reduced interaction." SIGNOR-263281 GPR132 protein Q9UNW8 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256945 sodium(1+) chemical CHEBI:29101 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29863287 f miannu "Axonal excitability is an important determinant for the accuracy, direction, and velocity of neuronal signaling. The mechanisms underlying spike generation in the axonal initial segment and transmitter release from presynaptic terminals have been intensely studied and revealed a role for several specific ionic conductances, including the persistent sodium current (INaP )." SIGNOR-265182 HHAT protein Q5VTY9 UNIPROT SHH protein Q15465 UNIPROT up-regulates palmitoylation 9606 15075292 t gcesareni "Our molecular analysis of knockout mice deficient in skn, the murine homolog of the drosophila ski gene, which catalyzes hh palmitoylation, and gene-targeted mice producting a non palmitoylated form of shh indicates that hh palmitoylation is essential for its activity as well as the generation of a protein gradient in the developing embryos" SIGNOR-124118 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN2 protein Q9H2S1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258027 RELA protein Q04206 UNIPROT CD80 protein P33681 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12860928 f "Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells." SIGNOR-253935 BPLF1 protein P03186 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates activity" deubiquitination 9606 BTO:0000007 23365429 t scontino "EBV-encoded BPLF1 interacts with and deubiquitinates TRAF6 to inhibit NF-κB signaling during lytic infection. Once lytic replication is induced, BPLF1 then deubiquitinates and inactivates TRAF6 to further block NF-κB signaling, promoting efficient viral genome replication." SIGNOR-266739 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Ser203 APAPDEGsDLFYDDY 9606 BTO:0000567 11546811 t lperfetto "The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm." SIGNOR-110383 PHLPP2 protein Q6ZVD8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 9606 BTO:0001544 19261608 t "The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells." SIGNOR-248732 9b protein P59636 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates quantity by destabilization" 9606 25135833 f miannu "SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6." SIGNOR-260243 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 15498859 t lperfetto "Pim-1 is know to be up regulated by signal transducer and activator of transcription 5 (stat5)" SIGNOR-259436 STUB1 protein Q9UNE7 UNIPROT PLK1 protein P53350 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27390342 t miannu "As indicated in xref , all three Plk1 fragments were ubiquitinated by CHIP, suggesting that CHIP targets multiple sites of Plk1 for ubiquitination.|Mechanistically, CHIP mediated degradation of AR and Plk1 leads to enhanced efficacy of HSP90 inhibitors." SIGNOR-278532 pemetrexed chemical CHEBI:63616 ChEBI GART protein P22102 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205883 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275776 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM FLT1 protein P17948 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259807 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation Ser141 TVKQKYLsFTPPEKD 9606 BTO:0000007 16204230 t gcesareni "Pak2 is autophosphorylated at eight sites;ser-141 and ser-165 in the regulatory domain and thr-402 in the activation loop are identified as key sites in activation of the protein kinase." SIGNOR-140907 GSK3B protein P49841 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by repression" phosphorylation Ser76 SNLQRMGsSESTDSG 9606 BTO:0000567 20348946 t lperfetto "Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a" SIGNOR-164742 MC5R protein P33032 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257393 GDF6 protein Q6KF10 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 16049014 t gcesareni "We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins." SIGNOR-139093 HDAC1 protein Q13547 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates deacetylation Lys380 PTESSMYkYPSDISY 9606 24058639 t miannu "Hdac1 interacts with fli1 and mediates its deacetylation / our previous studies have shown that pcaf-dependent acetylation of fli1 at lysine 380 decreases its protein stability / p300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380" SIGNOR-202689 PPP2CB protein P62714 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t "In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation." SIGNOR-248602 CXCL5 protein P42830 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000584 34237033 f miannu " We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis." SIGNOR-277733 GHRL protein Q9UBU3 UNIPROT GHSR protein Q92847 UNIPROT up-regulates binding 9606 15070777 t fspada "In contrast to wild-type mice, acute treatment of ghsr- mice with ghrelin stimulated neither gh release nor food intake, showing that the ghsr is a biologically relevant ghrelin receptor." SIGNOR-123948 SRC protein P12931 UNIPROT G6PD protein P11413 UNIPROT "up-regulates activity" phosphorylation Tyr112 NSYVAGQyDDAASYQ -1 33686238 t miannu "Here, we show that tyrosine kinase c-Src interacts with and phosphorylates G6PD at Tyr 112. This phosphorylation enhances catalytic activity of G6PD by dramatically decreasing its Km value and increasing its Kcat value for substrate glucose-6-phosphate." SIGNOR-277550 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM1 protein P11229 UNIPROT "up-regulates activity" "chemical activation" 10029 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258647 FGF2 protein P09038 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 15780951 t gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts." SIGNOR-134788 EEF1A1 protein P68104 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269516 "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR "up-regulates activity" 9606 31108873 f "De novo biosynthesis of both purines and pyrimidines has been observed to be altered in cancer and requires the generation of 5-phosphoribose-1-pyrophosphate (PRPP), the activated form of ribose derived from ribose 5-phosphate, which is produced through the oxidative and nonoxidative arms of the pentose phosphate pathway (PPP) parallel to glycolysis." SIGNOR-267387 SALL4 protein Q9UJQ4 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001883 24051379 f miannu "In primary human AML cells, downregulation of SALL4 led to decreased HOXA9 expression and enhanced apoptosis. We found that SALL4 bound a specific region of the HOXA9 promoter in leukemic cells. SALL4 overexpression led to enhanced binding of histone activation markers at the HOXA9 promoter region, as well as increased HOXA9 expression in these cells." SIGNOR-255125 CTDP1 protein Q9Y5B0 UNIPROT MASTL protein Q96GX5 UNIPROT "down-regulates activity" dephosphorylation Ser90 DALALSKsPFIVHLY 9606 26653855 t lperfetto "Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl." SIGNOR-276972 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 15024053 t llicata "Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta)" SIGNOR-123453 RIMBP3 protein Q9UFD9 UNIPROT RIMS2 protein Q9UQ26 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264365 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr115 QPQPDSVyLVPTPSK 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246381 JAK3 protein P52333 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 t "Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated" SIGNOR-256254 DTL protein Q9NZJ0 UNIPROT SDE2 protein Q6IQ49 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 27906959 t miannu "Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction. The cleaved SDE2 products need to be degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner, and failure to degrade SDE2 impairs S phase progression and cellular survival." SIGNOR-272807 NLGN1 protein Q8N2Q7 UNIPROT NRXN2 protein Q9P2S2 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264154 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 t miannu "PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1." SIGNOR-262866 POU5F1 protein Q01860 UNIPROT TBXT protein O15178 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254929 CDK2 protein P24941 UNIPROT KLF10 protein Q13118 UNIPROT "up-regulates quantity" phosphorylation Ser206 NIPCAAVsPNRSKCE 9606 25728284 t miannu "In this study we have shown that CDK2 phosphorylates KLF10 at residue Ser 206 in vivo and in vitro .|In this study, we have shown that KLF10 protein has tightly controlled expression and that the expression level varies in a cell cycle dependent manner whereby CDK2 up-regulates activity the protein level of KLF10 through interference with the protein 's association with SIAH1." SIGNOR-278394 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 22137581 t lperfetto "Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction" SIGNOR-216608 KHDRBS1 protein Q07666 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates activity" "post transcriptional regulation" 10090 BTO:0000232 22196734 t Gianni "Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA binding protein SAM68 which associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system." SIGNOR-269057 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-70444 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Arg70 ESGLTEYrLVSINKS -1 10978167 t lperfetto "Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site." SIGNOR-263572 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Thr309 SDGATMKtFCGTPEY 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248630 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-216797 "Neuronal AP-3" complex SIGNOR-C445 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 22203680 f miannu "Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes" SIGNOR-268522 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT "up-regulates activity" phosphorylation Tyr183 HDDEDDSyLEPDSPE 9534 BTO:0004055 12709437 t lperfetto "By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk" SIGNOR-246592 AUTS2 protein Q8WXX7 UNIPROT PREX1 protein Q8TCU6 UNIPROT "up-regulates activity" binding 10090 BTO:0001909 25533347 t miannu "Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells." SIGNOR-266817 SLC1A3 protein P43003 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "up-regulates quantity" relocalization 9606 26687113 t miannu "After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). In glia or in neurons, EAATs mediate the re-uptake of synaptically released glutamate via the coupled co-transport of three Na+, one H+, and one glutamate, in counter-transport to one K+." SIGNOR-264802 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT "down-regulates activity" dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 16461343 t "In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22." SIGNOR-248838 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser272 FSGIESSsPEVKGYW 9606 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262916 XIAP protein P98170 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates quantity" ubiquitination 9606 28661476 t miannu "As XIAP can directly ubiquitinate Cdc42, we tested if the RING domain of XIAP is required for modulating the protein levels of Cdc42 in vivo .|We then investigated the molecular mechanisms behind XIAP mediated Cdc42 degradation." SIGNOR-278799 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates binding 9606 16282323 t gcesareni "Cytokine stimulation promotes bim(el) binding to 14-3-3 proteins. Akt could directly phosphorylate a gst-bim(el) fusion protein and identified the akt phosphorylation site in the bim(el) domain as ser(87). we propose that ser87 of bimel is an important regulatory site that is targeted byakt to attenuate thepro-apoptotic function of bim el, thereby promoting cell survival." SIGNOR-141577 ELAVL1 protein Q15717 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 19221430 t miannu "Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure" SIGNOR-266862 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression." SIGNOR-183688 ITGB1BP1 protein O14713 UNIPROT ITGB5 protein P18084 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257660 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding -1 10219247 t gcesareni "Nterleukin-4 (il-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. Il-4 binds with high affinity and specificity to the ectodomain of the il-4 receptor alpha chain (il4-bp)." SIGNOR-67217 NTS protein P30990 UNIPROT NTSR1 protein P30989 UNIPROT up-regulates binding 9606 BTO:0000975 1331689 t gcesareni "The rat neurotensin receptor cdna sequence was transfected in chinese hamster ovary cells and cellular clones which stably express the corresponding protein were isolated and characterized. The scatchard analysis of the specific binding of [3h]neurotensin indicated a kd value of 0.45 +/- 0.08 nm and a bmax value of 3.27 +/- 0.29 pmol/mg of protein. ...Neurotensin Stimulated the phosphoinositides hydrolysis" SIGNOR-17369 SMC5/6 complex SIGNOR-C374 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 27427983 f miannu "The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks" SIGNOR-265487 "1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate" smallmolecule CHEBI:18348 ChEBI "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "form complex" binding 9606 24789820 t lperfetto "AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. " SIGNOR-260664 MGluR proteinfamily SIGNOR-PF55 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264930 PKN2 protein Q16513 UNIPROT MEFV protein O15553 UNIPROT "down-regulates activity" phosphorylation Ser242 SGKMRPRsLEVTIST 10090 BTO:0004732 27270401 t no miannu "PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome." SIGNOR-275463 CDK2 protein P24941 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 SIGNOR-C16 20530684 t gcesareni "The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry." SIGNOR-165872 TP53 protein P04637 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14522900 f miannu " In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction" SIGNOR-254482 DCAF11 protein Q8TEB1 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 31409866 t miannu "(WDR23) isoforms differentially ubiquitinate (GEN1). In the presence of the necessary components for a successful ubiquitination reaction (CUL4A-DDB1-WDR23 complex, UBE1, UBE2D1, ubiquitin, and ATP) GEN1 receives the addition of ubiquitin in a time dependent manner." SIGNOR-272262 CSNK2A1 protein P68400 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT "down-regulates activity" phosphorylation Ser575 AGESLDQsMEEEEEE 9606 BTO:0000567 12591939 t llicata "We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified" SIGNOR-250844 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 19130553 t gcesareni "Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna" SIGNOR-183158 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR6 protein P50406 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257525 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI AKT1 protein P31749 UNIPROT up-regulates "chemical activation" 9606 16293724 t gcesareni "Pge2 also stimulated akt activity in a pi3k-dependent manner." SIGNOR-141817 ATR protein Q13535 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Thr691 YGLEEYDtQDGIAIN 9606 16943440 t lperfetto "In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents" SIGNOR-149309 FBXO4 protein Q9UKT5 UNIPROT FXR1 protein P51114 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 29142209 t miannu "Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinomaThe Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4. " SIGNOR-272795 CAMK1 protein Q14012 UNIPROT NUMB protein P49757 UNIPROT down-regulates phosphorylation Ser276 EQLARQGsFRGFPAL 9606 17022975 t esanto "Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2." SIGNOR-149993 RPL18A protein Q02543 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262480 PRKCA protein P17252 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation Thr638 TRGQPVLtPPDQLVI 9606 15277524 t lperfetto "Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function" SIGNOR-127257 SMARCC1 protein Q92922 UNIPROT "Muscle cell-specific SWI/SNF ARID1B variant" complex SIGNOR-C482 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270709 LUBAC complex SIGNOR-C527 SIGNOR GLYR1 protein Q49A26 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys338 VSDPKAAkDLVLGPS 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations." SIGNOR-272836 tRNA(Ala) smallmolecule CHEBI:29170 ChEBI Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI "up-regulates quantity" "precursor of" 9606 32314272 t miannu "Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N)." SIGNOR-270451 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249008 FOXO1 protein Q12778 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f "inferred from family member" gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-267787 MAPK8 protein P45983 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 t gcesareni "Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells." SIGNOR-178930 BDKRB1 protein P46663 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257149 ZMYND8 protein Q9ULU4 UNIPROT MMP3 protein P08254 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 27477906 t lperfetto "Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported" SIGNOR-262043 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 20651737 t lperfetto "Under resting conditions cellular inhibitor of apoptosis (ciap) proteins target nuclear factor-kb (nf-kb)-inducing kinase (nik) for ubiquitylation and proteasomal degradation." SIGNOR-167066 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR PTPRC protein P08575 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001271 22740448 f miannu "Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced." SIGNOR-255686 TRIM33 protein Q9UPN9 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" binding 9606 25639486 t Luana "Tumour suppressor TRIM33 targets nuclear β-catenin degradation" SIGNOR-260896 MAP4K4 protein O95819 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni "Hpk1 binds and phosphorylates mekk1 directly" SIGNOR-44040 NDUFS4 protein O43181 UNIPROT "NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262178 PTPN1 protein P18031 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" dephosphorylation Tyr421 RLPSSPVyEDAASFK 9606 27824079 t lperfetto "We conclude that Mena INV promotes invadopodium maturation by inhibiting normal dephosphorylation of cortactin at tyrosine 421 by the phosphatase PTP1B." SIGNOR-277027 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249390 BPLF1 protein P03186 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" deubiquitination 9606 24586164 t scontino "In the current study, we have found that BPLF1 interferes with innate immune activation by targeting multiple intermediates along the TLR signal transduction pathway, including TRAF6, NEMO, and IκBα. BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes." SIGNOR-266743 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 SIGNOR "up-regulates activity" "chemical activation" 9606 18790874 t brain lperfetto "Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS)." SIGNOR-263789 AKT1 protein P31749 UNIPROT RPS3 protein P23396 UNIPROT "up-regulates activity" phosphorylation Thr70 GRRIRELtAVVQKRF 10116 BTO:0003060 20605787 t miannu "Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage." SIGNOR-259815 UBE2I protein P63279 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation Lys159 APSSMMVkDEYVHDF 9606 12621041 t gcesareni "The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses" SIGNOR-98997 PRKCA protein P17252 UNIPROT ARHGDIB protein P52566 UNIPROT down-regulates phosphorylation Ser31 YKPPPQKsLKELQEM 9606 22469974 t llicata "These results reveal a mechanism of downregulation of rhogdi2 activity through pkc-mediated phosphorylation of ser31." SIGNOR-196765 SIRT1 protein Q96EB6 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" deacetylation 9606 25280219 t "SIRT1 overexpression was associated with down-modulation of p53 activity in FLT3-ITD AML CD34+ cells. SIRT1 can negatively regulate p53 by deacetylating several lysine sites" SIGNOR-261562 DLST protein P36957 UNIPROT OGDC complex SIGNOR-C397 SIGNOR "form complex" binding 9606 15953811 t miannu "The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH." SIGNOR-266254 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT "up-regulates activity" phosphorylation Ser418 VEEDPLNsGDDVSEQ -1 12107178 t llicata "ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled." SIGNOR-250872 "Elongin E3-Cul-5" complex SIGNOR-C531 SIGNOR CLEC1B protein Q9P126 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 19785988 t miannu "In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex" SIGNOR-272783 FGR protein P09769 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Tyr222 MEAPTTAyKKTTPIE -1 10066823 t "We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn. this interaction is weakened by phosphorylation of Tyr-222, through an allosteric mechanism that ultimately causes the detachment of fully phosphorylated HS1 from c-Fgr." SIGNOR-251144 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT "down-regulates activity" phosphorylation Thr670 IAKPIPQtPESAGNK 9606 21335236 t gcesareni "We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks." SIGNOR-172225 SREBF2 protein Q12772 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21123766 t miannu "Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes." SIGNOR-254459 CDK5 protein Q00535 UNIPROT PLD2 protein O14939 UNIPROT "up-regulates activity" phosphorylation Ser134 ARFAVAYsPARDAGN 9606 18625302 t miannu "In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion.|We determined that Cdk5 phosphorylates PLD2 at Ser 134 of PLD2 and that this phosphorylation was suggested to be important for EGF-dependent insulin secretion." SIGNOR-278395 ETNK1 protein Q9HBU6 UNIPROT O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI "up-regulates quantity" "chemical modification" 36583229 t lperfetto "ETNK1 encodes ethanolamine kinase 1, which is involved in the de novo biosynthesis of phosphatidylethanolamine and is responsible for the phosphorylation of ethanolamine to phosphoethanolamine" SIGNOR-275641 PREX2 protein Q70Z35 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260571 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser587 YLRPRIPsPIGFTPG 9606 22966201 t llicata "Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress." SIGNOR-198996 PTGER3 protein P43115 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256995 TRIP12 protein Q14669 UNIPROT SOX6 protein P35712 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23663701 t miannu "In this article, we focused on Trip 12, an E3 ubiquitin ligase, which polyubiquitinates Sox6.|Therefore, Sox6 is a specific substrate to Trip12, by which it is polyubiquitinated and degraded." SIGNOR-278579 Ub:E2 complex SIGNOR-C497 SIGNOR RING1 protein Q06587 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270984 STT3A protein P46977 UNIPROT "OST-A complex" complex SIGNOR-C535 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272064 ELOVL2 protein Q9NXB9 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI "down-regulates quantity" "chemical modification" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267890 "messenger RNA" smallmolecule CHEBI:33699 ChEBI 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR "form complex" binding 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269172 AKT proteinfamily SIGNOR-PF24 SIGNOR HJURP protein Q8NCD3 UNIPROT "up-regulates activity" phosphorylation Ser486 GLETRRLsLPSSKAK -1 17256767 t miannu "These data define a new protein complex in mammalian cells where 14‐3‐3 associates with FAKTS through phosphorylated S479. Our research identifies a widely expressed eukaryotic protein FAKTS, as a new Akt/PKB substrate localized in the nucleus. Akt/PKB promotes FAKTS association with 14‐3‐3, placing FAKTS under the control of 14‐3‐3 proteins. FAKTS may play an important role in transmitting Akt/PKB‐mediated signals in the complex network of intracellular signal transduction." SIGNOR-262623 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000567 15208625 t gcesareni "Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme." SIGNOR-126055 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9741627 t lperfetto "Shc is subsequently phosphorylated at tyrosine 317 and recruits grb2" SIGNOR-60160 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-126069 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Platelet_morphogenesis phenotype SIGNOR-PH135 SIGNOR up-regulates 9606 BTO:0000132 27871158 f lperfetto "Each step in platelet shape change involves the participation of a variety of actin filament-related proteins that are highly concentrated in platelets (Fig. 1). In resting human platelets, the actin filaments from the core to the membrane skeleton are tightly bound to the plasma membrane by GP1b/IX-filamin A complexes " SIGNOR-261839 ANGPT1 protein Q15389 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241529 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr583 RRPPGLEyCYNPSHN 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto "In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1" SIGNOR-236183 PTPN2 protein P17706 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 12612081 f acerquone "We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling." SIGNOR-98811 CDKN1B protein P46527 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002392 22343731 f fcortellessa "The results of the MTT assay and growth curves revealed that the cells transfected with pEGFP-p27kip1 had a significant growth inhibition when compared with cells transfected with pEGFP-NC (Fig. 5B and D). These data indicated that overexpression of p27kip1 could arrest cell-cycle progression and decrease proliferation of SGC-7901 cells." SIGNOR-261687 F2RL2 protein O00254 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257360 NANOGP8 protein Q6NSW7 UNIPROT JUN protein P05412 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10900 BTO:0000667 23839044 f Luana "Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun." SIGNOR-266091 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "up-regulates activity" binding 16896351 t lperfetto "In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1" SIGNOR-252014 promethazine chemical CHEBI:8461 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257788 IL6ST protein P40189 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 9126968 t milica "Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase." SIGNOR-250574 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg334 KNCPKKTrNLKKITR -1 7989361 t lperfetto "The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994." SIGNOR-263628 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR DPPA4 protein Q7L190 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269243 "2-N,6-N-Bis(2,3-dihydroxy-N-benzoyl)-L-serine amide" chemical CHEBI:1219 ChEBI DRD3 protein P35462 UNIPROT "up-regulates activity" "chemical activation" -1 7576010 t miannu "D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole." SIGNOR-258437 GYS2 protein P54840 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI "down-regulates quantity" "chemical modification" 9606 26882899 t miannu "Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor." SIGNOR-267937 GSK3B protein P49841 UNIPROT ZC3HAV1 protein Q7Z2W4 UNIPROT "up-regulates activity" phosphorylation Ser267 FLASASAsAERSCTP 9606 22514281 t miannu "GSK3beta sequentially phosphorylated Ser 270, Ser 266, Ser 262, and Ser 257 of rat ZAP.|Inhibition of GSK3\u03b2 by inhibitor SB216763 or down-regulation of GSK3\u03b2 by RNAi reduced the antiviral activity of Zinc-finger antiviral protein." SIGNOR-278402 SRC protein P12931 UNIPROT VAV3 protein Q9UKW4 UNIPROT up-regulates phosphorylation Tyr173 EDEGGEVyEDLMKAE 9606 BTO:0000785 17998938 t gcesareni "Activation of rac1 and the exchange factor vav3 are involved in npm-alk signaling in anaplastic large cell lymphomas." SIGNOR-159240 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT "up-regulates activity" phosphorylation Thr150 LVHQRSHtGEKPYLC 9606 BTO:0002552 31399647 t miannu "We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A." SIGNOR-276754 CHEK1 protein O14757 UNIPROT E2F8 protein A0AVK6 UNIPROT "down-regulates activity" phosphorylation 9606 29363506 t miannu "Chk1 inhibits the transcriptional repressor function of E2F7 and E2F8 to promote cell cycle progression and prevent apoptosis.|Here, we demonstrate that Chk1 phosphorylates both E2F7 and E2F8 in response to DNA damage." SIGNOR-279693 AMPK complex SIGNOR-C15 SIGNOR GYS2 protein P54840 UNIPROT "down-regulates activity" phosphorylation Ser8 MLRGRSLsVTSLGGL -1 22233421 t miannu "Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations)." SIGNOR-263101 GSK3B protein P49841 UNIPROT CD274 protein Q9NZQ7 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser184 GKTTTTNsKREEKLF 9606 BTO:0002548 27572267 t miannu "We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP." SIGNOR-277275 MCL1 protein Q07820 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni "Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax" SIGNOR-149774 CUL3 protein Q13618 UNIPROT MAP1S protein Q66K74 UNIPROT "down-regulates quantity" ubiquitination 10090 BTO:0000142 18680552 t miannu "Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B." SIGNOR-268947 silodosin chemical CHEBI:135929 ChEBI ADRA1B protein P35368 UNIPROT "down-regulates activity" "chemical inhibition" 10029 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258449 MIR1-1 mirna URS000075CF56_9606 RNAcentral IGF1 protein P05019 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 25477897 t miannu "The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT1" SIGNOR-255793 ZNF804A protein Q7Z570 UNIPROT CLIC2 protein O15247 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 23434502 t miannu "ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3)." SIGNOR-269465 "1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester" chemical CHEBI:92418 ChEBI CHRM3 protein P20309 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258637 GDNF protein P39905 UNIPROT NCAM1 protein P13591 UNIPROT "up-regulates activity" binding 10116 BTO:0002881 15212950 t miannu "Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable." SIGNOR-252189 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 t miannu "Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex." SIGNOR-265947 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val42 GRSLIGKvDGTSHVT -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263588 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0000567 11337501 t lperfetto "Taken together, our findings support the idea that binding of pkr to dsrna increases autophosphorylation in the activation loop of the kinase domain (fig. 9). Because dsrna binding promotes dimerization, this would facilitate trans-autophosphorylation of thr-446 and thr-451 by the two kinase moieties in a pkr dimer" SIGNOR-107511 EGFR protein P00533 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Tyr154 PPFTARIyAAGFDSS 9606 BTO:0000815 36841821 t miannu "EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase.  EGFR phosphorylated PELI1 leading to its K63-linked auto-ubiquitination." SIGNOR-277873 TRIM63 protein Q969Q1 UNIPROT PPP3CA protein Q08209 UNIPROT "down-regulates quantity" ubiquitination 9606 24526353 t miannu "First, downregulation of MuRF1 significantly attenuates degradation of CnA in cardiomyocytes in vitro, indicating that endogenous MuRF1 negatively regulates the stability of CnA in a cell-autonomous manner.|Furthermore, MuRF1 directly ubiquitinated CnA in vitro.|These results suggest that MuRF1 directly polyubiquitinates CnA." SIGNOR-278736 TBK1 protein Q9UHD2 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" phosphorylation Ser2159 RIQSIAPsLQVITSK 9606 32854217 t miannu "They later demonstrated that TANK-binding kinase 1 (TBK1) interacts with and phosphorylates mTOR on Ser 2159, to promote catalytic activity of mTOR [216]." SIGNOR-278237 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7330 RASSRRGsDASDFDL 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264435 "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR NOTCH2 protein Q04721 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000578 31659254 t miannu "Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription." SIGNOR-265560 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 t "Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival." SIGNOR-252563 TTC3 protein P53804 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "down-regulates quantity" ubiquitination 9606 33718111 t miannu "Tribbles homolog 3 ( TRB3 ) and Tetratricopeptide Repeat Domain 3 ( TTC3 ) directly ubiquitinate Smurf2 , thereby mediating Smurf2 degradation in a proteasome-dependent manner .|Tribbles homolog 3 (TRB3) and Tetratricopeptide Repeat Domain 3 (TTC3) directly ubiquitinate Smurf2, thereby mediating Smurf2 degradation in a proteasome dependent manner." SIGNOR-278739 EGR1 protein P18146 UNIPROT CYP2B6 protein P20813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18303024 f miannu "The CYP2B6 enzyme metabolizes commonly used therapeutics and also activates pro-drugs. The CAR directly binds to the distal enhancer element of the CYP2B6 promoter, which is essential in converging to its drug-sensing function onto promoter activity. However, this binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter." SIGNOR-253874 PTGER1 protein P34995 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256954 IFNG protein P01579 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "up-regulates activity" binding 9606 BTO:0000801 23898330 t lperfetto "In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation" SIGNOR-249487 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 16226275 t "First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185" SIGNOR-248483 FZD7 protein O75084 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 22179044 t apalma "In non-canonical Wnt signalling, Wnt proteins bind Fzd and glypican-4, to activate Dsh at the cell membrane, leading to activation of Rho and JNK" SIGNOR-255893 RUNX1 protein Q01196 UNIPROT HHEX protein Q03014 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 28213513 t "We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML." SIGNOR-256305 CPS1 protein P31327 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI "down-regulates quantity" "chemical modification" 9606 15096496 t "CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules" SIGNOR-267198 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12773393 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-249213 "A10/b1 integrin" complex SIGNOR-C167 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257709 SLC12A5 protein Q9H2X9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "down-regulates quantity" relocalization 21613606 t lperfetto "Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). " SIGNOR-264637 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Thr250 KEEVVGLtETSSQPK 9606 BTO:0000776 7678037 t llicata "These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-251013 ABCA1 protein O95477 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 23077142 f miannu "Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL)." SIGNOR-252109 RPS6KA5 protein O75582 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 27196759 t miannu "Co-transfection of MSK1 increased beta-catenin transcriptional activity in a dose dependent manner (XREF_FIG).|Our in vitro kinase assay showed that MSK1 can directly phosphorylate beta-catenin at Ser 552." SIGNOR-278247 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT "up-regulates activity" phosphorylation Ser557 LEEFDVFsPKQDLVP 9606 BTO:0002181 25452387 t miannu "The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. " SIGNOR-276443 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNA1 protein Q09470 UNIPROT "down-regulates quantity" phosphorylation Ser446 SDLSRRSsSTMSKSE 9606 BTO:0002178 23774215 t done miannu "Phosphorylation of KCNA1 at Ser446 by PKA is involved on its cytoplasmic retention" SIGNOR-273777 MAP3K1 protein Q13233 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 10647776 t miannu "As yet, the apparent discrepancy between these and above data is not clear, but obviously the type of cell under study and the cellular context may play an important role.In endothelial cells, Smad2 activity is stimulated by MEKK1, a component of the Stress Activated Protein Kinase and c-Jun N terminal kinase (SAPK and JNK) pathway.|Phosphorylation of Smad2 by MEKK1 increased its association with Smad4, its nuclear accumulation and its transcription induction activity ." SIGNOR-279064 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" SIGNOR-252878 RNF5 protein Q99942 UNIPROT ATG4B protein Q9Y4P1 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23093945 t miannu "These results substantiate the notion that RNF5 negatively regulates ATG4B availability with concomitant effect on LC3 processing and autophagy under normal growth conditions.|These results suggest that RNF5 directly induces ATG4B ubiquitination." SIGNOR-278664 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser99 KEEEEGIsQESSEEE -1 2806554 t llicata "Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol." SIGNOR-250894 CDK1 protein P06493 UNIPROT PPP6R2 protein O75170 UNIPROT "down-regulates activity" phosphorylation Ser771 ESGPRCSsPVDTECS -1 29764989 t done miannu "We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit." SIGNOR-273587 DPF3 protein Q92784 UNIPROT "Muscle cell-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C483 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex." SIGNOR-270730 PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 24647478 t "AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring" miannu "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks." SIGNOR-65409 ANXA3 protein P12429 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 BTO:0000018 27995049 f miannu "We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells." SIGNOR-262211 PKI-587 chemical CID:44516953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252650 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 BTO:0004980 17242212 t gcesareni "Our data suggest that il-6 impairs the vasodilator effects of insulin that are mediated by the irs-1/pi3-kinase/akt/enos pathway through activation of jnk and erk1/2." SIGNOR-152418 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" phosphorylation Ser29 ATKAARKsAPATGGV 9606 20129940 t gcesareni "Upon activation of the erk and p38 mapk pathways, the msk1/2-mediated nucleosomal response, including h3 phosphorylation at serine 28 or 10, is coupled with the induction of immediate-early (ie) gene transcription." SIGNOR-163712 ATM protein Q13315 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates phosphorylation Ser135 EWETPDLsQAEIEQK 9606 19962312 t llicata "We show that, upon dna damage, rassf1a is phosphorylated by atm on ser131 and is involved in the activation of both mst2 and lats1, leading to the stabilization of p73." SIGNOR-161934 BRF1 protein Q92994 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR "form complex" binding 29378333 t lperfetto "Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1)." SIGNOR-266190 GSK3B protein P49841 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates activity" phosphorylation Thr367 NNSSRPStPTINVLE 9606 27494834 t miannu "GSK3\u03b2 phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3\u03b2 upregulates Thr367 phosphorylationin vivo." SIGNOR-278175 SMAD1 protein Q15797 UNIPROT SATB2 protein Q9UPW6 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268934 FGB protein P02675 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 f lperfetto "In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation." SIGNOR-253374 DCK protein P27707 UNIPROT "2'-deoxycytosine 5'-monophosphate(2-)" smallmolecule CHEBI:57566 ChEBI "up-regulates quantity" "chemical modification" 20637175 t lperfetto "Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis" SIGNOR-275807 TRIM25 protein Q14258 UNIPROT DDX58 protein O95786 UNIPROT "up-regulates activity" ubiquitination Lys172 ENWPKTLkLALEKER 9606 24493797 t miannu "Lys63 linked polyubiquitination of RIG-I at Lys 172 catalyzed by TRIM25 is an important step for RIG-I activation." SIGNOR-278730 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201310 ABL1 protein P00519 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0001271 23399893 t gcesareni "We show that the grb2-related adapter protein, gads, also associates with bcr-abl, specifically through y177 and demonstrate that bcr-abl-driven lymphoid disease requires gads" SIGNOR-200871 ARP2/3 complex SIGNOR-C146 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 12479800 f lperfetto "The Arp2/3 complex concentrates at leading edges, where it catalyzes the growth of branched actin networks that are believed to provide the protrusive force for leading edge extension." SIGNOR-251511 RPS15 protein P62841 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262437 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "precursor of" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266523 NAA15 protein Q9BXJ9 UNIPROT NatA complex SIGNOR-C415 SIGNOR "form complex" binding 9606 BTO:0000007 15496142 t miannu "Protein acetyltransferases and deacetylases have been implicated in oncogenesis, apoptosis and cell cycle regulation. Most of the protein acetyltransferases described acetylate epsilon-amino groups of lysine residues within proteins. We now describe the human homologue of Nat1p, NATH (NAT human), as the partner of the hARD1 (human ARD1) protein. Included in the characterization of the NATH and hARD1 proteins is the following: (i) endogenous NATH and hARD1 proteins are expressed in human epithelial, glioma and promyelocytic cell lines; (ii) NATH and hARD1 form a stable complex, as investigated by reciprocal immunoprecipitations followed by MS analysis; (iii) NATH-hARD1 complex expresses N-terminal acetylation activity; (iv) NATH and hARD1 interact with ribosomal subunits, indicating a co-translational acetyltransferase function" SIGNOR-267225 PTPN11 protein Q06124 UNIPROT MPZL1 protein O95297 UNIPROT down-regulates dephosphorylation Tyr263 NKSESVVyADIRKN 9606 10681522 t gcesareni "In vitro, tyrosine-phosphorylated pzr was efficiently dephosphorylated by the full-length form of shp-2 but not by its sh2 domain-truncated form. The coexisting binding and dephosphorylation of pzr by shp-2 may function to terminate signal transduction initiated by pzr and shp-2 and to set a threshold for the signal transduction to be initiated." SIGNOR-75220 LMP1 protein P03230 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 9606 26428373 f scontino "Soon, it has been recognized that TES1 and 2 coincide with two regions named C-terminal activating regions (CTAR) 1 and 2, respectively, that are responsible for interaction of LMP1 with cellular signaling molecules. Early studies revealed that both CTAR1 and CTAR2 contribute to the activation of NF-κB, Later, it became evident that CTAR1 primarily activates the non-canonical NF-κB pathway, while CTAR2 is responsible for canonical NF-κB activation." SIGNOR-267616 PDYN protein P01213 UNIPROT OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258415 USP36 protein Q9P275 UNIPROT EZH2 protein Q15910 UNIPROT "up-regulates quantity by stabilization" deubiquitination Lys222 PRKFPSDkIFEAISS 9606 BTO:0002030 31434700 t miannu "We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination.  Furthermore, we identify USP36 as the deubiquitinating enzyme that deubiquitinates EZH2 at K222." SIGNOR-277481 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 BTO:0000017 10358079 t gcesareni "We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5." SIGNOR-68159 N protein P59595 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 9606 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein." SIGNOR-260340 TEAD1 protein P28347 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22286761 f gcesareni "Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-194371 CDX2 protein Q99626 UNIPROT CDH17 protein Q12864 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972;BTO:0004168 20568120 t "The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC|we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L)" SIGNOR-253963 PLK1 protein P53350 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" phosphorylation Thr424 VKTEVEDtLTPPPSD 9606 27579997 t miannu "As illustrated in , the turnover of nuclear SREBP1a was attenuated in the presence of Plk1, confirming that Plk1 stabilizes nuclear SREBP1 by reducing its degradation.|Plk1 phosphorylates T424, S467 and S486 in nuclear SREBP1 during mitosis." SIGNOR-279381 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT "down-regulates activity" dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 11259588 t "Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity" SIGNOR-248351 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr581 SDGHEYIyVDPMQLP 9606 BTO:0000599 9642269 t miannu "We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins." SIGNOR-250255 SMARCB1 protein Q12824 UNIPROT "SWI/SNF ACTL6A-ARID1A-SMARCA2 variant" complex SIGNOR-C470 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269825 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 t lperfetto "Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively" SIGNOR-180775 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM2B protein Q8NHM5 UNIPROT "up-regulates activity" "chemical activation" 29981745 t lperfetto "Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3." SIGNOR-273472 ATM protein Q13315 UNIPROT UFL1 protein O94874 UNIPROT "up-regulates activity" phosphorylation Ser462 DDDSDDEsQSSHTGK 9606 BTO:0001938 30886146 t lperfetto "Furthermore, ATM phosphorylates UFL1 at serine 462, enhancing UFL1 E3 ligase activity and promoting ATM activation in a positive feedback loop." SIGNOR-265075 TLX3 protein O43711 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" binding 9606 BTO:0002504 22516263 t irozzo "We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement." SIGNOR-259098 "OST-B complex" complex SIGNOR-C536 SIGNOR Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272056 GSK3B protein P49841 UNIPROT CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 t lperfetto "Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells" SIGNOR-154668 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 18362890 t "inferred from 70% family members" gcesareni "These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1" SIGNOR-270220 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 12213813 t lperfetto "Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation." SIGNOR-249163 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "A4/b7 integrin" complex SIGNOR-C187 SIGNOR "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259011 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT "up-regulates activity" phosphorylation Thr451 PIPKALGtPVLTPPT 10090 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-248003 ARHGAP22 protein Q7Z5H3 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260477 EGFR protein P00533 UNIPROT SOX2 protein P48431 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr277 LRDMISMyLPGAEVP 9606 31823521 t miannu "These data indicate that EGFR\u2010induced SOX2 Tyr277 phosphorylation prevents the autophagic degradation of SOX2 and enhances its stability." SIGNOR-279036 LCK protein P06239 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" phosphorylation Tyr394 LNTIGLIyEKISLPK 9606 BTO:0002181 28618271 t miannu "The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. " SIGNOR-276723 tandutinib chemical CHEBI:90237 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258297 adenosine smallmolecule CHEBI:16335 ChEBI AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "precursor of" 9606 18957298 t miannu "Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. Given adenosine's important role in modulating synaptic transmission, several mechanisms exist to regulate its extracellular availability. One of these is the intracellular enzyme adenosine kinase (ADK), which phosphorylates adenosine to AMP." SIGNOR-265465 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 10090 BTO:0004052 23996074 t irozzo "In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL.The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1" SIGNOR-255869 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0003316 11777913 t miannu "4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E." SIGNOR-250097 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-261716 NEUROG3 protein Q9Y4Z2 UNIPROT ASH1L protein Q9NR48 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19028584 f miannu "Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated." SIGNOR-254629 GDP smallmolecule CHEBI:17552 ChEBI PRPS1 protein P60891 UNIPROT "down-regulates activity" "chemical inhibition" 29074724 t lperfetto "PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP" SIGNOR-265738 ENPP1 protein P22413 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "down-regulates quantity" "chemical modification" 20923972 t "Phosphodiesterases Catalyze Hydrolysis of cAMP-bound to Regulatory Subunit of Protein Kinase A and Mediate Signal Termination" SIGNOR-253018 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAP3K7 protein O43318 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 22337877 t lperfetto "Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts" SIGNOR-235560 MSX1 protein P28360 UNIPROT DLX5 protein P56178 UNIPROT "down-regulates activity" binding 10090 BTO:0000946 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240987 AP3B1 protein O00203 UNIPROT "AP-3 complex" complex SIGNOR-C247 SIGNOR "form complex" binding 9606 21097499 t lperfetto "Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)" SIGNOR-260681 Kisspeptin-10 smallmolecule CHEBI:80307 ChEBI KISS1R protein Q969F8 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257527 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t "14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling." SIGNOR-251484 "Angiotensin 1-7" protein P01019-PRO_0000420660 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 9606 24168260 f miannu "We hypothesized that the ACE2/Ang-(1-7)/Mas axis protects against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway.In summary, our study demonstrate that exogenous Ang-(1-7) and ACE2 overexpression protect against BLM- or AngII-induced pulmonary fibrosis by down-regulating the MAPK/NF-κB pathway. However, constant infusion of Ang-(1-7) paradoxically initiates an inflammatory response in the lungs. The antifibrotic effects of Ang-(1-7) noted here make the heptapeptide a strong candidate for a therapeutic target in humans with pulmonary fibrosis." SIGNOR-260447 UBE3A protein Q05086 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "down-regulates activity" ubiquitination 9606 BTO:0000007 28559284 t "Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A" SIGNOR-270339 MDM2 protein Q00987 UNIPROT ATXN1 protein P54253 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 28212558 t miannu "NICD and MDM2 ubiquitinate and degrade ATXN1.|These results suggest that NICD and MDM2 synergistically reduce ATXN1 expression at the posttranscriptional level." SIGNOR-278823 EBNA1 protein P03211 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "down-regulates activity" 9606 29659505 f scontino "EBNA1 has been reported to block p65 activation by inhibiting IKKα/β through an unknown mechanism, we suggest that, in NPC, NF-κB signaling and EBNA1 may form a regulatory loop which supports EBV latent gene expression, while also limiting NF-κB activity" SIGNOR-266802 CDK1 protein P06493 UNIPROT OSBP2 protein Q969R2 UNIPROT "up-regulates activity" phosphorylation 30925160 t lperfetto "CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes." SIGNOR-264878 M protein P59596 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "down-regulates activity" binding 9534 17705188 t lperfetto "Together, these results indicate that SARS-CoV M suppresses NF-kappaB activity probably through a direct interaction with IKKbeta, resulting in lower Cox-2 expression." SIGNOR-260261 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" relocalization 9606 BTO:0001130 23633519 t lperfetto "Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring." SIGNOR-236490 PTPRB protein P23467 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates dephosphorylation 9606 12840032 t "inferred from 70% of family members" gcesareni "When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well" SIGNOR-269911 LMP2 protein P13285 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "down-regulates quantity by destabilization" 9606 19718044 f scontino "The EBV-encoded Latent Membrane Proteins, LMP2A and LMP2B, Limit the Actions of Interferon by Targeting Interferon Receptors for Degradation. LMP2A and LMP2B increase the turnover and degradation of IFNAR1 and IFNGR1. LMP2A and LMP2B reduce the half-life of IFNAR1 and IFNGR1." SIGNOR-266825 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9069290 t "The effect has been demonstrated using Q06413-3" lperfetto "We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation." SIGNOR-47136 YAP1 protein P46937 UNIPROT GINS1 protein Q14691 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001939 30224758 f lperfetto "By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ." SIGNOR-276566 CYP19A1 protein P11511 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000975 27702664 t lperfetto "The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively" SIGNOR-268672 ZBTB16 protein Q05516 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0002882 9710637 f fcortellessa "PLZF expression in 32DG/GM cells is associated with growth suppression and G1 arrest." SIGNOR-261685 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr398 SQFTKYWtESNGVES 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141026 TGFBR1 protein P36897 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates phosphorylation Ser300 EMHHEALsEALPGDN 9606 20832312 t llicata "Phosphorylation of eEF1A1 at Ser300 by T_R-I results in inhibition of mRNA translation" SIGNOR-167943 HOXA9 protein P31269 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo "Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function." SIGNOR-255864 EIF2AK2 protein P19525 UNIPROT NCK1 protein P16333 UNIPROT "down-regulates activity" phosphorylation 9606 18835251 t miannu "In these assays, we observed that GST\u2013Nck-1 was clearly phosphorylated by GST\u2013PKR while GST was not ( Fig. 4 , upper panels)." SIGNOR-279039 PURA protein Q00577 UNIPROT MYH6 protein P13533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12933792 f miannu "In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene." SIGNOR-253902 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding BTO:0001103 12361602 t apalma "Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk" SIGNOR-255380 RAC1 protein P63000 UNIPROT GIT1 protein Q9Y2X7 UNIPROT "up-regulates activity" binding 9606 39000072 t miannu "Activated RAC1 interacts with GIT1, a GAP protein of ARF6, and causes the inactivation of ARF6 [78]. As ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane [78], the inactivation of ARF6 by RAC1 reduces the recycling of macropinosomes." SIGNOR-277783 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser305 QPGVDSLsPVASLPK 25855382 t lperfetto "PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant" SIGNOR-275558 STRN protein O43815 UNIPROT PPP2CA protein P67775 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 29802198 t miannu "The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms" SIGNOR-261698 PRKCD protein Q05655 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr566 FIQRWNFtKTTKAKY 9606 20733000 t "Translocation from Cytoplasm to the Edge of Lamellipodia" gcesareni "Finally, we show that thr566 of pld2 is directly phosphorylated by pkc and that pld2 mutation in this region prevents pld2 activation, pld2 translocation to the edge of lamellipodia, rac translocation, and cell spreading after integrin activation" SIGNOR-167577 ATM protein Q13315 UNIPROT NOP53 protein Q9NZM5 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr289 PATEQAAtQESTFQE 9606 BTO:0000007 27829214 t miannu "PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1. " SIGNOR-273507 AKT1 protein P31749 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 20086174 t "inferred from 70% of family members" llicata "We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2." SIGNOR-269945 "Blood vessel damage" stimulus SIGNOR-ST26 SIGNOR F12 protein P00748 UNIPROT up-regulates NBK482253 f lperfetto "It begins with the activation of Factor XII (a zymogen, inactivated serine protease) which becomes Factor XIIA (activated serine protease) after exposure to endothelial collagen. Endothelial collagen is only exposed when endothelial damage occurs." SIGNOR-263514 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" phosphorylation Ser15 NVIKMKSsDFLESAE -1 18408713 t miannu "These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1)" SIGNOR-276162 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CRY2 protein Q49AN0 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 17463251 t miannu " We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex. This regulation by SCF(Fbxl3) is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. HEK293T cells were transfected with Cry2, Skp1, Cul1, and Roc1 in the absence or presence of either FLAG-tagged Fbxl3 or a FLAG-tagged Fbxl3(ΔF-box) mutant. Fbxl3, but not an inactive Fbxl3(ΔF-box) mutant (4), induced the ubiquitination of Cry2 (Fig. 2D), which supports the notion that the effect of Fbxl3 on Cry2 is direct." SIGNOR-271650 ARNTL protein O00327 UNIPROT PER1 protein O15534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 22750052 f "Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins." SIGNOR-253628 KDM5C protein P41229 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264306 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro." SIGNOR-164675 RAB5A protein P20339 UNIPROT RAB7A protein P51149 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 30485418 t miannu "The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis" SIGNOR-277780 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000599 10187842 t "inferred from 70% family members" lperfetto "We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution." SIGNOR-270079 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-4 protein Q16695 UNIPROT "down-regulates activity" binding 9606 21041483 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266971 MICU1 protein Q9BPX6 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270867 FBXO33 protein Q7Z6M2 UNIPROT EIF3F protein O00303 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0000165 18354498 t miannu "Mediation of eIF3-f polyubiquitination by the SCFMAFbx. The association of MAFbx with the essential Skp1, Roc 1 and Cul1 proteins, specific components of an E3 ubiquitin–protein ligase (SCFMAFbx), was previously described. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome." SIGNOR-271768 HUNK protein P57058 UNIPROT ITM2A protein O43736 UNIPROT "up-regulates activity" phosphorylation Thr35 TVRTQILtGKELRVA 9606 BTO:0000007 31438969 t miannu "ITM2A is phosphorylated at T35 and the phosphorylation status of ITM2A contributes to breast cancer proliferation. Moreover, we found that ITM2A was phosphorylated at T35 by HUNK, a serine/threonine kinase significantly correlated with human breast cancer overall survival and HER2-induced mammary tumorigenesis." SIGNOR-273640 PREX2 protein Q70Z35 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "catalytic activity" 9606 BTO:0000007 25829446 t irozzo "Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity." SIGNOR-259191 "MSH release-inhibiting hormone" smallmolecule CID:56842142 PUBCHEM MC1R protein Q01726 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257536 NEDD4 protein P46934 UNIPROT DCUN1D1 protein Q96GG9 UNIPROT "up-regulates quantity" monoubiquitination Lys149 PKMEQELkEPGRFKD 9606 BTO:0000007 21813641 t miannu "Here we revealed a previously unknown mechanism that regulates hDCNL1. In cultured mammalian cells ectopically expressed hDCNL1 was mono-ubiquitinated predominantly at K143, K149, and K171. Using a classical chromatographic purification strategy, we identified Nedd4-1 as an E3 ligase that can catalyze mono-ubiquitination of hDCNL1 in a reconstituted ubiquitination system.Taken together, these results suggest a mono-ubiquitination-mediated mechanism that governs nuclear-cytoplasmic trafficking of hDCNL1," SIGNOR-272718 "GABA-B receptor" complex SIGNOR-C336 SIGNOR GNB/GNG complex SIGNOR-C202 SIGNOR "up-regulates activity" binding 9606 BTO:0000938 20655485 t miannu "The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release." SIGNOR-265068 SYK protein P43405 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates phosphorylation Ser361 LAEGTPRsNHSAQDS 9606 BTO:0001271 23071339 t miannu "Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function." SIGNOR-199096 "CAK complex" complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser371 AHSSHLKsKKGQSTS 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-269327 PRKD3 protein O94806 UNIPROT MFF protein Q9GZY8 UNIPROT "up-regulates activity" phosphorylation Ser172 GQLVRNDsLWHRSDS 34010649 t lperfetto "The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275" SIGNOR-275940 CAMK2A protein Q9UQM7 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" gcesareni "As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2)." SIGNOR-124344 DNA_damage stimulus SIGNOR-ST1 SIGNOR RAD23A protein P54725 UNIPROT up-regulates 24086043 f lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein)." SIGNOR-275686 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 11864573 t "The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX." SIGNOR-248531 TRIM2 protein Q9C040 UNIPROT NEFL protein P07196 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 18687884 t miannu "Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination." SIGNOR-271776 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr424 IREYPPItSDQQRQL 9606 21545357 t lperfetto "Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions." SIGNOR-173639 EXOC6 protein Q8TAG9 UNIPROT "Exocyst_EXOC6 variant" complex SIGNOR-C492 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270789 GRM3 protein Q14832 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264353 FGF13 protein Q92913 UNIPROT SCN4A protein P35499 UNIPROT "down-regulates activity" binding 9606 BTO:0001103 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253431 IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "chemical modification" 9606 29090344 t miannu "Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases." SIGNOR-253134 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFA12 protein Q9UI09 UNIPROT "up-regulates activity" phosphorylation Thr142 QEWIPPStPYK 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275595 ABL1 protein P00519 UNIPROT DDB2 protein Q92466 UNIPROT down-regulates phosphorylation 9606 12107171 t miannu "C-abl might act as a negative regulator of uv-ddb by phosphorylating ddb2" SIGNOR-90446 KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-156906 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 15821101 t gcesareni "Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2" SIGNOR-135207 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT "up-regulates activity" phosphorylation Ser614 RRPSVASsVSEEYFE -1 24554596 t lperfetto "These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway." SIGNOR-264766 NLGN4Y protein Q8NFZ3 UNIPROT NRXN3 protein Q9HDB5 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264168 3b protein P59633 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" 9606 21561061 f Luana "SARS-CoV Accessory Protein 3b Induces AP-1 TranscriptionalActivity" SIGNOR-260757 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr653 QDSPDGQyENSEGGW 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246417 RBMX2 protein Q9Y388 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270674 RAPGEF6 protein Q8TEU7 UNIPROT HRAS protein P01112 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183796 STK25 protein O00506 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation 9606 30948712 t miannu "In sum, these data reveal that STK25 activates LATS kinases through a mechanism that is distinct from what has been characterized for the MAP4K/MST kinases (Fig.\u00a0 xref ).|Mechanistically, we demonstrate that STK25 promotes LATS phosphorylation at the activation loop in the absence of hydrophobic motif phosphorylation, which distinguishes it from all of the other known LATS-activating kinases discovered to date." SIGNOR-279294 PTK2 protein Q05397 UNIPROT CTTN protein Q14247 UNIPROT "down-regulates activity" phosphorylation Tyr421 RLPSSPVyEDAASFK 9606 22952866 t miannu "FAK can directly phosphorylate cortactin at Y421 and Y466, and these sites are also phosphorylated by Src and Abl/Arg tyrosine kinases.|GFP-FAK re-expression in FAK-/- MEFs enhances FA turnover (XREF_FIG) and cortactin knockdown slows FA turnover (XREF_FIG)." SIGNOR-278284 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 f "We observed GR binding on or near Cebpβ, Cebpδ, Klf5, Klf9, Cebpα, and Pparγ gene loci at 4 h but not at 0 h of adipogenesis. Thus, at least one of the mechanisms by which GR promotes adipogenesis in culture is by directly activating the expression of multiple adipogenic TFs." SIGNOR-256120 GTF2I protein P78347 UNIPROT FOS protein P01100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 16611241 f lperfetto "For example, TFII-I binds to the Inr element of the T cell receptor Vbeta gene and activates its transcription in reporter gene assays (Cheriyath et al. 1998). TFII-I also activates transcription of c-fos and Goosecoid through binding to the serum response element and the distal element, respectively (Grueneberg et al. 1997; Ku et al. 2005)." SIGNOR-268535 AKT1 protein P31749 UNIPROT FAS protein P25445 UNIPROT down-regulates 9606 15004527 f gcesareni "Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27" SIGNOR-252473 hsa-miR-148a-3p mirna URS00003BBF48_9606 RNAcentral VIM protein P08670 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002745 33026174 f Parnian "MiR-148a-3p overexpression increased the expression of E-cadherin, accompanying decreased N-cadherin and vimentin expression." SIGNOR-278854 MZF1 protein P28698 UNIPROT CCN3 protein P48745 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25899830 f miannu "we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV." SIGNOR-226356 NFIA protein Q12857 UNIPROT WNT5A protein P41221 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268877 USH1G protein Q495M9 UNIPROT "TIP-LINK complex" complex SIGNOR-C291 SIGNOR "form complex" binding 10090 BTO:0000630 23217710 t lperfetto "The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction." SIGNOR-262578 CCP110 protein O43303 UNIPROT CALM2 protein P0DP24 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-266332 LMP1 protein P03230 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" 9606 26428373 f scontino "Activation of the PI3-K/AKT pathway was first linked to LMP1 in the year 2003. Although it is still unclear whether this interaction is direct, expression of LMP1 CTAR1 caused (i) an enrichment of the PI3-K substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3) in the plasma membrane and (ii) the phosphorylation and activation of AKT kinase, also known as protein kinase B, at serine 473." SIGNOR-267618 PAPOLA protein P51003 UNIPROT "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity by stabilization" "chemical modification" 9606 19224921 t lperfetto "Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner." SIGNOR-268327 GRB10 protein Q13322 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0001516 23246379 t "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation" SIGNOR-255946 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway" SIGNOR-252947 Calcineurin complex SIGNOR-C155 SIGNOR DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t "CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII)." SIGNOR-252317 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser597 VPMNPNLsSEDPNLF 9606 15379552 t lperfetto "Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)" SIGNOR-129192 CREB5 protein Q02930 UNIPROT RASGRP3 protein Q8IV61 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002815 21132541 f miannu "Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition)," SIGNOR-253808 RPS6K proteinfamily SIGNOR-PF26 SIGNOR STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto "Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK." SIGNOR-252805 DNMT3A protein Q9Y6K1 UNIPROT DPP6 protein P42658 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000596 23409053 t lperfetto "In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells." SIGNOR-268962 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t milica "In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2." SIGNOR-230713 CDK2 protein P24941 UNIPROT HIRA protein P54198 UNIPROT "up-regulates activity" phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 BTO:0001938 SIGNOR-C16 11238922 t lperfetto "Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle." SIGNOR-105548 mTORC1 complex SIGNOR-C3 SIGNOR APOB protein P04114 UNIPROT "down-regulates quantity by repression" "translation regulation" 9606 23721961 f miannu "Activation of mTORC1 also has dual effects on ApoB synthesis: it inhibits ApoB secretion by decreasing ApoB translation, but promotes ApoB secretion by inhibiting sortilin." SIGNOR-252117 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3)." SIGNOR-257854 STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 20508200 f lperfetto "Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation." SIGNOR-249533 ABL1 protein P00519 UNIPROT PLCG1 protein P19174 UNIPROT "down-regulates activity" phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0002181 12652307 t miannu "C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity." SIGNOR-276001 PDZRN3 protein Q9UPQ7 UNIPROT MUSK protein O15146 UNIPROT "down-regulates quantity" ubiquitination 9534 BTO:0000298 17576800 t miannu "We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Together, these data demonstrate that PDZRN3 is a catalytically active RING-type E3 ubiquitin ligase" SIGNOR-271664 GSK3B protein P49841 UNIPROT ZC3HAV1 protein Q7Z2W4 UNIPROT "up-regulates activity" phosphorylation Ser257 RDRFFQGsQEFLASA 9606 22514281 t miannu "GSK3beta sequentially phosphorylated Ser 270, Ser 266, Ser 262, and Ser 257 of rat ZAP.|Inhibition of GSK3\u03b2 by inhibitor SB216763 or down-regulation of GSK3\u03b2 by RNAi reduced the antiviral activity of Zinc-finger antiviral protein." SIGNOR-278403 IKBKB protein O14920 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates activity" phosphorylation Thr121 NVRERQRtQSLNEAF 9606 23375009 t miannu "Hence, our current study supports the pivotal role of beta-TRCP in IKKbeta mediated Twist degradation.|More importantly, IKK\u03b2-dependent phosphorylation of Twist at T125 and S127 governs its nuclear localization." SIGNOR-278404 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1B protein P28222 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257517 HSD3B1 protein P14060 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI "up-regulates quantity" "chemical modification" 10116 BTO:0000534;BTO:0000056 1537836 t lperfetto "We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids." SIGNOR-268637 Erlin complex SIGNOR-C532 SIGNOR RNF170 protein Q96K19 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 21610068 t miannu "In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound." SIGNOR-271917 MAPK3 protein P27361 UNIPROT NUP50 protein Q9UKX7 UNIPROT "down-regulates activity" phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata "Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta" SIGNOR-187378 NPTX1 protein Q15818 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" relocalization 10090 BTO:0000938 23069675 t lperfetto "Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential" SIGNOR-261483 Ub:E2 complex SIGNOR-C497 SIGNOR RNF144B protein Q7Z419 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271181 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser849 NMLNRRDsSASTISS 9606 10693759 t lperfetto "Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3." SIGNOR-75343 POMC protein P01189 UNIPROT MC5R protein P33032 UNIPROT up-regulates binding 9606 BTO:0000007 11785979 t gcesareni "The purpose of this study was to identify the peptide that functions as a natural ligand at the mc5r in the skin. alpha-msh, acth1-39, acth1-17, acth1-10, and acth4-10 all increased the production of camp in hek293 cells transfected with the mouse mc5r. alpha-msh and acth1-17 were the most potent in this respect. In addition, all peptides stimulated a rapid and transient increase in [ca(2+)](i)." SIGNOR-114058 PRKCQ protein Q04759 UNIPROT CBL protein P22681 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000782 26284074 t Barakat "PKC-θ-mediated phosphorylation of serine and tyrosine residues of c-Cbl prevents its inhibitory effect. Phosphorylation of c-Cbl by PKC-θ inhibits the recruitment of Sh2-containing proteins and subsequent association of cbl E3 ubiquitin ligase with its target proteins" SIGNOR-274144 GDNF protein P39905 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252184 EIF4E protein P06730 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR "form complex" binding 9606 11408474 t miannu "Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f." SIGNOR-108515 FLCN protein Q8NFG4 UNIPROT RRAGD protein Q9NQL2 UNIPROT "up-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 24095279 t "The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur" SIGNOR-256504 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation 9606 15657420 t "inferred from 70% family members" lperfetto "The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity." SIGNOR-270047 KHDRBS1 protein Q07666 UNIPROT CREBBP protein Q92793 UNIPROT "down-regulates activity" binding 9606 BTO:0000093 12496368 t miannu "These results suggest that Sam68 and CBP interact in vivo in a manner dependent on the FXE/DXXXL motif. Sam68 Represses CBP-dependent Transcriptional Activation" SIGNOR-266202 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1349 STFIGEHyVHVNATY 9606 BTO:0000007 12475979 t "When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365))," SIGNOR-248702 DCTPP1 protein Q9H773 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003878 27612427 f Monia "DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically; Moreover, low expression of DCTPP1 led to the increase in intracellular 5-methyl-dCTP, which was strongly associated with the promoter hyper-methylation, leading to the subsequent low-expression of MDR1 and the increased intracellular accumulation of 5-FU in DCTPP1-knockdown BGC-823 cells. These results provide new insights into the roles of DCTPP1 as a chemosensitizer in clinical application." SIGNOR-261178 tRNA(Lys) smallmolecule CHEBI:29185 ChEBI Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270409 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser126 PPGTPLVsQDEKRDA 9606 21824916 t lperfetto "We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro." SIGNOR-176020 GSK3B protein P49841 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" 10090 24260231 f miannu "Involvement of GSK3 Inhibition by the PI3K/Akt Pathway in Regulation of Etoposide-induced Chk1 Activation. GSK3ß regulates etoposide-induced Chk1 activation. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. Thus, proteasomal degradation of Chk1 as well as GSK3 activation may be involved in negative regulation of etoposide-induced Chk1 by imatinib in these cells." SIGNOR-263050 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM FGFR3 protein P22607 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258081 PP1 proteinfamily SIGNOR-PF54 SIGNOR AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t lperfetto "Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1." SIGNOR-264657 MAPK3 protein P27361 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "down-regulates activity" phosphorylation 9606 12809513 t "inferred from family member" llicata "We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay." SIGNOR-270301 UNC5B protein Q8IZJ1 UNIPROT DCC protein P43146 UNIPROT "down-regulates activity" binding 9606 BTO:0001484 25881791 t miannu "In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists." SIGNOR-268166 VBP1 protein P61758 UNIPROT "Prefoldin co-chaperone" complex SIGNOR-C513 SIGNOR "form complex" binding 9606 32699605 t miannu "The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)" SIGNOR-270935 CD82 protein P27701 UNIPROT Cell_invasion phenotype SIGNOR-PH226 SIGNOR down-regulates 9606 BTO:0002552 16488391 f "This result indicated that the enhanced expression of KAI1/CD82 in the H1299 cells was associated with a reduced invasive ability of the cancer cells." SIGNOR-278113 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto "In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction." SIGNOR-158655 "dovitinib; bis(lactic acid)" chemical CID:56973714 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191418 NF1 protein P21359 UNIPROT ADCY7 protein P51828 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204246 Tocilizumab antibody DB06273 DRUGBANK IL6R protein P08887 UNIPROT "down-regulates activity" binding 9606 32446778 t "doi: 10.1016/j.cytogfr.2020.05.003" miannu "Tocilizumab is a humanized anti-IL-6 receptor IgG1 monoclonal antibody used for the treatment of rheumatoid arthritis and other chronic inflammatory diseases [14]. By blocking the IL-6-receptor interaction, Tocilizumab inhibits the IL-6-mediated signal transduction. Although clinical data on the use of Tocilizumab in COVID-19 patients derive from small series, some authors recommend its use in critically ill COVID-19 patients with significantly elevated IL-6 levels." SIGNOR-260857 "CCAN complex" complex SIGNOR-C365 SIGNOR Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 18007590 f lperfetto "Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis." SIGNOR-265214 WNT3A protein P56704 UNIPROT LRP5 protein O75197 UNIPROT "up-regulates activity" binding 9606 21078818 t gcesareni "Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have" SIGNOR-169657 G1/S_transition phenotype SIGNOR-PH50 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 21524151 f lperfetto "In addition to the successive phosphorylation of pRb by active Cyclin/Cdk complexes, other factors can also impact upon S-phase entry Subsequently, the initiation of replication requires the formation of a pre-initiation complex (pre-IC) that is initiated by phosphorylation of Mcm2-7 by CyclinE/Cdk2 and DDK (Dbf4- and Drf1-dependent kinase) and recruitment of Cdc45 onto the chromatin (Figure 1). This recruitment is thought to be the critical step for the activation of the Mcm2-7 helicase activity and replication initiation. Finally, unwinding of the chromatin enables DNA-polymerase _ to initiate DNA synthesis and DNA-polymerase _ to continue replication" SIGNOR-245489 ROR1 protein Q01973 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation 9606 BTO:0000551 22439932 t miannu "Ror1 binds to and phosphorylates c-src / ror1 kinase-dependent c-src activation" SIGNOR-196751 PRKCA protein P17252 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t lperfetto "In vitro kinase assays show that Ser-59 can be uniquely phosphorylated by mitogen-activated protein kinase and that Ser-42 can be phosphorylated by either protein kinase A or protein kinase C." SIGNOR-248936 ITGAV protein P06756 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253203 SNRPA protein P09012 UNIPROT "U1 snRNP complex" complex SIGNOR-C480 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270678 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248517 MT-ND3 protein P03897 UNIPROT "NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262145 Z-RNA stimulus SIGNOR-ST29 SIGNOR ZBP1 protein Q9H171 UNIPROT "up-regulates activity" binding 10090 32200799 t gianni "Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis." SIGNOR-266432 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral EDNRA protein P25101 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004094 26675258 t Parnian "Altogether, these findings demonstrate that miR-30a functionally binds the ETAR 3′UTR, thereby inhibiting ETAR expression and cell proliferation." SIGNOR-277997 GHSR protein Q92847 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257167 SYK protein P43405 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates phosphorylation Ser364 GTPRSNHsAQDSAVE 9606 BTO:0001271 23071339 t miannu "Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function." SIGNOR-199100 CDH23 protein Q9H251 UNIPROT "TIP-LINK complex" complex SIGNOR-C291 SIGNOR "form complex" binding 10090 BTO:0000630 23217710 t lperfetto "The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction." SIGNOR-262579 FOXO proteinfamily SIGNOR-PF27 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-256644 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser149 TNVNFGRsRSAQEPA 9606 24309468 t lperfetto "Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1." SIGNOR-203456 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-252326 SEPTIN4 protein O43236 UNIPROT XIAP protein P98170 UNIPROT "down-regulates quantity" binding 9534 BTO:0004055 15029247 t lperfetto "The mitochondrial ARTS protein promotes apoptosis through targeting XIAP.|Binding of ARTS to XIAP is direct, as recombinant ARTS and XIAP proteins can bind to each other in vitro. ARTS binding to XIAP is specific and related to its pro-apoptotic function, as mutant forms of ARTS (or related septins) that fail to bind XIAP failed to induce apoptosis. ARTS leads to decreased XIAP protein levels and caspase activation. Our data suggest that ARTS induces apoptosis by antagonizing IAPs." SIGNOR-267671 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75930 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 12167717 t lperfetto "PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473," SIGNOR-244429 PHLPP2 protein Q6ZVD8 UNIPROT PRKCA protein P17252 UNIPROT "down-regulates quantity" dephosphorylation Ser657 QSDFEGFsYVNPQFV 9606 BTO:0000067 18162466 t gcesareni "In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha" SIGNOR-237051 NFIA protein Q12857 UNIPROT NEUROD4 protein Q9HD90 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268891 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser66 GVYATRSsAVRLRSS -1 11895474 t miannu "In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK. " SIGNOR-250241 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t lperfetto "These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase" SIGNOR-40423 PRKCZ protein Q05513 UNIPROT MARK2 protein Q7KZI7 UNIPROT down-regulates phosphorylation Thr596 RGVSSRStFHAGQLR 9606 15084291 t lperfetto "Hpar-1b is phosphorylated by apkc on threonine 595 importantly, phosphorylation of hpar-1b on t595 negatively regulates the kinase activity and plasma membrane localization of hpar-1b in vivo." SIGNOR-124217 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser700 FGEKRKNsILNPINS -1 1377674 t miannu "CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795." SIGNOR-250348 UBE3A protein Q05086 UNIPROT SOX9 protein P48436 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 24155239 t miannu "We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes." SIGNOR-272134 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248739 TRAF4 protein Q9BUZ4 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys119 YQRLDLCkLGPNDND 9606 31076633 t miannu "TRAF4 acts as an E3 ubiquitin ligase to ubiquitinate the K119 site of Smurf2 through the K48 ubiquitin chain and degrade Smurf2." SIGNOR-278617 OTULIN protein Q96BN8 UNIPROT UBB protein P0CG47 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000567 26235645 t miannu "Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors." SIGNOR-270819 MARCHF5 protein Q9NX47 UNIPROT ERN1 protein O75460 UNIPROT "down-regulates activity" ubiquitination Lys481 LQHQQFQkELEKIQL 9606 31368599 t miannu "MITOL promotes K63-linked chain ubiquitination of IRE1\u03b1 at lysine 481 (K481), thereby preventing hyper-oligomerization of IRE1\u03b1 and regulated IRE1\u03b1-dependent decay (RIDD)." SIGNOR-278609 ASXL1 protein Q8IXJ9 UNIPROT RARA protein P10276 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 16606617 t irozzo "Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells." SIGNOR-255910 SCN4A protein P35499 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu "The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons." SIGNOR-253451 PRKCG protein P05129 UNIPROT OCLN protein Q16625 UNIPROT "up-regulates activity" phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 11502742 t lperfetto "Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X." SIGNOR-249107 FUS protein P35637 UNIPROT SNRNP70 protein P08621 UNIPROT "up-regulates activity" binding 9606 26124092 t "FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP" SIGNOR-262823 PIM1 protein P11309 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002552 19749799 t lperfetto "Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation" SIGNOR-187905 P2RY12 protein Q9H244 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257107 H3C1 protein P68431 UNIPROT "Nucleosome_H3.1 variant" complex SIGNOR-C324 SIGNOR "form complex" binding -1 21812398 t miannu "The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP." SIGNOR-263721 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 24585778 t miannu "Length-dependent activation is modulated by cardiac troponin i bisphosphorylation at ser23 and ser24 but not by thr143 phosphorylation. Thr143 is a known target of protein kinase c (pkc) whose activity is increased in cardiac disease" SIGNOR-204666 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC5 protein Q9Y5F6 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265683 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273039 RARB protein P10826 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "up-regulates activity" binding 9606 15650024 t "inferred from family member" gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-267807 CTBP1 protein Q13363 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 16287852 t gcesareni "We identify the ctip and ctbp corepressors as novel components of the human rbp-jkappa/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. Functionally, ctip and ctbp augment sharp-mediated repression." SIGNOR-141613 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr989 VPSSRGDyMTMQMSC 9606 17827393 t gcesareni "Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K)." SIGNOR-157758 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248685 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 19836242 t "We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173" SIGNOR-248699 SSH2 protein Q76I76 UNIPROT CFL1 protein P23528 UNIPROT "up-regulates activity" dephosphorylation Ser3 sGVAVSDG 9606 14531860 t "Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH)." SIGNOR-248733 ITGB3 protein P05106 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257718 SP4 protein Q02446 UNIPROT MAOB protein P27338 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11259630 f miannu "Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2." SIGNOR-253869 "dasatinib (anhydrous)" chemical CHEBI:49375 ChEBI BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0001056 23409026 t miannu "Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy." SIGNOR-259270 pomalidomide chemical CHEBI:72690 ChEBI CRBN protein Q96SW2 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 22552008 t miannu "Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide." SIGNOR-259283 MAPK14 protein Q16539 UNIPROT HBP1 protein O60381 UNIPROT up-regulates phosphorylation Ser402 GFSKNCGsPGSSQLS 9606 14612426 t lperfetto "A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression." SIGNOR-119138 ITGA1 protein P56199 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253169 TGFBR2 protein P37173 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates phosphorylation Ser345 RGDGSGFsL 9606 BTO:0004183 15761148 t lperfetto "We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345." SIGNOR-227484 PDE4DIP protein Q5VU43 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates binding 9606 21569246 t miannu "This study ascribes a novel function to mmgl isoform 4: it meets all criteria for classification as an akap, and we show that is involved in the phosphorylation of cmybpc as well as ctni, hence mmgl is an important regulator of cardiac contractility." SIGNOR-173766 GOLGA7 protein Q7Z5G4 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" palmitoylation 9606 BTO:0000007 16000296 t miannu "Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein." SIGNOR-261351 CSNK2A1 protein P68400 UNIPROT PACS1 protein Q6VY07 UNIPROT "up-regulates activity" phosphorylation Ser278 SPDIDNYsEEEEESF 10090 BTO:0003532 14633983 t llicata "Phosphorylation of Ser278 by CK2 or a Ser278-->Asp mutation increased the interaction between PACS-1 and cargo, whereas a Ser278-->Ala substitution decreased this interaction. Moreover, the Ser278-->Ala mutation yields a dominant-negative PACS-1 molecule that selectively blocks retrieval of PACS-1-regulated cargo molecules to the TGN." SIGNOR-250925 HNF4G protein Q14541 UNIPROT AKR1C4 protein P17516 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003846 2044952 f 2 miannu "Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C." SIGNOR-240013 CHFR protein Q96EP1 UNIPROT SMARCB1 protein Q12824 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 22285184 t miannu "Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination." SIGNOR-271458 CDK11A protein Q9UQ88 UNIPROT CDK11B protein P21127 UNIPROT up-regulates phosphorylation Thr726 KHEYFREtPLPIDPS 9606 21078675 t lperfetto "Overall, our data indicated that thr-370 is responsible for the autophosphorylation, dimerization, and kinase activity of cdk11(p58)" SIGNOR-169628 DISC1 protein Q9NRI5 UNIPROT PAFAH1B1 protein P43034 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 17202468 t miannu "Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology " SIGNOR-252163 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249391 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAMAC protein Q9BTL3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 YLKRPPEsPPIVEEW 9606 27452456 t miannu "During differentiation, ERK1/2 phosphorylates RAM serine-36, targeting it for ubiquitination and proteasomal degradation, ultimately resulting in changes in gene expression associated with loss of pluripotency." SIGNOR-277267 GNA13 protein Q14344 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 23450633 t gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." SIGNOR-192111 FLT3 protein P36888 UNIPROT HK2 protein P52789 UNIPROT "up-regulates activity" 9606 BTO:0002144 28194038 f "FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity" SIGNOR-261322 PTPN11 protein Q06124 UNIPROT CDC73 protein Q6P1J9 UNIPROT "up-regulates activity" dephosphorylation 9606 21726809 t miannu "We found in this work that SHP2 dephosphorylates parafibromin and Cdc73, a component of the nuclear RNA polymerase II associated factor (PAF) complex, which can function as a tumor suppressor or oncoprotein in a context dependent manner." SIGNOR-277036 PTPN6 protein P29350 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 11021818 t gcesareni "The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase." SIGNOR-82764 PRKACA protein P17612 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "up-regulates activity" phosphorylation Ser279 KVAERRSsPLLRRKD 9606 22865920 t lperfetto "PKA/Cdk5-mediated phosphorylation of HDAC5 at Ser279 within the NLS promotes nuclear localization of HDAC5 and interaction with the nuclear corepressor complex" SIGNOR-198658 TBK1 protein Q9UHD2 UNIPROT REL protein Q04864 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C68 16888014 t miannu "The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel." SIGNOR-148623 AR protein P10275 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 16281084 f "After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes." SIGNOR-253675 FOXN4 protein Q96NZ1 UNIPROT PTF1A protein Q7RTS3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001175 17075007 f Luana " We conclude that Foxn4 functions upstream of Ptf1a to activate its expression, thereby regulating the generation of amacrine and horizontal cells during retinogenesis." SIGNOR-261608 MAPKAPK2 protein P49137 UNIPROT PDE4A protein P27815 UNIPROT "down-regulates activity" phosphorylation Ser152 SFLYRSDsDYDMSPK 9606 BTO:0000801 21323643 t miannu "Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP." SIGNOR-263078 ZFAT protein Q4KMQ4 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates quantity" 10090 24663380 f francesca "Ano6 deficiency significantly reduces ERK/AKT phosphorylation. In addition, Ano6-KD also affected levels of phosphorylated and total AKT levels." SIGNOR-261215 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 8845374 t lperfetto "Revealed that peptides derived from egfr residues y992, y1086, y1101, and y1148 bound directly to the sh2 domain of c-src (figure 8c). These experiments demonstrate that a specific subset of egfr receptor c-src phosphorylation sites are also ligands for the sh2 domain of c-src.Cellular src functions as a co-transducer of transmembrane signals emanating from a variety of growth factor receptors, including egfr" SIGNOR-44251 selumetinib chemical CHEBI:90227 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190191 RET protein P07949 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 16153436 t "inferred from 70% of family members" gcesareni "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-269894 CCNO protein P22674 UNIPROT CDK2 protein P24941 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 25364462 t lperfetto "Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O" SIGNOR-275616 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 t lperfetto "Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase" SIGNOR-235793 C8G protein P07360 UNIPROT "Membrane attack complex" complex SIGNOR-C313 SIGNOR "form complex" binding -1 30552328 t lperfetto "The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer" SIGNOR-263446 PLD1 protein Q13393 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI up-regulates "chemical modification" 9606 9873061 t gcesareni "The primary known function of phospholipase d (pld) is to generate phosphatidic acid (pa) via the hydrolysis of phosphatidylcholine. . phospholipase d (pld) hydrolyzes phospholipids to generate phosphatidic acid (pa)." SIGNOR-62882 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser775 EGVKRTLsFSLRSSR 9534 BTO:0000298 14523239 t lperfetto "We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA." SIGNOR-249231 MAPK14 protein Q16539 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser567 SLAWLSDsPLFDLIK 9606 20871633 t llicata "P38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates rb on ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not cdks, triggers an interaction between rb and the human homolog of murine double minute 2 (hdm2), leading to degradation of rb, release of e2f1 and cell death." SIGNOR-168178 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr474 VLLVNRHyAKISDFG 9606 BTO:0000661 9685404 t lperfetto "We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck" SIGNOR-249375 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000776 20185585 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-163944 RAB7A protein P51149 UNIPROT NTRK1 protein P04629 UNIPROT "down-regulates activity" binding 10116 16306406 t Sara "Endogenous TrkA and Rab7 form a complex. Inhibition of Rab7 potentiates the signaling of TrkA in response to brief stimulations with NGF" SIGNOR-261305 SARS1 protein P49591 UNIPROT serine smallmolecule CHEBI:17822 ChEBI "down-regulates quantity" "chemical modification" 9606 24095058 t miannu "As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis" SIGNOR-270494 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT "up-regulates activity" phosphorylation Ser610 GPGPRRPsVASSVSE 9606 24554596 t lperfetto "These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway." SIGNOR-264765 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser278 PISSPTFsPIEFQIG 9606 23442801 t lperfetto "It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation" SIGNOR-201519 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 17339337 t Manara "Evaluation of these calcium calmodulin kinase superfamily members as candidate Ser(20) kinases in vivo has shown that only CHK1 or DAPK-1 can stimulate p53 transactivation and induce Ser(20) phosphorylation of p53.| Thus, endogenous CHK1 is required for the majority of Ser20 site phosphorylation of ectopically expressed p53 in H1299 cells." SIGNOR-260776 DDB2 protein Q92466 UNIPROT DDB2/DDB1 complex SIGNOR-C39 SIGNOR "form complex" binding 9606 9418871 t miannu "Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna" SIGNOR-54099 ARHGAP1 protein Q07960 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260458 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" fspada "A specific pkg inhibitor inhibits h1r downregulation in cho cells (37). However, direct activation of pkg in these cells does not cause h1r down-regulation, indicating that more studies are required to clarify the role of pkg in h1r down-regulation." SIGNOR-124360 PTGES2 protein Q9H7Z7 UNIPROT "prostaglandin H2(1-)" smallmolecule CHEBI:57405 ChEBI "up-regulates quantity" "chemical modification" -1 10922363 t Luana "Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently." SIGNOR-269768 RUNX2/EP300 complex SIGNOR-C211 SIGNOR BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002648 12697832 f "Giulio Giuliani" "In agreement with our studies in ROS 17/2.8 cells, coexpression of p300 and Runx2/Cbfa1 resulted in marked enhancement of the OC promoter activity, further indicating that both factors cooperate to stimulate this promoter." SIGNOR-255420 E2F1 protein Q01094 UNIPROT USP37 protein Q86T82 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21596315 t lperfetto "USP37 was induced by E2F transcription factors in G1|Ectopic E2F1 activated the wild-type promoter, but not the mutant promoter, 3-fold over basal levels in 293T cells (Figure 4F), confirming the functionality of the E2F binding sites in the USP37 promoter." SIGNOR-265047 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 BTO:0004136 10208431 t miannu "The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. On physical interaction, AML1/ETO can form a complex with wild-type AML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex" SIGNOR-260094 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270399 calcium(2+) smallmolecule CHEBI:29108 ChEBI INS protein P01308 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000783 24843404 t miannu "The increased Ca2+ concentrations eventually trigger fusion of insulin‐containing granules with the plasma membrane and insulin secretion from the β cells. Increased Ca2+ levels also promote transcription of the proinsulin gene, thereby increasing the insulin content of the β cell. Activation of EPAC2 has been shown to increase the density of insulin‐containing granules near the plasma membrane to potentiate insulin secretion from the β cell." SIGNOR-278144 CDCA5 protein Q96FF9 UNIPROT WAPL protein Q7Z5K2 UNIPROT "down-regulates activity" binding 7227 21111234 t lperfetto "We show that DNA replication and cohesin acetylation promote binding of Sororin to cohesin, and that Sororin displaces Wapl from its binding partner Pds5. " SIGNOR-265266 RPS6KA1 protein Q15418 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 t gcesareni "S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function." SIGNOR-123993 serine smallmolecule CHEBI:17822 ChEBI Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI "up-regulates quantity" "precursor of" 9606 24095058 t miannu "As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis" SIGNOR-270500 MYLK protein Q15746 UNIPROT MYL6B protein P14649 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 BTO:0000671 10092231 t gcesareni "Cytoskeletal dynamics are primarily modulated by interactions of actin and myosin ii that are regulated by myosin light chain kinase (mlck)-mediated phosphorylation of the regulatory myosin light chain (mlc)." SIGNOR-65865 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto "Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70." SIGNOR-244501 ASXL3 protein Q9C0F0 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "down-regulates activity" binding 9606 BTO:0000972 25450400 t "inferred from family member" miannu "We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRŒ± and TRŒ≤, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRŒ± and TRŒ≤ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRŒ± target genes through its recruitment to the LXR-response elements." SIGNOR-270302 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKAR1A protein P10644 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258759 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 t "Phosphorylation is the signal for ubiquitination" gcesareni "We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases." SIGNOR-99721 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" lperfetto "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-244707 NEK2 protein P51955 UNIPROT NCAPD2 protein Q15021 UNIPROT "down-regulates activity" phosphorylation 9606 25704143 t miannu "Nek2 phosphorylates C-Nap1, rootletin and beta-catenin to regulate centrosome separation." SIGNOR-279234 ULK1 protein O75385 UNIPROT ATG9A protein Q7Z3C6 UNIPROT "up-regulates activity" phosphorylation Ser14 EYQRLEAsYSDSPPG 9606 27934868 t miannu "Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation." SIGNOR-266369 NCOA4 protein Q13772 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004191 18649734 f "The PSA promoter activity was detected by transient expression assay in the PC-J and LNCaP cells but not in androgen insensitive PC-3 cells. When the PC-J cells were cotransfected with androgen receptor, androgen receptor coactivators and PSA reporter vector cells, the reporter assays indicated that nuclear receptor coactivator 4 (NCOA4) but not androgen receptor activator 24 (ARA24) increased the sensitivity and maximum stimulation of dihydrotestosterone (DHT)-inducing PSA promoter activity." SIGNOR-253659 FZD3 protein Q9NPG1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 14977528 t gcesareni "Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families." SIGNOR-122895 GYS1 protein P13807 UNIPROT Glycogen_synthesis phenotype SIGNOR-PH39 SIGNOR up-regulates 9534 BTO:0004055 14593110 f lperfetto "Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation." SIGNOR-235751 QRICH1 protein Q2TAL8 UNIPROT GARS1 protein P41250 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269405 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI "up-regulates quantity" "precursor of" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267883 RXRA protein P19793 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16665 AMFR protein Q9UKV5 UNIPROT HMGCR protein P04035 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 25003069 t miannu "Gp78 mediates the sterol regulated ubiquitination of HMGCR." SIGNOR-278622 DAB2IP protein Q5VWQ8 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates activity" binding 9606 27858941 t miannu "DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene" SIGNOR-254770 TRAF6 protein Q9Y4K3 UNIPROT TAB2 protein Q9NYJ8 UNIPROT "up-regulates activity" binding 9606 25290089 t lperfetto "The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex." SIGNOR-205458 MAP3K14 protein Q99558 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 9020361 f amattioni "Nik stimulates nf-kappab activity" SIGNOR-46212 PAK4 protein O96013 UNIPROT MZF1 protein P28698 UNIPROT "up-regulates activity" phosphorylation Ser27 VMVKLEDsEEEGEAA -1 30622337 t miannu " Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1).  Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1.The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4." SIGNOR-277422 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto "In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F" SIGNOR-245480 RORA protein P35398 UNIPROT NR1D1 protein P20393 UNIPROT "down-regulates activity" binding 9606 BTO:0000599 20817722 t miannu "Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding." SIGNOR-267979 LYN protein P07948 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Tyr335 NEPKKKKyAKEAWPG -1 11104670 t "Lyn phosphorylates both Tyr-264 and Tyr-335, but that the phosphorylation of Tyr-335 is dependent on the association of NIPP1 with RNA. The inhibitory potency of the C-terminal site of NIPP1 was decreased by phosphorylation of Tyr-335 and by the addition of RNA." SIGNOR-251406 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 BTO:0000848 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-236155 "A9/b1 integrin" complex SIGNOR-C166 SIGNOR IL1B protein P01584 UNIPROT "up-regulates quantity by expression" 9606 24241034 f lperfetto "Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages." SIGNOR-253314 PCK1 protein P35558 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "chemical modification" 9606 30193097 t miannu "¬†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).¬†" SIGNOR-266587 GNAI1 protein P63096 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" binding -1 11007482 t "Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src" SIGNOR-256526 DEPTOR protein Q8TB45 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR "form complex" binding 9606 25628925 t lperfetto "Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)" SIGNOR-205603 PRKD2 protein Q9BZL6 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates phosphorylation Ser294 SNLKRTAsNPKVENE 9606 16912074 t "The effect has been demonstrated using Q9UBF8-2" gcesareni "Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity." SIGNOR-148880 CAMK2A protein Q9UQM7 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 t gcesareni "Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase." SIGNOR-58251 BACH1 protein O14867 UNIPROT HMOX1 protein P09601 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 14747657 t "These results indicate that ho-1 regulation involves a competition between the activator Nrf2 and the Bach1 repressor for interactions with the small Maf proteins." SIGNOR-259336 PIP5K1C protein O60331 UNIPROT "1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-)" smallmolecule CHEBI:58456 ChEBI "up-regulates quantity" "chemical modification" 9606 9367159 t miannu "Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities" SIGNOR-277286 STK38 protein Q15208 UNIPROT RBM24 protein Q9BX46 UNIPROT "up-regulates activity" phosphorylation 9606 28322254 t miannu "Phosphorylation of Rbm24 by Stk38 is crucial for the maintenance of cardiac sarcomeric gene expression in cardiac cells.|These results indicated that Stk38 increases Rbm24 protein stability probably by interfering with the ubiquitin-proteasome protein degradation pathway." SIGNOR-278291 PRKCA protein P17252 UNIPROT CSNK1D protein P48730 UNIPROT "up-regulates activity" phosphorylation Thr176 ENKNLTGtARYASIN -1 31096047 t miannu "In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity." SIGNOR-277450 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG -1 9139719 t lperfetto "In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33." SIGNOR-248972 CFLAR protein O15519 UNIPROT CASP8 protein Q14790 UNIPROT "down-regulates activity" binding 9606 14585074 t amattioni "Flip can be incorporated into the disc complex and blocks processing and activation of pro-caspase8" SIGNOR-96402 PIK3R4 protein Q99570 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" binding 10090 27411398 t lperfetto "Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity" SIGNOR-260709 PRKG1 protein Q13976 UNIPROT ITPR1 protein Q14643 UNIPROT unknown phosphorylation Ser1764 RPSGRREsLTSFGNG 10116 BTO:0004578 8132598 t lperfetto "Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase. | The synthetic peptide corresponding to serine 1755 (GRRESLTSFG) was phosphorylated with aKm in the range of 30-40 microM by both kinases. The kinetic analysis revealed that this peptide substrate is the best substrate described for cGMP kinase to date. Vascular smooth muscle cells prelabeled with [32P]orthophosphate and treated with atrial natriuretic peptide or sodium nitroprusside to elevate cGMP also resulted in increased labeling of the IP3 receptor. Phosphorylation of IP3 receptor by cGMP kinase may regulate the function of IP3 receptor in vascular smooth muscle cells and contribute to the effect of cGMP to regulate intracellular calcium levels." SIGNOR-248916 STAT1 protein P42224 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 16481475 t lperfetto "Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease." SIGNOR-217418 BAX protein Q07812 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates relocalization 9606 14585074 t "Translocation from Mitochondria to Cytosol" amattioni "Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi" SIGNOR-88590 IRF1 protein P10914 UNIPROT IRF8 protein Q02556 UNIPROT "up-regulates activity" binding 9606 11483597 t miannu "We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP." SIGNOR-222841 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252443 PRKACA protein P17612 UNIPROT IMMT protein Q16891 UNIPROT "down-regulates activity" phosphorylation Ser528 ELQFRRLsQEQVDNF -1 27153535 t miannu "PKA directly phosphorylated the Ser528 residue of MIC60. Phosphorylation of MIC60 Interrupts Parkin Recruitment and Formation of the MICOS Complex" SIGNOR-266302 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18339811 t "Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs." SIGNOR-248606 PRKACA protein P17612 UNIPROT PLN protein P26678 UNIPROT "up-regulates activity" phosphorylation Ser16 RSAIRRAsTIEMPQQ 10090 10988285 t miannu "Phospholamban (PLB) can be phosphorylated at Ser(16) by cyclic AMP-dependent protein kinase. phosphorylation of Ser(16) is sufficient for mediating the maximal cardiac responses to beta-adrenergic stimulation." SIGNOR-250030 LPAR4 protein Q99677 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257325 "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI "orotidine 5'-phosphate(3-)" smallmolecule CHEBI:57538 ChEBI "up-regulates quantity" "precursor of" 9606 2912371 t miannu "Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase)." SIGNOR-267435 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto "When subjected to phosphorylation by erk, the most efficient decrease in erk phosphorylation was observed with the s353a mutantamong the mechanisms underlying k protein ability to confer increased transcriptional output are interconversion of duplex and single-stranded dna (59) and association with the c/ebp_ (60), each of which could be better affected by the phosphorylated form of the k protein, which may increase affinity to associated proteins or dna." SIGNOR-105754 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser863 DPISTDAsRRSSEAS 9606 BTO:0000007 16611981 t lperfetto "The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3." SIGNOR-249590 CYP11B1 protein P15538 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000050 9814482 t lperfetto "Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol." SIGNOR-268679 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI SOS1 protein Q07889 UNIPROT up-regulates "chemical activation" 9606 17486115 t gcesareni "Phosphatidic acid interacts with a defined site in the sos ph domain with high affinity and specificity" SIGNOR-154676 FOXP1 protein Q9H334 UNIPROT SEMA5B protein Q9P283 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001176 24023716 t Gianni "FoxP1 stimulates angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells." SIGNOR-269050 FBXW7 protein Q969H0 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0002524 17298674 t miannu "Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme" SIGNOR-271640 TEAD proteinfamily SIGNOR-PF22 SIGNOR ANKRD1 protein Q15327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 31296870 t miannu "In this model, treatment with LIF, but not IL-6, significantly elevated YAP/TAZ-TEAD transcriptional activity and sequentially increased expression of YAP1-targeted genes, CNTF and ANKRD at mRNA, in human PDAC cells" SIGNOR-278035 FBXO8 protein Q9NRD0 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9534 BTO:0000298 18094045 t miannu "Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A)." SIGNOR-271765 AURKA protein O14965 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser308 KAEFCNKsKQPGLAR 9606 14990569 t lperfetto "Previous studies have shown that the brca1 breast cancer tumor suppressor also localizes to the centrosome and that brca1 inactivation results in loss of the g(2)-m checkpoint. We demonstrate here that aurora-a physically binds to and phosphorylates brca1. We propose that brca1 phosphorylation by aurora-a plays a role in g(2) to m transition of cell cycle" SIGNOR-123065 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT "up-regulates quantity" 9606 BTO:0000452 BTO:0001279 31623154 f "P00441:p.Gly94Ala (mutation increasing interaction)" "We demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying SOD1 pathogenic variants." SIGNOR-262784 PRKACB protein P22694 UNIPROT PHKA1 protein P46020 UNIPROT "down-regulates activity" phosphorylation 9606 10487978 t "Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme." SIGNOR-267413 Laminin-1 complex SIGNOR-C183 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 2351695 t lperfetto "In combination, the anti-alpha 1- and anti-alpha 6-specific antibodies completely inhibited JAR cell attachment to LN and fragment E1. Thus, the alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers each function as LN receptors and act together to mediate the interactions of human JAR choriocarcinoma cells with LN." SIGNOR-253256 TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT "up-regulates activity" binding 9606 18353649 t lperfetto "Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction" SIGNOR-178053 UNC80 protein Q8N2C7 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 19535918 t miannu "UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex. " SIGNOR-265179 PRKCD protein Q05655 UNIPROT LIMK2 protein P53671 UNIPROT down-regulates phosphorylation Ser283 EGTLRRRsLRRSNSI 9606 15923181 t "Translocation from Cytosol to Nucleus" flangone "Activation of pkc by phorbol ester treatment of endothelial cells stimulated limk2 phosphorylation at ser-283 and inhibited nuclear import of limk2" SIGNOR-137927 MAPK14 protein Q16539 UNIPROT PAK6 protein Q9NQU5 UNIPROT up-regulates phosphorylation Ser165 MPWPEPQsPRVLPNG 9606 15550393 t gcesareni "The activation of pak6 by both p38 map kinase and mkk6 suggests that pak6 plays a role in the cellular response to stress-related signals." SIGNOR-130979 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." SIGNOR-216992 lidocaine chemical CHEBI:6456 ChEBI SCN5A protein Q14524 UNIPROT "down-regulates activity" "chemical inhibition" 8355 BTO:0000964 8786356 t miannu "Surprisingly, hH1-beta 1 Na channels were threefold more sensitive to rested-state block by lidocaine (402 +/- 36 microM, n = 4-22) than were mu 1-beta 1 Na channels (1,168 +/- 34 microM, n = 7-19)." SIGNOR-258499 SCF-SKP2 complex SIGNOR-C136 SIGNOR CCNE2 protein O96020 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 phosphorylation:Ser383;Thr392 FRKGGQLsPVCNGGI;VCNGGIMtPPKSTEK 11533444 t lperfetto "The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro" SIGNOR-267559 PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR DCK protein P27707 UNIPROT "down-regulates activity" dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 t lperfetto "Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation" SIGNOR-275802 CYP21A2 protein P08686 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000050 25855791 t lperfetto "Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively" SIGNOR-268643 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Ser205 LATPPTLsSTVLIVR 9606 BTO:0001938 12815053 t lperfetto "M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1" SIGNOR-102490 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273035 F2RL3 protein Q96RI0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 17158345 t gcesareni "Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13)" SIGNOR-151162 NUP88 protein Q99567 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262076 RPS6K proteinfamily SIGNOR-PF26 SIGNOR IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0001103 21798082 t lperfetto "Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization." SIGNOR-252787 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 18852293 t lperfetto "Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6." SIGNOR-249532 Ub:E2 complex SIGNOR-C497 SIGNOR RNF215 protein Q9Y6U7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271238 gamma-secretase complex SIGNOR-C98 SIGNOR DSCAML1 protein Q8TD84 UNIPROT "down-regulates quantity" cleavage 9606 BTO:0000938 30745319 t miannu "γ‐secretase‐mediated intra‐membrane cleavage of DSCAM receptors results in the release of the DSCAM ICD, which is likely proceeded by shedding of the DSCAM ectodomain. Interaction of IPO5 with the NLS of DSCAM then leads to importin‐mediated nuclear import of the DSCAM ICD. In the nucleus, the DSCAM ICD may regulate the transcription of genes involved in neuronal development and function, thereby regulating processes such as neurite outgrowth, branching, and repulsion, as well as synapse formation, axon guidance, and neuronal cell death and survival." SIGNOR-264272 PHKG2 protein P15735 UNIPROT PYG proteinfamily SIGNOR-PF96 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0002049 22225877 t miannu "It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15" SIGNOR-267962 "bisphenol F" chemical CHEBI:34575 ChEBI AHR protein P35869 UNIPROT "up-regulates activity" "chemical activation" -1 31995776 t miannu "This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs." SIGNOR-268737 AKT3 protein Q9Y243 UNIPROT ADARB1 protein P78563 UNIPROT "down-regulates activity" phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 t miannu "AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively" SIGNOR-276195 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT "down-regulates activity" binding 9606 14701738 t miannu "Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively." SIGNOR-261721 CPT1C protein Q8TCG5 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 ChEBI "down-regulates quantity" "chemical modification" 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267122 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 t lperfetto "The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570." SIGNOR-176058 PIK-90 chemical CID:6857685 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206229 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 10068651 t lperfetto "Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro." SIGNOR-236254 AR protein P10275 UNIPROT UCN protein P55089 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001509 23801677 t lperfetto "When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter|These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively." SIGNOR-253688 CACNA1E protein Q15878 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission." SIGNOR-264327 ADGRG1 protein Q9Y653 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" binding 24949629 t "Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); | We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation." SIGNOR-253981 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr383 HYRYSDTtDSDPENE 9606 21779440 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-89830 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-118857 P2RY6 protein Q15077 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257343 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 12105215 t lperfetto "To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-216666 NOTCH proteinfamily SIGNOR-PF30 SIGNOR MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 12386158 t gcesareni "Other than a role in t-cell development, the hox genes may be involved in alternative notchregulated processes in hematopoietic stem cells. Notch signaling is clearly important for self-renewal of hematopoietic progenitors (reviewed by radkte et al. 57). Interestingly, hoxa5, a9 and a10 were found to be part of the stem cell profile'" SIGNOR-254347 EEA1 protein Q15075 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "Early endosomal antigen-1 (EEA1) is a well-characterized effector of Rab5 and one of the most widely used markers for EE due to its specific localization to this compartment. EEA1, in coordination with members of the SNARE family, is essential for EE fusion in vivo" SIGNOR-260623 CSK protein P41240 UNIPROT LCK protein P06239 UNIPROT down-regulates phosphorylation Tyr505 FTATEGQyQPQP 9606 BTO:0000782 1639064 t gcesareni "P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity." SIGNOR-20371 PTPN13 protein Q12923 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" dephosphorylation 9606 17638892 t miannu "Finally, we report that PTPL1 expression is sufficient to block the IRS-1/phosphatidylinositol 3-kinase/Akt signaling pathway, to inhibit the insulin-like growth factor-I effect on cell survival, and to induce apoptosis.|We first show by complementary approaches that PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1) in vitro and in cellulo." SIGNOR-277053 "L-selenocystathionine zwitterion" smallmolecule CHEBI:62226 ChEBI "L-selenocysteine zwitterion" smallmolecule CHEBI:57843 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275817 ATM protein Q13315 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 16497931 t lperfetto "Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export." SIGNOR-144813 ADRA1A protein P35348 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257279 SYVN1 protein Q86TM6 UNIPROT GPR37 protein O15354 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 18241051 t miannu "We demonstrated that endogenous HRD1 interacts with Pael-R, and that HRD1 promotes the degradation of Pael-R and protects cell death caused by the accumulation of Pael-R." SIGNOR-272631 HSD3B1 protein P14060 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000050 2139411 t lperfetto "The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione." SIGNOR-268636 "HIF-1 complex" complex SIGNOR-C418 SIGNOR LDHA protein P00338 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27692180 t miannu "HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID." SIGNOR-267456 ADA protein P00813 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI "down-regulates quantity" "chemical modification" -1 15926889 t Luana "Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates" SIGNOR-269735 CCL2 protein P13500 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu "High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity." SIGNOR-261027 CRP protein P02741 UNIPROT IL10 protein P22301 UNIPROT "down-regulates quantity by repression" "translation regulation" 9606 BTO:0000801 16917108 f Regulation miannu "CRP significantly decreased IL-10 mRNA stability" SIGNOR-251824 COPS3 protein Q9UNS2 UNIPROT "COP9 signalosome variant 2" complex SIGNOR-C487 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270764 PRKACA protein P17612 UNIPROT KCNQ5 protein Q9NR82 UNIPROT "up-regulates activity" phosphorylation Ser88 GKQGARMsLLGKPLS 9606 BTO:0001660 30061510 t miannu "We conclude that phosphorylation of S53 on the amino terminus of Kv7.5 is essential for PKA-dependent enhancement of channel activity in response to βAR activation in vascular and airway smooth muscle cells." SIGNOR-265980 ESR1 protein P03372 UNIPROT TFF1 protein P04155 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 11517191 f "ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression" SIGNOR-253938 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1B protein P28222 UNIPROT "up-regulates activity" "chemical activation" 10116 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258567 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t llicata "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-137959 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1626 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248769 DYRK2 protein Q92630 UNIPROT EDVP complex SIGNOR-C530 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 19287380 t miannu "DYRK2 functions as an adaptor in the EDVP E3 ligase complex. These experiments suggest that DYRK2 functions as a molecular assembler required for the specific recruitment of EDD to DDB1-VPRBP, thus forming a novel EDVP E3 ligase complex." SIGNOR-271792 HUWE1 protein Q7Z6Z7 UNIPROT PTOV1 protein Q86YD1 UNIPROT "down-regulates quantity" ubiquitination 9606 34654719 t miannu "Our data suggest that HUWE1 can ubiquitinate PTOV1 in vitro and depletion of HUWE1 in cells increases the stability of PTOV1 S36A protein in the nucleus.|Our data suggest that depletion of HUWE1 elevates PTOV1 protein levels, which, in turn, promote the expression of cJun, a pro-growth translational target of PTOV1 (18)\n In our model, we propose that HUWE1 mediates the degradation of PTOV1 in the nucleus." SIGNOR-278755 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity." SIGNOR-104921 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT "down-regulates activity" phosphorylation Thr680 QPLVGIEtLPPDLRD 9606 BTO:0000007 25755282 t miannu "Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues. " SIGNOR-273580 CDK1 protein P06493 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT "up-regulates activity" phosphorylation Thr1238 ASWDQPGtPGREPTQ 9606 BTO:0000567 37584777 t "phosphorylation site remapping based on mass spec table" lperfetto "CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects." SIGNOR-272966 3a protein P59632 UNIPROT "NLRP3 inflammasome" complex SIGNOR-C225 SIGNOR "up-regulates activity" 9606 BTO:0000567 30761102 f miannu "We found that the ion channel activity of SARS-CoV 3a protein is essential for activation of the NLRP3 inflammasome. In addition, both K+ efflux and mitochondrial ROS production are required for SARS-CoV 3a-mediated IL-1β secretion. In the case of SARS-CoV, the viroporin E forms forms Ca2+-permeable ion channels and activates the NLRP3 inflammasome.the 3a protein of SARS-CoV has the ability to induce the NLRP3 inflammasome activation by multiple mechanisms." SIGNOR-260594 PLK2 protein Q9NYY3 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser589 EQAADEIsFSSNSSF 9606 20531387 t lperfetto "Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle." SIGNOR-165999 FFAR4 protein Q5NUL3 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257246 E protein P59637 UNIPROT "NLRP3 inflammasome" complex SIGNOR-C225 SIGNOR "up-regulates activity" 9606 32133002 f miannu "Viroporins are small, highly hydrophobic proteins derived from viruses, which interact with membranes to modify the host cell's permeability to ions or other small molecules. Several viroporins are observed to localize to the Golgi apparatus and other cytoplasmic structures during viral infection.Examples include 2B proteins from EMCV, poliovirus, enterovirus 71 (EV71), and human rhinoviruses (HRV), the envelope (E) protein of severe acute respiratory syndrome coronavirus (SARS-CoV), as well as influenza virus M2 protein. These viroporins activate the NLRP3 inflammasome by inducing different ionic fluxes.N protein from SARS-CoV, cause the flux of calcium from intracellular storages to the cytosol, which is indispensable for NLRP3 activation" SIGNOR-261318 8b protein Q80H93 UNIPROT "NLRP3 inflammasome" complex SIGNOR-C225 SIGNOR "up-regulates activity" binding 9606 31231549 t miannu "We found that ORF8b triggers robust NLRP3 inflammasome activation and IL-1β release. NLRP3 activation was accompanied by direct binding of ORF8b to the LRR domain of NLRP3." SIGNOR-260591 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI IGF1R protein P08069 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258116 IKBKB protein O14920 UNIPROT ASB8 protein Q9H765 UNIPROT "up-regulates activity" phosphorylation Ser31 RTIAAIRsFPHDNVE 9606 BTO:0000007 31009856 t lperfetto "We found that ASB8 was phosphorylated at the N-terminal Ser-31 by host IkappaB kinase beta (IKKbeta). In turn, ASB8 facilitated K48-linked ubiquitination and degradation of IKKbeta via the ubiquitin-proteasome pathway, resulting in remarkable inhibition of I-kappa-B-alpha (IkappaBalpha) and of p65 phosphorylation, consequently suppressing NF-kappaB activity." SIGNOR-272242 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2279 PVQPNPMsPQQHMLP 9606 17623675 t lperfetto "Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo." SIGNOR-244533 GUCY1A3-B2 complex SIGNOR-C139 SIGNOR "3',5'-cyclic GMP" smallmolecule CHEBI:16356 ChEBI "up-regulates quantity" "chemical modification" 9606 10977868 t gcesareni "Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types" SIGNOR-244122 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by stabilization" deacetylation Lys70 EGILRRLkKYDNCWL 9606 BTO:0000007 21726808 t lperfetto "Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1" SIGNOR-267599 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates phosphorylation Tyr411 RVIEDNEyTAREGAK 9606 BTO:0000007 10934191 t gcesareni "Tyr(416) is the autophosphorylation site in the activation loop. Autophosphorylation of tyr(416) is required for hck activation." SIGNOR-80340 NRAS protein P01111 UNIPROT RAF1 protein P04049 UNIPROT up-regulates relocalization 9606 21779497 t "Translocation from Cytosol to Membrane" gcesareni "The raf family of proteins (raf-1, a-raf, and b-raf) bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-175231 MYC protein P01106 UNIPROT HK2 protein P52789 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 17785433 t "Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration." SIGNOR-259986 GIPR protein P48546 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 BTO:0000783 35065096 t miannu "The GPCRs are allocated in five families where the GLP-1R and GIPR are found within the secretin family, also classified as class B [31,32]. Upon stimulation by an extracellular stimuli (ligand), GPCRs undergo conformational changes, and triggers downstream intracellular signals by coupling with G proteins (or other intracellular proteins such as arrestins), causing a wide range of both physiological and pathological processes.To stimulate insulin secretion, and in the presence of elevated blood glucose concentrations, GLP-1R activation in pancreatic beta cells promote recruitment and activation of Gαs protein leading to adenylate cyclase-mediated cAMP production, elevation of Ca2+, and ERK1/2 phosphorylation (Fig. 3)" SIGNOR-278138 SOST protein Q9BQB4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 19874086 f "Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling." gcesareni "It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass" SIGNOR-188964 ERN1 protein O75460 UNIPROT JUN protein P05412 UNIPROT up-regulates 9606 BTO:0001976 18065414 f lperfetto "The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression" SIGNOR-253146 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT "up-regulates activity" phosphorylation Ser153 PSSKRSPsTATLSLP 9606 BTO:0001061 31730483 t miannu "Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells." SIGNOR-276774 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr556 LNGQPIQyARSTCEA 9606 BTO:0000763 20861316 t lperfetto "Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity" SIGNOR-167997 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-169686 S protein P59594 UNIPROT "Spike protein-ACE2" complex SIGNOR-C240 SIGNOR "form complex" binding 9534 BTO:0001444 18554741 t miannu "Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells." SIGNOR-260287 ACE2 protein Q9BYF1 UNIPROT "Spike protein-ACE2" complex SIGNOR-C240 SIGNOR "form complex" binding 9534 BTO:0001444 18554741 t miannu "Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells." SIGNOR-260288 CREB1 protein P16220 UNIPROT PAX3 protein P23760 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 21902831 f gcesareni "Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes." SIGNOR-176539 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR RAE1 protein P78406 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16036565 f miannu "Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein" SIGNOR-260869 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "precursor of" 9606 33179964 t miannu "The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP." SIGNOR-267328 ITCH protein Q96J02 UNIPROT OCLN protein Q16625 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 28542131 t miannu "Two mechanisms regarding junction protein turnover were illustrated in this process, that is, the Itch-induced occludin ubiquitination and proteasome degradation, and the caveolae-dependent endocytosis of junction proteins (JAM-A, N-cadherin, and \u03b2 -catenin), both of which led to the instability of junction apparatus between adjacent SCs and a subsequent damaged BTB." SIGNOR-278756 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8557118 t gcesareni "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-249651 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Thr1795 SRSSWRLtSSEMKKS -1 9242537 t lperfetto "Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity." SIGNOR-263634 NANOG protein Q9H9S0 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086;BTO:0005511 15983365 f miannu "Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta." SIGNOR-254621 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000891 10929712 t amattioni "Diablo may promote apoptosis by binding to iaps and preventing them from inhibiting caspases." SIGNOR-80225 3a protein P59632 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR "down-regulates quantity" 9606 20020050 f miannu "The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity." SIGNOR-260350 EIF3E protein P60228 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266396 "HIF-1 complex" complex SIGNOR-C418 SIGNOR BNIP3L protein O60238 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27692180 t miannu "HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID." SIGNOR-267455 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM3 protein P20309 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258632 PRPS2 protein P11908 UNIPROT "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI "up-regulates quantity" "chemical modification" 9606 16939420 t miannu "PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP." SIGNOR-267082 NHP2 protein Q9NX24 UNIPROT TERT protein O14746 UNIPROT "up-regulates activity" binding 18680434 t lperfetto "A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP" SIGNOR-263330 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" phosphorylation Thr382 PRSINTDtLSKETDS 9606 BTO:0000567 19509060 t lperfetto "Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation." SIGNOR-272993 PPARD protein Q03181 UNIPROT SLC25A20 protein O43772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19577614 f miannu "CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting." SIGNOR-255048 MARCHF5 protein Q9NX47 UNIPROT PMAIP1 protein Q13794 UNIPROT "down-regulates quantity" ubiquitination 9606 32015503 t miannu "MARCH5 promotes ubiquitination of MCL1 and NOXA.|Of note, MARCH5 depletion led to the accumulation of MCL1 and NOXA in asynchronous as well as G2 cells, suggesting that MARCH5 controls NOXA/MCL1 levels throughout the cell cycle." SIGNOR-278758 PRKAA1 protein Q13131 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 19491292 f gcesareni "Activation of ampk reduced p21 protein and mrna expression, which was associated with re- duced g1/s cell cycle transition and p21 promoter activity." SIGNOR-186061 TBK1 protein Q9UHD2 UNIPROT PRPS1 protein P60891 UNIPROT "up-regulates activity" phosphorylation Thr228 DMADTCGtICHAADK -1 34343500 t miannu "Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis. " SIGNOR-277316 MAPK1 protein P28482 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser641 DIKILIAsPSPTHIH 9606 BTO:0000567 18519666 t lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-178723 TRRAP protein Q9Y4A5 UNIPROT "SAGA complex" complex SIGNOR-C465 SIGNOR "form complex" binding 9606 34811519 t lperfetto "Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module" SIGNOR-269589 estrone smallmolecule CHEBI:17263 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" -1 9048584 t miannu "In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes." SIGNOR-258584 UMPS protein P11172 UNIPROT orotate smallmolecule CHEBI:30839 ChEBI "down-regulates quantity" "chemical modification" 9606 2912371 t miannu "Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase)." SIGNOR-267436 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-252957 NTN1 protein O95631 UNIPROT NEO1 protein Q92859 UNIPROT "up-regulates activity" binding 9606 BTO:0001484 28245592 t miannu "Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins." SIGNOR-268169 LMP2 protein P13285 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR "down-regulates quantity by destabilization" 9606 19718044 f scontino "The EBV-encoded Latent Membrane Proteins, LMP2A and LMP2B, Limit the Actions of Interferon by Targeting Interferon Receptors for Degradation.LMP2A and LMP2B increase the turnover and degradation of IFNAR1 and IFNGR1. LMP2A and LMP2B reduce the half-life of IFNAR1 and IFNGR1." SIGNOR-266824 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser295 LQASVPGsVPGVLGP -1 16027724 t "GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)" SIGNOR-251230 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131981 SMARCD3 protein Q6STE5 UNIPROT "SWI/SNF ACTL6A-ARID1A-SMARCA2 variant" complex SIGNOR-C470 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269820 LTB4R protein Q15722 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256970 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR GPSM3 protein Q9Y4H4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000876 phosphorylation:Ser35 STTRPWRsAPPSPPP 22843681 t lperfetto "Mutation of serine 35 completely abrogates the 14-3-3 interaction (e.g. Fig. 2, B–F), suggesting that phosphorylation of serine 35 is obligatory for 14-3-3 binding|The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins." SIGNOR-264866 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 t "Translocation from Endosome to Lysosome" fspada "In this study, we demonstrated that ser396 and ser398 are phosphorylated by pkc and, that phosphorylation of ser398 is particularly involved in pmainduced desensitization of the h1r." SIGNOR-66015 "Spike protein-ACE2" complex SIGNOR-C240 SIGNOR "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR up-regulates 17522231 f lperfetto "These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins" SIGNOR-260711 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT unknown phosphorylation Ser418 QQRKALLsPFSTPVR -1 15952796 t lperfetto "We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites." SIGNOR-249406 "CoV2 Spike protein-ACE2" complex SIGNOR-C254 SIGNOR "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR up-regulates 17522231 f lperfetto "These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins" SIGNOR-260756 PF-04691502 chemical CID:25033539 PUBCHEM AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates "chemical inhibition" 9606 Other t "Selleck;inhibitor of phosphorylation of AktT308 and AktS473" gcesareni SIGNOR-205977 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser705 TPSAMKSsPQIPHQT 9606 SIGNOR-C17 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-164495 naloxone chemical CHEBI:7459 ChEBI OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258942 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273082 CSNK2A1 protein P68400 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT "down-regulates activity" phosphorylation Ser393 VCHDSDEsDTAKAVE -1 25066127 t miannu "This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin." SIGNOR-276649 WWP2 protein O00308 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 21532586 t miannu "We have shown that WWP2 interacts with and ubiquitylates PTEN, promoting its degradation." SIGNOR-278650 WDR59 protein Q6PJI9 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR "form complex" binding 9606 23723239 t miannu "Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5" SIGNOR-255303 EIF1 protein P41567 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "down-regulates activity" 9606 14600024 f lperfetto "Binding of eIF1 to the 40S subunit would block access of the 60S" SIGNOR-269144 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 t amattioni "Bcl9 exert its function by physically linking pygo to beta-catenin. The recruitment of pygo permits beta-catenin to transcriptionally activate wnt target genes." SIGNOR-116552 S protein P0DTC2 UNIPROT "CoV2 Spike protein-ACE2" complex SIGNOR-C254 SIGNOR "form complex" binding 9534 BTO:0001444 32155444 t miannu "We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV." SIGNOR-260739 ACE2 protein Q9BYF1 UNIPROT "CoV2 Spike protein-ACE2" complex SIGNOR-C254 SIGNOR "form complex" binding 9534 BTO:0001444 32155444 t miannu "We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV." SIGNOR-260740 HIF1AN protein Q9NWT6 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates hydroxylation 9606 18299578 t gcesareni "We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation." SIGNOR-254324 ITGB1 protein P05556 UNIPROT "Av/b1 integrin" complex SIGNOR-C175 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253202 lenvatinib chemical CHEBI:85994 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191457 EFNB3 protein Q15768 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 t tpavlidou "Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor" SIGNOR-52624 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR GSN protein P06396 UNIPROT down-regulates cleavage 9606 BTO:0000130 9323209 t amattioni "Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation." SIGNOR-256461 bevacizumab antibody DB00112 DRUGBANK VEGFD protein O43915 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 15961063 t miannu "Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy." SIGNOR-259887 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248744 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t gcesareni "The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein." SIGNOR-105770 PCSK2 protein P16519 UNIPROT IAPP protein P10997 UNIPROT "up-regulates activity" cleavage Arg33 ESHQVEKrKCNTATC -1 10931181 t lperfetto "The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule" SIGNOR-261791 SEMA4D protein Q92854 UNIPROT PLXNB1 protein O43157 UNIPROT up-regulates binding 9606 12198496 t gcesareni "Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors." SIGNOR-92201 PRKN protein O60260 UNIPROT APEX1 protein P27695 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27148961 t miannu "Based on these results, we conclude that Parkin directly ubiquitinates APE1.|These results indicated that degradation of APE1 by Parkin was limited compared to the transiently expressed APE1, suggesting that a large portion of APE1 is not in contact with the Parkin and PINK1 without induction of stresses such as oxidative stress." SIGNOR-278531 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248519 calcium(2+) smallmolecule CHEBI:29108 ChEBI PPP3CA protein Q08209 UNIPROT up-regulates "chemical activation" 9606 21880741 t gcesareni "Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear." SIGNOR-176367 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 t gcesareni "Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation." SIGNOR-88720 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT "up-regulates activity" phosphorylation Tyr161 QGWVPSNyITPVNSL -1 34144039 t miannu " PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2." SIGNOR-277306 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 t esanto "Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89241 MRPL45 protein Q9BRJ2 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262351 MAPK1 protein P28482 UNIPROT DUSP16 protein Q9BY84 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser446 TNKLCQFsPVQELSE 9534 15689616 t lperfetto "Phosphorylation of Ser-446 determines stability of MKP-7.|We also determined that MKP-7 phosphorylated at Ser-446 has a longer half-life than unphosphorylated form of the wild type protein, as does a phospho-mimic mutant of MKP-7. These results indicate that activation of the ERK pathway strongly blocks JNK activation through stabilization of MKP-7 mediated by phosphorylation." SIGNOR-249389 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr71 TLSEKIVyGHLDDPA -1 17997986 t miannu "Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are ""in vitro"" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations." SIGNOR-262871 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr286 RLEEKVKtLKAQNSE 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170764 SOSTDC1 protein Q6X4U4 UNIPROT WNT7A protein O00755 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242710 tRNA(Trp) smallmolecule CHEBI:29181 ChEBI Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI "up-regulates quantity" "precursor of" 9606 14660560 t miannu "Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471)" SIGNOR-270515 hsa-miR-410-5p mirna URS00002233F4_9606 RNAcentral WNT7B protein P56706 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003964 25351956 t Parnian "Downregulated miR329 and miR410 Promote the Proliferation and Invasion of Oral Squamous Cell Carcinoma by Targeting Wnt-7b.| miR329 and miR410 directly target Wnt-7b." SIGNOR-278858 PTPRJ protein Q12913 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12771128 t "inferred from 70% of family members" gcesareni "A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation." SIGNOR-269897 FGR protein P09769 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" phosphorylation Tyr394 LNTIGLIyEKISLPK 9606 BTO:0002181 28618271 t miannu "The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. " SIGNOR-276722 GSK3A protein P49840 UNIPROT RICTOR protein Q6R327 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr1695 EAEAVLAtPPKQPIV 9606 BTO:0002181 25897075 t miannu "We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability. " SIGNOR-276899 KAT2B protein Q92831 UNIPROT H3-4 protein Q16695 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269613 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr404 HYETDYTtGGESCDE 9606 BTO:0000195 BTO:0000671 21545357 t lperfetto "Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions." SIGNOR-173635 ULK1 protein O75385 UNIPROT ENO1 protein P06733 UNIPROT "down-regulates activity" phosphorylation Ser115 ANAILGVsLAVCKAG 9606 BTO:0000007 27153534 t done miannu "Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown)." SIGNOR-274030 GSK3B protein P49841 UNIPROT RICTOR protein Q6R327 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr1695 EAEAVLAtPPKQPIV 9606 BTO:0002181 25897075 t miannu "We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability. " SIGNOR-276898 NEO1 protein Q92859 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 17204444 f miannu "Neogenin, a close relative of the axon guidance receptor Deleted in Colorectal Cancer (DCC), has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) families. While Netrin-1-Neogenin interactions result in a chemoattractive axon guidance response, the interaction between Neogenin and RGMa induces a chemorepulsive response." SIGNOR-268395 WASHC3 protein Q9Y3C0 UNIPROT "WASH complex" complex SIGNOR-C258 SIGNOR "form complex" binding 23721880 t lperfetto "The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53." SIGNOR-261017 PRKCA protein P17252 UNIPROT F11R protein Q9Y624 UNIPROT unknown phosphorylation Thr92 DRVTFLPtGITFKSV -1 7646439 t lperfetto "Internal amino acid sequence analysis of the F11 antigen provided information concerning 68 amino acids and suggested two consensus phosphorylation sites for protein kinase C (PKC). The phosphorylation by PKC of the isolated F11 antigen was observed following stimulation by phorbol 12-myristate 13-acetate." SIGNOR-248901 DLX2 protein Q07687 UNIPROT MSX1 protein P28360 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240918 PRKCB protein P05771 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR "up-regulates activity" phosphorylation -1 15894802 t "inferred from family member" lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-270277 FBXO33 protein Q7Z6M2 UNIPROT YBX1 protein P67809 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 16797541 t miannu "Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1" SIGNOR-271604 SRC protein P12931 UNIPROT AP2B1 protein P63010 UNIPROT down-regulates phosphorylation Tyr737 THRQGHIyMEMNFTN 9606 18938240 t gcesareni "The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin." SIGNOR-181743 RUNX1 protein Q01196 UNIPROT ITGA2B protein P08514 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17725493 f miannu "We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha." SIGNOR-254193 Merimepodib chemical CID:153241 PUBCHEM IMPDH2 protein P12268 UNIPROT "down-regulates activity" "chemical inhibition" 9606 11288107 t Federica "These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation." SIGNOR-261106 RNF34 protein Q969K3 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0005949 36696363 t miannu "Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34. " SIGNOR-277912 SREBF2 protein Q12772 UNIPROT PON1 protein P27169 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20728021 t miannu "we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity." SIGNOR-255224 ITCH protein Q96J02 UNIPROT GLIS3 protein Q8NEA6 UNIPROT "down-regulates quantity" ubiquitination 9606 26147758 t miannu "Itch promotes proteolytic degradation of Glis3.|Since Itch interacts with and ubiquitinates Glis3, it was of interest to determine which regions were necessary for Itch directed degradation of Glis3." SIGNOR-278653 CCNC protein P24863 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates phosphorylation 9606 15546612 t "Leads to a following ubiquitination and degradation" gcesareni "Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo." SIGNOR-254309 MC5R protein P33032 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257183 CCL21 protein O00585 UNIPROT ACKR4 protein Q9NPB9 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 23341447 t Luana " In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines." SIGNOR-268417 GCG protein P01275 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates 9606 23075495 f gcesareni "On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz." SIGNOR-199205 RANBP17 protein Q9H2T7 UNIPROT TCF3 protein P15923 UNIPROT up-regulates binding 9606 20503194 t miannu "Yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation analyses demonstrate specific interaction of e12 with ranbp17, a novel member of the importin-beta superfamily;this interaction maps to the crm1 homology region of ranbp17. Ectopic expression of ranbp17 leads to a approximately 3-fold increase in e2a/myod mediated transactivation of an e-box regulated luciferase reporter gene." SIGNOR-165655 KATNB1 protein Q9BVA0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates 9606 BTO:0000567 10751153 f miannu "Katanin, a heterodimeric microtubule-severing ATPase, is found localized at mitotic spindle poles. In this paper we demonstrate that human p60 katanin and the C-terminal domain of human p80 katanin both bind microtubules in vitro. Association of these two proteins results in an increased microtubule affinity and increased microtubule-severing activity in vitro. Association of these subunits in transfected HeLa cells increases microtubule disassembly activity and targeting to spindle poles. " SIGNOR-267181 FBXO11 protein Q86XK2 UNIPROT TP53 protein P04637 UNIPROT down-regulates neddylation Lys320 SSSPQPKkKPLDGEY 9606 17098746 t miannu "Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321" SIGNOR-150669 AKT1 protein P31749 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni "When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner." SIGNOR-252549 SELPLG protein Q14242 UNIPROT SELE protein P16581 UNIPROT up-regulates binding 9606 BTO:0000130 9024699 t gcesareni "PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro." SIGNOR-46330 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1647 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248806 NRP1 protein O14786 UNIPROT "CoV2 spike protein-NRP1" complex SIGNOR-C267 SIGNOR "form complex" binding 9606 BTO:0000007 other t https://doi.org/10.1101/2020.06.07.137802 miannu "Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system To determine whether SARS-CoV-2 uses NRP1 for virus entry, we generated replication deficient lentiviruses pseudotyped with SARS-CoV-2 spike protein (S) that drive expression of green fluorescent protein (GFP) upon infection. When expressed alone, ACE2 rendered cells susceptible to infection (Fig. 1a). NRP1 alone allowed lower, yet detectable levels of infection, both in HEK-293T and in Caco2 cells (Fig. 1a,b), while cells transfected with plasmids encoding only TMPRSS2 were not infected (Fig. 1a). The co-expression of TMPRSS2 with either ACE2 or NRP1 potentiated the infection, with ACE2 together with TMPRSS2 being twice as efficient as NRP1 with TMPRSS2 (Fig. 1c)" SIGNOR-261672 S protein P0DTC2 UNIPROT "CoV2 spike protein-NRP1" complex SIGNOR-C267 SIGNOR "form complex" binding 9606 BTO:0000007 other t https://doi.org/10.1101/2020.06.07.137802 miannu "Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system To determine whether SARS-CoV-2 uses NRP1 for virus entry, we generated replication deficient lentiviruses pseudotyped with SARS-CoV-2 spike protein (S) that drive expression of green fluorescent protein (GFP) upon infection. When expressed alone, ACE2 rendered cells susceptible to infection (Fig. 1a). NRP1 alone allowed lower, yet detectable levels of infection, both in HEK-293T and in Caco2 cells (Fig. 1a,b), while cells transfected with plasmids encoding only TMPRSS2 were not infected (Fig. 1a). The co-expression of TMPRSS2 with either ACE2 or NRP1 potentiated the infection, with ACE2 together with TMPRSS2 being twice as efficient as NRP1 with TMPRSS2 (Fig. 1c)" SIGNOR-261671 ROS stimulus SIGNOR-ST2 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates 9534 BTO:0004055 12646569 f lperfetto "We have also provided evidence that the mitochondrial GSTA4-4 level markedly increases in COS cells under oxidative stress conditions, suggesting its critical role in maintaining the GSH homeostasis under conditions of chemical and oxidative stress" SIGNOR-264797 CYTH2 protein Q99418 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 14565977 f miannu "ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha" SIGNOR-264909 MARCHF5 protein Q9NX47 UNIPROT SOD1 protein P00441 UNIPROT "down-regulates quantity" ubiquitination 9606 19741096 t miannu "Cycloheximide-chase assay in the Neuro2a cells indicated that MITOL overexpression promoted mSOD1 degradation and suppressed both the mitochondrial accumulation of mSOD1 and mSOD1-induced reactive oxygen species generation.|In vitro ubiquitination assay revealed that MITOL directly ubiquitinates mSOD1." SIGNOR-278654 GABRB3 protein P28472 UNIPROT "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR "form complex" binding 9606 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263772 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto "Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action." SIGNOR-93554 WWTR1 protein Q9GZV5 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 22153608 t "Runx family members play key roles in regulating mesenchymal stem cell differentiation during bone formation, and therefore the regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation." gcesareni "Taz binding to the transcription factor runx2 promotes osteoblast lineage specification, whereas taz binding to the transcription factor ppargamma inhibits adipogenesis." SIGNOR-195218 crizotinib chemical CHEBI:64310 ChEBI MET protein P08581 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258102 AMPK complex SIGNOR-C15 SIGNOR HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 21892142 t lperfetto "Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)." SIGNOR-216558 AVPR1A protein P37288 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256948 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 18439900 t lperfetto "The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress." SIGNOR-216430 miR-155 mirna URS000062749E_9606 RNAcentral MYC protein P01106 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 19933931 t "On the basis of bioinformatics tools, biochemical assays, and in vivo models, we demonstrate that (1) insulin-like growth factor-1 (IGF-1) and IGF-1 receptor are targets of miR-1" SIGNOR-255721 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1090 TNTGFPRyPNDSVYA 9606 14711813 t llicata "Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites." SIGNOR-121145 SPOP protein O43791 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "down-regulates quantity by destabilization" binding 9606 24239470 t miannu "Mutations in SPOP represent the most common point mutations in primary prostate cancer,with recurrent mutations in SPOP in 6% to 15% of multiple independent cohorts. Wild-type SPOP will bind and promote the degradation of SRC-3,whereas prostate cancer–derived SPOP mutants lose this ability,leading to increased androgen signaling in certain model systems." SIGNOR-251529 BCL2L2 protein Q92843 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni "Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax." SIGNOR-152989 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr642 CIAGSPLtPRRVTEV 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104703 "CKM complex" complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 15546612 t gcesareni "Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo." SIGNOR-273150 PRKCB protein P05771 UNIPROT ORAI1 protein Q96D31 UNIPROT down-regulates phosphorylation Ser30 TTSGSRRsRRRSGDG 9606 20534587 t llicata "We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30." SIGNOR-166044 KDM6A protein O15550 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" demethylation 9606 24561908 t "This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions." miannu "Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation." SIGNOR-265360 MAPK3 protein P27361 UNIPROT MAGEA11 protein P43364 UNIPROT up-regulates phosphorylation Ser174 ESPSPPQsPQEESFS 9606 BTO:0000848 19828458 t llicata "Mage-11 ser-174 appears to be a post-translational regulatory site phosphorylated by erk1, based on the inhibitory effect of the s174a mutation in the context of shorter ar nh2-terminal fragments (19), and the greater transcriptional activity of gal-mage-11 fusion proteins containing the s174d phosphomimetic." SIGNOR-188466 SEC13 protein P55735 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262091 Ub:E2 complex SIGNOR-C497 SIGNOR RNF152 protein Q8N8N0 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271199 NF2 protein P35240 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 24012335 t "The opposite changes in Lats/YAP and Mst1/2 phosphorylation upon loss of NF2 therefore argue against the generally assumed linear model in which NF2 signals through activation of Mst1/3" flangone "As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2" SIGNOR-202604 AGTR2 protein P50052 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto "There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3" SIGNOR-252268 MECP2 protein P51608 UNIPROT MET protein P08581 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000007 24150225 t Luana "MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2" SIGNOR-264683 TRIM27 protein P14373 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000671 12807881 f miannu "Here we show that ectopic expression of rfp in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria." SIGNOR-256667 SRF protein P11831 UNIPROT ACTA2 protein P62736 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 15269336 f gcesareni "The primary goal of the present study was to directly assess the role of the degeneracy of sm ?-Actin cargs in the regulation of smc-selective gene expression in vivo. in addition, our present studies address the possible role of this carg degeneracy, and the smc-selective srf coactivator myocardin, in regulating differential expression of carg-dependent smc genes and growth regulatory genes." SIGNOR-126923 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 12763138 t gcesareni "The stat3-mediated transactivation was reduced by blocking the stat3 serine phosphorylation with the mek inhibitor u0126 or by expression of kinase-inactive msk1." SIGNOR-101251 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000093 8790407 t Luana "These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens." SIGNOR-269755 HMGB2 protein P26583 UNIPROT POU2F2 protein P09086 UNIPROT "up-regulates activity" binding 10090 7720710 t 2 miannu "HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins" SIGNOR-240108 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser17 ARRSYVSsGEMMVGG -1 7822264 t llicata "On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II." SIGNOR-250627 KLKB1 protein P03952 UNIPROT MST1 protein P26927 UNIPROT "up-regulates activity" cleavage Arg483 DQRRSKLrVVGGHPG -1 10068459 t miannu "Proteolytic cleavage of pro-MSP at a single site yields active MSP, a disulfide-linked alphabeta-chain heterodimer. human kallikrein cleaved only at Arg483–Val484, the cleavage site for formation of a- and b-chains." SIGNOR-256511 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Gsk3b phosphorylates tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171046 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral VEGFA protein P15692 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004094 26675258 t Parnian "Overexpression of miR-30a reverts EMT phenotype and impairs cell invasion and plasticity, and VEGF production" SIGNOR-278001 "4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid" chemical CHEBI:91366 ChEBI AURKA protein O14965 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258250 HSPH1 protein Q92598 UNIPROT HSPA1A protein P0DMV8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19754877 f miannu "Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress." SIGNOR-255242 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI "down-regulates quantity" "chemical modification" 9606 16115609 t "The microsomal heme oxygenase system consists of heme oxygenase (HO) and NADPH-cytochrome P450 reductase, and plays a key role in the physiological catabolism of heme which yields biliverdin, carbon monoxide, and iron as the final products. Heme degradation proceeds essentially as a series of autocatalytic oxidation reactions involving heme bound to HO" SIGNOR-259333 ATP(4-) smallmolecule CHEBI:30616 ChEBI 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI "up-regulates quantity" "precursor of" 23258413 t lperfetto "Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family." SIGNOR-276594 POMC protein P01189 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates activity" 9606 BTO:0000848 16274845 f miannu "Alpha-MSH is an anti-inflammatory peptide which signals by binding to the melanocortin-1 receptor (MC1R) and elevating cyclic AMP in several different cells and tissues. The carboxyl terminal peptides of alpha-MSH (KPV/GKPV) are the smallest minimal sequences that prevent inflammation, but it is not known if they operate via MC1R or cyclic AMP. Immobilized alpha-melanocyte stimulating hormone 10-13 (GKPV) inhibits tumor necrosis factor-alpha stimulated NF-kappaB activity." SIGNOR-252371 GLI1 protein P08151 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209620 PPP2CA protein P67775 UNIPROT ELF1 protein P32519 UNIPROT "down-regulates activity" dephosphorylation Thr231 CPKYIKWtQREKGIF 9606 18714041 t "Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response" SIGNOR-248634 TSC2 protein P49815 UNIPROT TSC complex SIGNOR-C101 SIGNOR "form complex" binding 9606 12172553 t lperfetto "TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR)." SIGNOR-217913 MAP4K2 protein Q12851 UNIPROT PSMD2 protein Q13200 UNIPROT "up-regulates activity" phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu "Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B). " SIGNOR-273900 retinal smallmolecule CHEBI:15035 ChEBI "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "precursor of" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265127 TP63 protein Q9H3D4 UNIPROT PLEC protein Q15149 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 28595999 t lperfetto "Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets." SIGNOR-263279 ID1 protein P41134 UNIPROT TCF12 protein Q99081 UNIPROT "down-regulates activity" binding 10090 BTO:0004058 SIGNOR-C128 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241104 MLH1/PMS2 complex SIGNOR-C59 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 29175432 f "MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans" SIGNOR-257600 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Ser78 NKDQHSIsYTLSRAQ -1 19264966 t miannu "The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites." SIGNOR-276133 PPP2CA protein P67775 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR "form complex" binding 9606 23454242 t gcesareni "[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity." SIGNOR-243433 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 11154281 t lperfetto "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis." SIGNOR-249134 SMOC1 protein Q9H4F8 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT "up-regulates quantity" 10090 30127878 f lperfetto "In conclusion, the results of the present study suggested that SMOC1 silencing suppressed the Ang II-induced myocardial fibrosis of mouse MFBs through affecting the BMP2/Smad signaling pathway." SIGNOR-260403 TACR2 protein P21452 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256736 SNAI1 protein O95863 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000599 27239445 f "Marta Tosoni" "Compelling evidence has demonstrated that SNAI1 plays a key role in the induction of EMT" SIGNOR-278097 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 9753485 t "Crohn's Disease" gcesareni SIGNOR-251690 lurasidone chemical CHEBI:70735 ChEBI ADRA2C protein P18825 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 20404009 t Luana "Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors." SIGNOR-257837 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT "up-regulates activity" phosphorylation Ser185 KKREKRRsTSRQFVD 9606 BTO:0000567 14744859 t llicata "It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1" SIGNOR-250587 MYC protein P01106 UNIPROT USP22 protein Q9UPT9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26049753 f "USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells." SIGNOR-261560 FUS protein P35637 UNIPROT MPHOSPH9 protein Q99550 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262804 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr519 EDPYAGStDENTDSE 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523" SIGNOR-165431 TGFB1 protein P01137 UNIPROT LPL protein P06858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 11742878 f "Regulation of expression" miannu "TGF-β1 inhibited gene expression and cell surface activity of LPL. TGF-β1 did not have an effect on LPL activity when it was added directly to the LPL activity assay (data not shown); however, as shown in the Table, TGF-β1 significantly reduced LPL mRNA by 55.0%" SIGNOR-251847 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" phosphorylation 9606 21460634 t lperfetto "Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit." SIGNOR-209916 MAPK3 protein P27361 UNIPROT KARS1 protein Q15046 UNIPROT up-regulates phosphorylation Ser207 PYEITLLsPCLHMLP 9606 19524539 t gcesareni "Lysrs serves as a key signaling molecule in the immune response by regulating gene expression. Lysrs was phosphorylated on serine 207 in a mapk-dependent manner, released from the multisynthetase complex, and translocated into the nucleus." SIGNOR-186125 vildagliptin chemical CHEBI:135285 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" 9606 19149538 t Luana "Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched." SIGNOR-257812 HSD17B1 protein P14061 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI "up-regulates quantity" "chemical modification" -1 8994190 t Luana "Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues. " SIGNOR-269758 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Thr330 TRLSRSRtASLTSAA 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 t llicata "Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344" SIGNOR-129676 CDK1 protein P06493 UNIPROT USP24 protein Q9UPU5 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2604 HLQQGSEsPMMIGEL 9606 BTO:0000018 27991932 t lperfetto "Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604." SIGNOR-275603 PPM1D protein O15297 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" dephosphorylation Thr68 SSLETVStQELYSIP -1 16311512 t "an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C." SIGNOR-248318 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT "down-regulates activity" phosphorylation Thr7 tPCSSMSN 9606 26057687 t miannu "Our findings illustrate a unique molecular mechanism underlying PLK1 dependent inactivation of NDR1 and define a novel role for PLK1-NDR1 signaling cascade in governing accurate spindle orientation to ensure faithful chromosome segregation in mitosis.|PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1 dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis." SIGNOR-278420 SBDS protein Q9Y3A5 UNIPROT EFL1 protein Q7Z2Z2 UNIPROT up-regulates binding 9606 BTO:0001271 21536732 t miannu "Sbds stimulates 60s-dependent gtp hydrolysis by efl1" SIGNOR-173533 NTHL1 protein P78549 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275717 "imatinib methanesulfonate" chemical CHEBI:31690 ChEBI BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000740 15206509 t miannu "Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia." SIGNOR-259357 GATA2 protein P23769 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12432220 f irozzo "Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression." SIGNOR-256056 GGCX protein P38435 UNIPROT F7 protein P08709 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265919 GRK6 protein P43250 UNIPROT LTB4R protein Q15722 UNIPROT "down-regulates activity" phosphorylation Thr308 VAKLLEGtGSEASST 9534 BTO:0000298 12077128 t "Thr(308) is a major residue involved in GRK6-mediated desensitization of BLT1 signaling." SIGNOR-251213 CSNK2A1 protein P68400 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser170 KEGDVDVsDSDDEDD 9606 18559419 t llicata "Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation." SIGNOR-178939 HOXC11 protein O43248 UNIPROT HNF1A protein P20823 UNIPROT up-regulates 9606 9582375 f miannu "The observed stimulatory effect of hoxc11 on hnf1_ may be due to a similar stabilizing effect on hnf1_ dna binding and/or an increase in transcriptional activity of hnf1_." SIGNOR-57484 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT "down-regulates activity" phosphorylation Thr407 EIKSIDDtSNFDEFP 9606 26057687 t miannu "Our findings illustrate a unique molecular mechanism underlying PLK1 dependent inactivation of NDR1 and define a novel role for PLK1-NDR1 signaling cascade in governing accurate spindle orientation to ensure faithful chromosome segregation in mitosis.|PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1 dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis." SIGNOR-278421 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT "down-regulates activity" phosphorylation Thr183 TLLMKKDtLTEEETQ 9606 26057687 t miannu "Our findings illustrate a unique molecular mechanism underlying PLK1 dependent inactivation of NDR1 and define a novel role for PLK1-NDR1 signaling cascade in governing accurate spindle orientation to ensure faithful chromosome segregation in mitosis.|PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1 dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis." SIGNOR-278422 BRD7 protein Q9NPI1 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270601 sunitinib chemical CHEBI:38940 ChEBI PDGFRA protein P16234 UNIPROT down-regulates "chemical inhibition" 9606 21423276 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-172923 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252751 MAPK1 protein P28482 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 t gcesareni "Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis." SIGNOR-134837 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr937 ADEEPEStPVPLLGS 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159582 PRKCG protein P05129 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251633 TWIST1 protein Q15672 UNIPROT ATM protein Q13315 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255511 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258091 LBX1 protein P52954 UNIPROT SNAI1 protein O95863 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 19651985 t Luana "Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively " SIGNOR-266053 RFX5 protein P48382 UNIPROT HLA-DRA protein P01903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000460 10586057 t Luana "In this report, we correlate the loss of IFN-γ induction of MHC class II genes with the identification of a molecular defect in an essential regulator, namely RFX5. | We have further confirmed this finding by showing that new RFX5 leucine mutants created in vitro are incapable of transactivating a class II promoter, suggesting the identification of residues essential for RFX activity." SIGNOR-266228 Alkannin chemical CHEBI:2578 ChEBI PKM protein P14618 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000093;BTO:0000018 21516121 t lperfetto "Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2." SIGNOR-262009 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr230 DSKEIFLtVPVGGGE 9606 19530738 t lperfetto "We found that substitutions at borealin t230, recently identified as an mps1 phosphorylation site, can modulate the dimerization state of borealin. Mutation of this single residue to alanine or valine impairs aurora b activity during mitosis and causes chromosome segregation defects" SIGNOR-186147 HIF1A protein Q16665 UNIPROT PDK1 protein Q15118 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003291 16517405 t miannu "Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA." SIGNOR-267444 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser176 TNAENTAsQSPRTRG 9606 BTO:0000567 19789335 t lperfetto "we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1." SIGNOR-109680 AATK protein Q6ZMQ8 UNIPROT STK39 protein Q9UEW8 UNIPROT down-regulates 9606 17267545 f gcesareni "Taken together, our data are consistent with aatyk1 indirectly inhibiting the spak/wnk4 activation of the cotransporter by scaffolding an inhibitory phosphatase in proximity to a stimulatory kinase." SIGNOR-152921 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t Manara "Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A" SIGNOR-260834 AKT1 protein P31749 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21619873 t gcesareni "Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5" SIGNOR-252514 CDK9 protein P50750 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15546612 f gcesareni "Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells." SIGNOR-130703 ITGB3BP protein Q13352 UNIPROT "CCAN complex" complex SIGNOR-C365 SIGNOR "form complex" binding 9606 BTO:0000567 18007590 t lperfetto "CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S)." SIGNOR-265206 PIM1 protein P11309 UNIPROT FLT3 protein P36888 UNIPROT "up-regulates quantity" phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 BTO:0005720 24040307 t "Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway." SIGNOR-259927 BCL7A protein Q4VC05 UNIPROT "Embryonic stem cell-specific SWI/SNF" complex SIGNOR-C484 SIGNOR "form complex" binding 10090 BTO:0001086 19279220 t miannu "An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency" SIGNOR-270723 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser173 MLETLSQsPPKGVTI 9606 BTO:0000664 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262914 INPP4B protein O15327 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation 9606 24070612 t miannu "Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and PTP activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation.|Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and protein tyrosine phosphatase activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation." SIGNOR-277106 NUP210 protein Q8TEM1 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262072 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207251 TLR4 protein O00206 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." SIGNOR-261929 ITCH protein Q96J02 UNIPROT LATS1 protein O95835 UNIPROT "down-regulates quantity" destabilization 9606 BTO:0002181 31569999 t "Marta Tosoni" "These findings suggest that Galpha13 induced phosphorilation of LATS1 at S909 recruits ITCH to trigger LATS1 degradation, leading to EMT-related phenotypes" SIGNOR-278052 dopamine smallmolecule CHEBI:18243 ChEBI DRD4 protein P21917 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257480 BRAF protein P15056 UNIPROT PAX3 protein P23760 UNIPROT "up-regulates activity" phosphorylation Ser205 APQSDEGsDIDSEPD 9606 27906130 t miannu "BRAF activates PAX3 to control muscle precursor cell migration during forelimb muscle development.|We found that BRAF clearly induced phosphorylation of PAX3 at Ser205 in both cell types (XREF_FIG)." SIGNOR-278435 CDK1 protein P06493 UNIPROT CREM protein Q03060 UNIPROT "down-regulates quantity" phosphorylation Ser271 QGVVMAAsPGSLHSP 9606 BTO:0001033 21767532 t miannu "In this report data is presented demonstrating that ICER is phosphorylated by the mitotic kinase cdk1. Phosphorylation of ICER on a discrete residue targeted ICER to be monoubiquitinated. Different from unphosphorylated, phosphorylated and polyubiquitinated ICER, monoubiquitinated ICER was found to be cytosolic. Taken together, these results hinted on a mechanism for the observed abnormal subcellular localization of ICER in human prostate tumors." SIGNOR-276346 FYN protein P06241 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 19917775 t miannu "Because Fyn deletion prevented FAK phosphorylation at tyrosine residues 397 and 576 (XREF_FIG), we generated a phosphorylation mimicking mutant of FAK to test whether restoring FAK phosphorylation in the fyn -/- mouse lung could restore lung vascular permeability responses to PAR1 agonist to the level seen in WT mice.|Our findings that interaction of activated FAK with p120-catenins subsequent to Fyn activation of FAK facilitates reannealing of AJ leading to reestablishment of the basal endothelial barrier suggest that the Fyn-FAK pathway plays a critical role in restoring endothelial barrier function." SIGNOR-278441 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 7538655 f lperfetto "We demonstrate that il4r triggering induced the tyrosine phosphorylation of jak3" SIGNOR-34756 adenosine smallmolecule CHEBI:16335 ChEBI ADORA1 protein P30542 UNIPROT "up-regulates activity" binding -1 14662005 t Luana "Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3." SIGNOR-268419 ASH2L protein Q9UBL3 UNIPROT TBX1 protein O43435 UNIPROT "up-regulates activity" binding 9606 20463296 t Regulation miannu "Tbx1 interacts with Ash2l in both yeast and mammalian cells and Ash2l acts as a transcriptional co-activator in luciferase reporter assays." SIGNOR-251868 MAPK1 protein P28482 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates activity" phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 t miannu "Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events." SIGNOR-262841 NEK7 protein Q8TDX7 UNIPROT TERF1 protein P54274 UNIPROT "up-regulates activity" phosphorylation Ser114 AIIHGLSsLTACQLR 9606 28216227 t miannu "Using KR-TRF2 to induce telomeric DNA damage, we found that TRF1 degradation was also exacerbated when ATM was inhibited after damage induction (55.2% of mock treated cells) (XREF_FIG), indicating that the ATM signal pathway is required for Nek7 mediated TRF1 stabilization.|We show that Nek7 phosphorylates TRF1 at Ser114 and in turn maintains stability of the shelterin complex at telomeres." SIGNOR-278447 DIO3 protein P55073 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "chemical modification" 9606 12746313 t scontino "Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144." SIGNOR-266942 "Immunoglobulin delta heavy chain" protein P0DOX3 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR "form complex" binding 9606 BTO:0000776 20176268 t scontino "Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes." SIGNOR-268195 NFATC2 protein Q13469 UNIPROT NF90-NF45 complex SIGNOR-C443 SIGNOR "up-regulates activity" binding 9606 BTO:0000782 33555115 t miannu "Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2-like sequences in rDNA promoter upon T-cell activation in vitro. NF45/NF90‐mediated rDNA transcription contributes to T‐cell activation by interacting with NFATc2 in the nucleolus" SIGNOR-268492 DGC complex SIGNOR-C217 SIGNOR "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR "up-regulates quantity" binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu " In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses." SIGNOR-265433 telmisartan chemical CHEBI:9434 ChEBI AGTR1 protein P30556 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9878991 t miannu "Telmisartan is a nonpeptide angiotensin II receptor antagonist which selectively and insurmountably inhibits the angiotensin II AT1 receptor subtype without affecting other receptor systems involved in cardiovascular regulation." SIGNOR-259072 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT down-regulates phosphorylation Tyr54 HTVEAVAyAPKKELI 9606 9461559 t llicata "Here we demonstrate that c-abl interacts constitutively with rad51. We show that c-abl phosphorylates rad51 on tyr-54 in vitro. The results also show that treatment of cells with ionizing radiation induces c-abl-dependent phosphorylation of rad51. Phosphorylation of rad51 by c-abl inhibits the binding of rad51 to dna and the function of rad51 in atp-dependent dna strand exchange reactions." SIGNOR-55482 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192620 SMAD1 protein Q15797 UNIPROT GADD45G protein O95257 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268937 MED22 protein Q15528 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266661 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 t llicata "In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites." SIGNOR-250935 ziprasidone chemical CHEBI:10119 ChEBI HTR1E protein P28566 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258503 BACE1 protein P56817 UNIPROT APP protein P05067 UNIPROT "up-regulates activity" cleavage 28923680 t "Beta-secretase 1 (BACE1) cleaves the type-I transmembrane protein APP to form the N-terminus of Aβ." SIGNOR-255480 ESR2 protein Q92731 UNIPROT TGFA protein P01135 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 11517191 f "ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression" SIGNOR-253944 AKT2 protein P31751 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251624 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176805 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RARG protein P13631 UNIPROT "up-regulates activity" "chemical activation" 9606 18321241 t miannu "Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma)." SIGNOR-259236 ITGB2 protein P05107 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253204 KARS1 protein Q15046 UNIPROT "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR "form complex" binding 9606 32644155 t miannu "In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes)." SIGNOR-270353 CDC25A protein P30304 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 BTO:0000093 15672448 t gcesareni "We found that cdc25a physically interacted with and de-phosphorylated phospho-erk both in vitro and in cell culture." SIGNOR-133392 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT down-regulates relocalization 9606 23151663 t gcesareni "This is counteracted by respondin 1, which induces znrf3 internalization" SIGNOR-199629 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120060 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-236206 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 t Manara "Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A" SIGNOR-260835 SRC protein P12931 UNIPROT INPPL1 protein O15357 UNIPROT up-regulates phosphorylation Tyr987 SFNNPAYyVLEGVPH 9606 12235291 t lperfetto "Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo." SIGNOR-92935 SCARB1 protein Q8WTV0 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" binding 10090 26059978 t Giulio "Importantly, coimmunoprecipitation of SR-BI and Src demonstrated that the two proteins are directly associated in WT macrophages (Fig. 7B), suggesting that SR-BI plays a direct role in activation of Src in macrophages." SIGNOR-260314 CAD protein P27708 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "down-regulates quantity" "chemical modification" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267419 "SAE1/SAE2 complex" complex SIGNOR-C294 SIGNOR MBD4 protein O95243 UNIPROT "up-regulates activity" sumoylation Lys137 KNGETSLkPEDFDFT 31476572 t lperfetto "MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro." SIGNOR-275679 GOPC protein Q9HD26 UNIPROT CFTR protein P13569 UNIPROT down-regulates binding 9606 11707463 t miannu "Cal binds to cftr / cal affects insertion of cftr to the plasma membrane as well as its half-life in the plasma membrane." SIGNOR-111671 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "down-regulates activity" phosphorylation Ser105 TGAGAAGsPAQQHAH 26375055 t lperfetto "We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity" SIGNOR-276524 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 10090 21145499 t milica "Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component." SIGNOR-170361 PPM1A protein P35813 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates activity" dephosphorylation Ser127 PQHVRAHsSPASLQL 9606 33630828 t lperfetto "Although the authors show an in vitro kinase assay where PPM1A supposedly dephosphorylates YAP on Ser127, Fig. 4A lacks a positive control to ensure that PPM1A purified from cells is active.|The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration." SIGNOR-276984 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser31 LKLGSGPsIKALDGR 9606 BTO:0000567 24781523 t miannu "CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase" SIGNOR-276382 CSNK2A1 protein P68400 UNIPROT ACE protein P12821 UNIPROT "up-regulates activity" phosphorylation Ser1299 SHGPQFGsEVELRHS 9823 BTO:0001176 12386153 t lperfetto "CK2 coprecipitated with ACE from endothelial cells, and CK2 phosphorylated both ACE and a peptide corresponding to the cytoplasmic tail. Mutation of serine(1270) within the CK2 consensus sequence almost abolished ACE phosphorylation.|These results indicate that the CK2-mediated phosphorylation of ACE regulates its retention in the plasma membrane and may determine plasma ACE levels." SIGNOR-264425 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates phosphorylation Ser337 FVQLRRKsDLETSEP 9606 SIGNOR-C13 17959673 t llicata "In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab." SIGNOR-158595 TOP1 protein P11387 UNIPROT ARNTL protein O00327 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 22904072 t miannu "We examined the mechanism of topoisomerase I (Top1) to understand the role of the unique chromatin structure in Bmal1 gene regulation.  Promoter assays showed that the Top1-binding site is required for transcriptional suppression and that it functions cooperatively with the distal RORE, supporting that Bmal1 transcription is upregulated by Top1 inhibition. " SIGNOR-277354 MK-2206 chemical CHEBI:67271 ChEBI AKT2 protein P31751 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001286 21841310 t gcesareni "Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation." SIGNOR-176046 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t "We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction" SIGNOR-259919 ATM protein Q13315 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Ser314 SHEDLPAsQERSEVN 9606 22099307 t lperfetto "We also demonstrate that mitotically activated atm phosphorylates bub1, a critical kinetochore protein, on ser314. Atm-mediated bub1 ser314 phosphorylation is required for bub1 activity and is essential for the activation of the spindle checkpoint" SIGNOR-177276 CDK1 protein P06493 UNIPROT TFCP2L1 protein Q9NZI6 UNIPROT "up-regulates activity" phosphorylation Thr177 HCISTEFtPRKHGGE 9606 31709755 t miannu "In addition, overexpression of TFCP2L1 and CDK1 in T24 cells increased clonogenic activity in a clonogenic limiting dilution assay (Fig\u00a05H), confirming the importance of CDK1\u2010TFCP2L1 pathways for the stemness features of BC cells.High levels of co\u2010expression of p\u2010TFCP2L1 and CDK1 were associated with distant metastasis in our cohort of BC patients (Table\u00a01).|Tfcp2l1 Thr177 phosphorylation by CDK1 is essential for proliferation and cell cycle progression of ESCs.|Tfcp2l1 is phosphorylated at Thr177 by CDK1." SIGNOR-278472 TYMS protein P04818 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI "up-regulates quantity" "chemical modification" 9606 21876188 t lperfetto "In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR." SIGNOR-268232 DYRK1A protein Q13627 UNIPROT SIRT1 protein Q96EB6 UNIPROT "up-regulates activity" phosphorylation Thr530 YLSELPPtPLHVSED 9606 20167603 t miannu "DYRK1A and DYRK3 directly phosphorylate SIRT1 at Thr(522), promoting deacetylation of p53.|DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1." SIGNOR-278473 MAP3K7 protein O43318 UNIPROT SMAD1 protein Q15797 UNIPROT "up-regulates activity" phosphorylation Ser465 HNPISSVs 9606 19536134 t miannu "This analysis showed that phosphorylation of Smad1 at the C-terminal serines S463 and S465 was increased by co-expression of constitutively active TAK1." SIGNOR-279420 INPP5D protein Q92835 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 12421919 t gcesareni "Two inositol phosphatases implicated in the degradation of PI(3, 4, 5)P3, namely the 5_ phosphatase Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and the 3_ phosphatase and tensin homolog deleted on chromosome ten" SIGNOR-252428 ATM protein Q13315 UNIPROT RAD17 protein O75943 UNIPROT unknown phosphorylation Ser656 SASELPAsQPQPFSA 9606 10608806 t lperfetto "We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself." SIGNOR-73524 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-81161 TRIB2 protein Q92519 UNIPROT PKM protein P14618 UNIPROT "up-regulates activity" phosphorylation Ser37 MCRLDIDsPPITARN 9606 BTO:0000018 35790734 t miannu " This study demonstrated that TRIB2, not a ""pseudokinase"", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells. " SIGNOR-275431 ERBB2 protein P04626 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 23027125 t miannu "HER2 stabilizes EGFR and itself by altering autophosphorylation patterns in a manner that overcomes regulatory mechanisms and promotes proliferative and transformation signaling.|While blocking autophosphorylation on the c-Cbl and the Grb2 binding sites, HER2 promotes EGFR phosphorylation on Y1173 and its own phosphorylation on Y1248 and Y1221/1222 ( xref )." SIGNOR-278474 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-183636 CDK2 protein P24941 UNIPROT PTHLH protein P12272 UNIPROT down-regulates phosphorylation Thr121 YKEQPLKtPGKKKKG 9606 10373465 t llicata "Phosphorylation at the cyclin-dependent kinases site (thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization" SIGNOR-68548 RIMBP2 protein O15034 UNIPROT RIMS3 protein Q9UJD0 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264371 MAPK1 protein P28482 UNIPROT PRDX6 protein P30041 UNIPROT up-regulates phosphorylation Thr177 TAEKRVAtPVDWKDG 9606 BTO:0000763 19140803 t miannu "These results show that the mapks can mediate phosphorylation of prdx6 at thr-177 with a consequent marked increase in its aipla(2) activity." SIGNOR-183379 ABT-737 chemical CID:11228183 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271;BTO:0000776;BTO:0000785 17200714 t gcesareni "A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells." SIGNOR-151781 NOTCH1 protein P46531 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 BTO:0000776 9528794 t gcesareni "We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk." SIGNOR-56150 NANOG protein Q9H9S0 UNIPROT GATA4 protein P43694 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 22795133 f lperfetto "Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)" SIGNOR-253162 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation Ser189 DEEFREPsTGKTCLP -1 19661060 t miannu "We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4." SIGNOR-276233 ADSS1 protein Q8N142 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 10496970 f miannu "Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP." SIGNOR-267835 quetiapine chemical CHEBI:8707 ChEBI HTR1F protein P30939 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258536 DUSP9 protein Q99956 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 BTO:0000887 11988087 t "This interaction is observed for Mus musculus Pyst3 gene, which encodes for DUSP9" gcesareni "These properties define the ability of this enzyme to dephosphorylate and inactivate erk1/2 and p38a, but not jnk (c-jun n-terminal kinase) in vivo." SIGNOR-87150 FYN protein P06241 UNIPROT DAB1 protein O75553 UNIPROT "down-regulates activity" phosphorylation 9606 21534960 t miannu "Tyrosine phosphorylation of Dab1 by Fyn inhibits its interaction with APP, while increasing its interaction with Fyn." SIGNOR-278476 FYN protein P06241 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Tyr261 PFEGDNIyKLFENIG 9606 20142099 t miannu "Moreover, Fyn kinase directly phosphorylated LKB1 on tyrosine 261 and 365 residues and mutations of these sites resulted in LKB1 export into the cytoplasm and increased AMPK phosphorylation." SIGNOR-278477 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni "Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation." SIGNOR-160982 SOX3 protein P41225 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10549281 t gcesareni "Two additional sox proteins, xsox17alfa and xsox3, likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity." SIGNOR-72039 PFAS protein O15067 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "down-regulates quantity" "chemical modification" 9606 33179964 t miannu "The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure." SIGNOR-267310 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr690 PLNSDVQyTEVQVSS 9606 BTO:0000007 12972546 t miannu "PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1." SIGNOR-262867 ESR1 protein P03372 UNIPROT ESR2 protein Q92731 UNIPROT up-regulates binding 9606 10022879 t tpavlidou "It was recently shown that er? And er? Could form a heterodimer complex both in vitro and in vivo" SIGNOR-64427 FRK protein P42685 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr1552 HDLTETSyLPRQDLE 9606 BTO:0003323 29156836 t miannu "Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. Rak-mediated tyrosine phosphorylation of BRCA1 is essential for its stability and function" SIGNOR-275454 GRID2 protein O43424 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264952 TYSND1 protein Q2T9J0 UNIPROT TYSND1 protein Q2T9J0 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000567 22002062 t miannu "Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer." SIGNOR-261053 RNF4 protein P78317 UNIPROT KDM5B protein Q9UGL1 UNIPROT "down-regulates quantity by destabilization" sumoylation 9606 33859667 t SaraGualdi "Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015)." SIGNOR-271575 CDK5 protein Q00535 UNIPROT CLOCK protein O15516 UNIPROT up-regulates phosphorylation Thr451 AVSDPSStPTKIPTD 9606 24235147 t lperfetto "Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock." SIGNOR-203227 YWHAE protein P62258 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 12042314 t miannu "14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue." SIGNOR-88297 XRCC3 protein O43542 UNIPROT "D1-D2-G-X3 complex" complex SIGNOR-C301 SIGNOR "form complex" binding 9606 18212739 t lperfetto "These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). " SIGNOR-263257 KLF4 protein O43474 UNIPROT THBD protein P07204 UNIPROT "up-regulates activity" "transcriptional regulation" 9606 19661484 f miannu "Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4." SIGNOR-254546 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation Thr526 GEAGGPLtPRRVSSD 9606 7588608 t lperfetto "Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf" SIGNOR-29505 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BS1 protein P57053 UNIPROT "down-regulates activity" monoubiquitination Lys35 RKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271984 atomoxetine chemical CHEBI:127342 ChEBI SLC6A3 protein Q01959 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2." SIGNOR-259070 SOAT1 protein P35610 UNIPROT "cholesteryl ester" smallmolecule CHEBI:17002 ChEBI "down-regulates quantity" "chemical modification" 9606 31848472 t miannu "Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters" SIGNOR-265160 MAK protein P20794 UNIPROT CDH1 protein P12830 UNIPROT down-regulates phosphorylation 9606 21986944 t miannu "Finally, we speculate that there are two mechanisms whereby MAK inactivates CDH1 : the first is kinase dependent inactivation, modeled after CDK, where phosphorylation dissociates CDH1 from APC/C; the second is through physical binding of CDH1 with MAK.|These results suggest a cell cycle-dependent phosphorylation of CDH1 by MAK." SIGNOR-278486 GALT protein P07902 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI "down-regulates quantity" "chemical modification" 9606 2011574 t miannu "Cytosolic galactose-1-phosphate uridylyltransferase (GALT) catalyzes the reaction of alpha-D-galactose 1-phosphate and UDP glucose to form D-glucose 1-phosphate and UDP galactose" SIGNOR-280268 MAPK3 protein P27361 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates phosphorylation Ser52 MPHTETVsPLPSSMD 9606 24793005 t miannu "We found that activation of ERK1 signaling inhibited transactivation activity of Nanog.|We showed the direct phosphorylation of Nanog by ERK1 and clearly showed that Ser52 is the major phosphorylation site and Ser65 is weakly phosphorylated by ERK1." SIGNOR-278487 MYC protein P01106 UNIPROT GLS protein O94925 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001518 19219026 f Luana "Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. " SIGNOR-268038 BRCA1 protein P38398 UNIPROT ATM protein Q13315 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001130 22832221 f gcesareni "Brca1/e2f1/ctipbinding to atm promoter activates atm transcription." SIGNOR-198467 PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 15175348 t lperfetto "In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation" SIGNOR-244934 GRIP1 protein Q9Y3R0 UNIPROT GRIPAP1 protein Q4V328 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 10896157 t Giorgia "We have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. GRIP1 has seven PDZ domains, which mediate protein–protein interactions, allowing the recruitment of GRASP-1 to a large signal-transducing complex" SIGNOR-260638 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT "up-regulates activity" phosphorylation Ser526 PVKEEAKsPAEAKSP 10116 BTO:0000938 9592082 t lperfetto "The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation." SIGNOR-249424 TSC22D3 protein Q99576 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000738 20018851 t "GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells." SIGNOR-256148 PFKL protein P17858 UNIPROT "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266472 MAPK1 protein P28482 UNIPROT PTPN7 protein P35236 UNIPROT "up-regulates activity" phosphorylation Thr66 EPICSVNtPREVTLH -1 16226275 t lperfetto "First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|" SIGNOR-249437 INPPL1 protein O15357 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates binding 9606 BTO:0000567 15668240 t gcesareni "This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor." SIGNOR-133388 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto "In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway" SIGNOR-252811 TBX21 protein Q9UL17 UNIPROT IL4 protein P05112 UNIPROT down-regulates "transcriptional regulation" 9606 BTO:0000782 17541280 f "IL-4 gene transcription is inhibited by T-bet via the suppression of its promoter activity, independently of IFN-gamma. T-bet facilitates Th1 differentiation through not only upregulation of IFN-gamma, but also downregulation of IL-4 gene transcription" SIGNOR-254496 TFE3 protein P19532 UNIPROT ATP6V0D1 protein P61421 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 24448649 f lperfetto "Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A)." SIGNOR-276809 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 19762596 t miannu " We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus. " SIGNOR-271883 PLXNB3 protein Q9ULL4 UNIPROT ARHGDIA protein P52565 UNIPROT "up-regulates activity" binding 10116 BTO:0000526 20696765 t miannu "Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays." SIGNOR-268435 PRKCA protein P17252 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 25058461 t miannu "As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha." SIGNOR-278492 EP300 protein Q09472 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000018 14565864 f miannu "We also showed that forced expression of p300 upregulated TXAS gene in a dose-dependent manner. Mutation of NF-E2 site, but not TATA or initiator site, abolished the p300-mediated activation of TXAS gene." SIGNOR-253906 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CCNE1 protein P24864 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002524 17298674 t miannu "Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme" SIGNOR-271639 PTEN protein P60484 UNIPROT RAB7A protein P51149 UNIPROT "up-regulates activity" dephosphorylation Ser72 AGQERFQsLGVAFYR 9606 26869029 t lperfetto "PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation." SIGNOR-276960 PRKCA protein P17252 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 25058461 t miannu "As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha." SIGNOR-278493 SPOP protein O43791 UNIPROT CD274 protein Q9NZQ7 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0005672 29160310 t Barakat "Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens." SIGNOR-274978 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Lys72 SASVLTGkLTTVFLP -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263594 PMCH protein P20382 UNIPROT MCHR1 protein Q99705 UNIPROT up-regulates binding 9606 BTO:0000007 10421367 t gcesareni "Here we show that the 353-amino-acid human orphan g-protein-coupled receptor slc-1 expressed in hek293 cells binds mch with sub-nanomolar affinity, and is stimulated by mch to mobilize intracellular ca2+ and reduce forskolin-elevated cyclic amp levels." SIGNOR-69517 RAC1 protein P63000 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" binding 10090 BTO:0000142 8107774 t gcesareni "A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways." SIGNOR-248236 RPS6KB1 protein P23443 UNIPROT TARBP2 protein Q15633 UNIPROT "up-regulates activity" phosphorylation Ser286 LRSCSLGsLGALGPA -1 27407113 t miannu "We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. " SIGNOR-274068 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 15262992 t lperfetto "Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2." SIGNOR-126863 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Thr8 MSSILPFtPPVVKRL 9606 12193595 t lperfetto "We show that phosphorylation of Smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (ERK1) increases the amount of Smad2 protein and leads to enhanced transcriptional activity.[] A site of ERK-dependent phosphorylation on Smad2 was located to Thr8" SIGNOR-227514 CFHR1 protein Q03591 UNIPROT CFH protein P08603 UNIPROT "down-regulates activity" binding -1 27814381 t lperfetto "Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b" SIGNOR-263476 NADPH(4-) smallmolecule CHEBI:57783 ChEBI FASN protein P49327 UNIPROT "up-regulates activity" binding 9606 34765544 t miannu "We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH." SIGNOR-267371 MCHR1 protein Q99705 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257034 TJP2 protein Q9UDY2 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 9606 21808241 t milica "In addition, yap and taz interact with another tight junction protein zo-2, which was reported to increase nuclear localization of yap and tight-junction localization of taz." SIGNOR-175931 citrate(3-) smallmolecule CHEBI:16947 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI "up-regulates quantity" "precursor of" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266241 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Ser355 SALQGFNsPGMLSLG 9606 BTO:0000567 10849446 t lperfetto "We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo." SIGNOR-236587 QRICH1 protein Q2TAL8 UNIPROT VARS2 protein Q5ST30 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269409 PSMB2 protein P49721 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263358 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1715686 t gcesareni "Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta." SIGNOR-21299 FGF14 protein Q92915 UNIPROT SCN1A protein P35498 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253421 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT "down-regulates activity" phosphorylation 9606 SIGNOR-C15 SIGNOR-C3 21460634 t lperfetto "Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2." SIGNOR-173035 5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylidene]thiazolidine-2,4-dione chemical CHEBI:94690 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189912 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A1 protein P30531 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206960 CYSLTR1 protein Q9Y271 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257019 PAK proteinfamily SIGNOR-PF13 SIGNOR VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation -1 11895474 t "inferred from 70% family members" miannu "In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.¬†" SIGNOR-269975 ACHE protein P22303 UNIPROT acetylcholine smallmolecule CHEBI:15355 ChEBI "down-regulates quantity" "chemical modification" 15841900 t "Acetylcholinesterase (AChE) is one of the most crucial enzymes for nerve response and function. AChE catalyzes the hydrolysis of acylcholine esters with a relative specificity for acetylcholine.|The intracellular effects of acetylcholine are mediated by the activation of nicotinic and muscarinic acetylcholine receptors (AChRs). AChE terminates transmission of neuronal impulses by rapid hydrolysis of acetylcholine." SIGNOR-253983 DLK2 protein Q6UY11 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 21419176 t gcesareni "In this work, we demonstrate, for the first time, that dlk2 interacts with itself, with dlk1, and with the same notch1 receptor region as dlk1 does. We demonstrate also that the interaction of dlk2 with notch1 similarly results in an notch signaling in preadipocytes and mouse embryo fibloblasts." SIGNOR-172864 NFIB protein O00712 UNIPROT EPHA8 protein P29322 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268903 TOPORS protein Q9NS56 UNIPROT TP53 protein P04637 UNIPROT down-regulates ubiquitination 9606 phosphorylation:Ser718 KDRDGYEsSYRRRTL 19473992 t lperfetto "Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation." SIGNOR-185848 ABT-737 chemical CID:11228183 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271;BTO:0000776;BTO:0000785 17200714 t gcesareni "A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells." SIGNOR-151784 "A6/b1 integrin" complex SIGNOR-C164 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257706 FBP1 protein P09467 UNIPROT "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "up-regulates quantity" "chemical modification" 9606 30616754 t lperfetto "FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle" SIGNOR-267611 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 21454698 t gcesareni "The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation." SIGNOR-173017 MEF2D protein Q14814 UNIPROT MYH7 protein P12883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 17111365 f Regulation miannu "Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner." SIGNOR-251957 ABL1 protein P00519 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" phosphorylation Tyr486 YPAEDSTyDEYENDL 9606 20861316 t miannu "Because phosphorylation by c-Abl augments nmMLCK-cortactin interaction to a greater degree than does pp60src phosphorylation, it is likely that phosphorylation sites on nmMLCK unique to c-Abl (i.e., other than Y464 and Y846) are responsible for this enhanced protein-protein interaction.|Moreover, our data indicate that cortactin is itself rapidly phosphorylated on Y486 by c-Abl in EC after S1P (Figure 9)." SIGNOR-278504 Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT ACE2 protein Q9BYF1 UNIPROT "up-regulates activity" binding 9606 32201502 t miannu "At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function." SIGNOR-260226 PRKACA protein P17612 UNIPROT HNRNPD protein Q14103 UNIPROT up-regulates phosphorylation Ser87 SNSSPRHsEAATAQR 9606 11903055 t gcesareni "Protein kinase a enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein d in a hierarchical fashion." SIGNOR-116144 SIAH1 protein Q8IUQ4 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 11752454 t gcesareni "We report that siah-1 interacts directly with and promotes the degradation of the cell fate regulator numb." SIGNOR-113469 POLR2C protein P19387 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266163 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT "up-regulates activity" phosphorylation Ser422 IACDEEFsDSEDEGE 9606 BTO:0000567 12082111 t llicata "HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2." SIGNOR-250887 HTR6 protein P50406 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257443 MAPKAPK2 protein P49137 UNIPROT KRT20 protein P35900 UNIPROT "up-regulates activity" phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 t miannu "P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13." SIGNOR-263072 AURKA protein O14965 UNIPROT GMNN protein O75496 UNIPROT "up-regulates activity" phosphorylation Thr25 NSSVPRRtLKMIQPS 9606 23695679 t miannu "Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis.|Thr25 of geminin is phosphorylated by Aurora-A." SIGNOR-278509 BLK protein P51451 UNIPROT FCGR2C protein P31995 UNIPROT "up-regulates activity" phosphorylation Tyr294 YETADGGyMTLNPRA -1 8756631 t miannu "Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation" SIGNOR-262672 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser527 RFRKRTHsAGTSPTI 9606 BTO:0000007 16914728 t lperfetto "Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites." SIGNOR-148903 GSK3B protein P49841 UNIPROT CTPS1 protein P17812 UNIPROT "down-regulates activity" phosphorylation Ser574 YSDRSGSsSPDSEIT 9606 BTO:0000007 17681942 t miannu "We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity." SIGNOR-276068 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1647 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248770 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-238813 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 SIGNOR-C15 21205641 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-170863 FUBP1 protein Q96AE4 UNIPROT CDKN2B protein P42772 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19637194 f irozzo "The cell cycle inhibitor p15 was also up-regulated upon FBP1 knockdown. Our analysis of HCC cells after FBP1 knockdown suggests that p15 mRNA levels may also (directly or indirectly) depend on FBP1 activity." SIGNOR-259126 CDK1 protein P06493 UNIPROT NDUFA12 protein Q9UI09 UNIPROT "up-regulates activity" phosphorylation Thr142 QEWIPPStPYK 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275587 arginine smallmolecule CHEBI:29016 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264756 atropine chemical CHEBI:16684 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 2704370 t miannu "In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium." SIGNOR-258391 MYC protein P01106 UNIPROT LDHA protein P00338 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 9192621 f "Our studies have linked c-Myc to the induction of LDH-A, whose expression increases lactate production and is necessary for c-Myc-mediated transformation" SIGNOR-259367 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 9335504 t llicata "In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1" SIGNOR-52691 BTRC protein Q9Y297 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0002572 16611981 t "The interaction between BTRC and Gli2 occur whne Gli2 is phosphorilated." lperfetto "The phosphorylated gli2 protein interacts with beta-trcp, and is ubiquitinated and degraded by the proteasome" SIGNOR-146109 ALYREF protein Q86V81 UNIPROT "TREX complex" complex SIGNOR-C444 SIGNOR "form complex" binding 9606 33191911 t miannu "The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56." SIGNOR-268511 CYP11B1 protein P15538 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000050 9814482 t lperfetto "Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol." SIGNOR-268678 "Orexin A" smallmolecule CHEBI:80319 ChEBI HCRTR1 protein O43613 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257510 EIF2AK2 protein P19525 UNIPROT SPHK1 protein Q9NYA1 UNIPROT "up-regulates activity" phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 32801355 t miannu "This suggests that PKR is critical in the phosphorylation of SPHK1 at Ser225.|We confirmed that phosphorylated PKR activates SPHK1 kinase activity, but it remained necessary to determine whether there has mutual correlation or any reciprocal effect between these two kinases in stressed cells." SIGNOR-278514 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK8 protein P45983 UNIPROT down-regulates "chemical inhibition" 9606 18922779 t "BI-78D3 is substrate competitive." gcesareni "Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell." SIGNOR-181647 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT unknown phosphorylation Ser70 EAMNYEGsPIKVTLA 9606 BTO:0001271 19933706 t gcesareni "Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c." SIGNOR-161805 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI "up-regulates quantity" "precursor of" 9606 34674502 t scontino "Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬†" SIGNOR-268126 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr539 RGLDKVItVLTRSKR 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141034 1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one chemical CHEBI:93578 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258851 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser41 SLSESEEsQDSSDSI 9606 20730097 t lperfetto "We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf2" SIGNOR-167568 NMUR2 protein Q9GZQ4 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256874 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 22397367 t lperfetto "Ezrin, a member of the erm family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. In particular, ezrin phosphorylation on y477 by src is specific to ezrin within the erm family, and is required for hgf-induced scattering of epithelial cells." SIGNOR-196443 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t fspada "Using ghr hyper-phosphorylated by elk kinase, we have identified tc-ptp, ptp- , pyst-2, sap1, meg-2, ptp1b, and ptph1 as having substrate specificity for this receptor. In addition, we have shown that these same ptps (or rather their nonmutated counterparts) can dephosphorylate the ghr." SIGNOR-104577 CARM1 protein Q86X55 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates methylation 10090 BTO:0001103 29163212 t FFerrentino "The first evidence alluding to a role of PRMTs in mediating skeletal muscle plasticity, specifically myogenesis, arose from the identification of CARM1 as a glucocorticoid receptor-interacting protein 1 (GRIP1) binding protein. (Chen et al., 2000). Here, GRIP1 and MEF2 were co-expressed in the nucleus during skeletal muscle differentiation. These initial findings led to an investigation that revealed that this methyltransferase was responsible for coactivating the transcription of myocyte enhancer factor-2C (MEF2C) via GRIP1 " SIGNOR-255964 UBE2K protein P61086 UNIPROT RNF138 protein Q8WVD3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16714285 t miannu "NARF exhibits E3 ubiquitin-ligase activity in cooperation with the ubiquitin conjugating enzyme, E2-25K. These data show that the auto-ubiquitylating activity of NARF is coordinated with E2-25K, and that the RING finger domain of NARF is indispensable for this reaction." SIGNOR-271594 MRPL46 protein Q9H2W6 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262350 PKA proteinfamily SIGNOR-PF17 SIGNOR DIAPH1 protein O60610 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr768 PVLPFGLtPKKLYKP 9606 BTO:0002588 23325789 t miannu " DIAPH1 is phosphorylated in response to dibutyryl cAMP (Bt2cAMP) at Thr-759 via a pathway that requires extracellular signal-related kinase (ERK).We also show that Bt2cAMP promotes the PKA- and ERK-dependent phosphorylation of DIAPH1 at T759 and that mutation of this site alters the stability of the protein and the rate of cAMP-stimulated mitochondrial movement." SIGNOR-276484 RARG protein P13631 UNIPROT RXRB protein P28702 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16662 MMP2 protein P08253 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272364 TFEB protein P19484 UNIPROT CYP17A1 protein P05093 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 33176151 f lperfetto "Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)" SIGNOR-276786 UBQLN2 protein Q9UHD9 UNIPROT HNRNPA3 protein P51991 UNIPROT "up-regulates quantity by stabilization" binding 25616961 t lperfetto "We screened a yeast two-hybrid library using the central domain of ubiquilin-2 hoping to identify proteins whose binding is affected by the UBQLN2 mutations.||Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein" SIGNOR-262272 YWHAE protein P62258 UNIPROT NEFL protein P07196 UNIPROT "down-regulates activity" binding 9606 23230147 t miannu "These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments." SIGNOR-252398 CDK8 protein P49336 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Ser727 TDNLLPMsPEEFDEV 29239838 t lperfetto "We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation." SIGNOR-273179 MAPK14 protein Q16539 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates 9606 17003045 f gcesareni "The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha. In the present study we determined the role of siah2 phosphorylation in the regulation of its activity toward phd3. We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3." SIGNOR-149887 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HYAL1 protein Q12794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004796 18718911 f miannu "In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription." SIGNOR-253880 SLC9A8 protein Q9Y2E8 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265598 TBPL2 protein Q6SJ96 UNIPROT TAF3/TRF3 complex SIGNOR-C23 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 18851836 t lperfetto "We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation" SIGNOR-181614 BMX protein P51813 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 9606 22348200 t miannu "BMX activates STAT3 in glioblastoma stem cells.|BMX has previously been identified as an activator of STAT3, and BMX can phosphorylate STAT3 in vitro." SIGNOR-279497 SOX2 protein P48431 UNIPROT ABCC6 protein O95255 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21531766 f miannu "ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters." SIGNOR-255182 PARP1 protein P09874 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" relocalization 9606 17891139 t miannu "We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus." SIGNOR-261321 4-methylumbelliferone chemical CHEBI:17224 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258057 panobinostat chemical CHEBI:85990 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257753 CASP3 protein P42574 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000938 15231831 t lperfetto "Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant." SIGNOR-126727 SRPK2 protein P78362 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19592491 f lperfetto "Compared with control, srpk2 wild type evidently elevated cyclin d1 transcription, and the catalytic activity was lost in srpk2 kd, suggesting that kinase activity of srpk2 is required for this effect." SIGNOR-186763 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser334 PLGDDEAsATVSKTE -1 9099669 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-248966 mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f "The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size." SIGNOR-256063 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273080 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser144 DSPALEVsDSESDEA 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo" SIGNOR-251040 PDCD1 protein Q15116 UNIPROT DNM1L protein O00429 UNIPROT "down-regulates activity" 9606 BTO:0000782 34535949 f Barakat "Mechanistically, we provided evidence that PD1 signaling downregulates Drp1 activating phosphorylation on Ser616 (and consequently mitochondrial fragmentation) via the inhibition of ERK1/2 and mTOR kinases." SIGNOR-275406 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates 9606 10795740 t "We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation" SIGNOR-256252 "Fanconi anemia core complex" complex SIGNOR-C300 SIGNOR FANCI protein Q9NVI1 UNIPROT "up-regulates activity" ubiquitination 18985065 t lperfetto "Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding" SIGNOR-263267 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 t gcesareni "Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation." SIGNOR-158604 Ub:E2 complex SIGNOR-C497 SIGNOR ZNRF2 protein Q8NHG8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270975 PDPK1 protein O15530 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-126066 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by stabilization" deacetylation Lys71 GILRRLKkYDNCWLA 9606 BTO:0000007 21726808 t lperfetto "Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1" SIGNOR-267601 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269333 CDK5 protein Q00535 UNIPROT BAG3 protein O95817 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser291 STPLHSPsPIRVHTV 9606 BTO:0002181 31955914 t miannu "CDK5-mediated phosphorylation on S297 promotes BAG3 degradation." SIGNOR-277502 STAT3 protein P40763 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001103 21408055 f "andrea cerquone perpetuini" "Additionally, cMyc, a STAT3 downstream gene, was significantly up-regulated in SCs at T24 versus PRE [...]An increase in the number of cMyc+ SCs indicated that human SCs were induced to proliferate under the control of STAT3 signaling." SIGNOR-255413 POLR3F protein Q9H1D9 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266128 RACK1 protein P63244 UNIPROT CLEC1B protein Q9P126 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 19785988 t miannu "In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex" SIGNOR-272781 PRKCZ protein Q05513 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 BTO:0000938 BTO:0000671 9679146 t gcesareni "These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc." SIGNOR-59303 RXRB protein P28702 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 t gcesareni "We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active." SIGNOR-123094 LPAR2 protein Q9HBW0 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257382 CDK5 protein Q00535 UNIPROT MEF2D protein Q14814 UNIPROT "down-regulates activity" phosphorylation Ser444 SIKSEPVsPSRERSP 9606 19812325 t miannu "In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity." SIGNOR-279509 PRKG1 protein Q13976 UNIPROT EVL protein Q9UI08 UNIPROT "down-regulates activity" phosphorylation 9606 15066263 t miannu " Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts" SIGNOR-268290 ATP5MC1 protein P05496 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261409 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG -1 11955436 t "β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)" SIGNOR-260016 KLHL9 protein Q9P2J3 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000527 25303533 t miannu "KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ." SIGNOR-272455 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAPK14 protein Q16539 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 17074887 t "p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors." gcesareni "One way this occurs is via the interaction of JLP with the Cdo cytoplasmic tail. JLP is, in turn, bound to p38α/β. This interaction facilitates p38 activation during differentiation and is important for Cdo's effects in myogenesis." SIGNOR-272542 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t gcesareni "These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase." SIGNOR-76088 ATF4 protein P18848 UNIPROT WARS2 protein Q9UGM6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269430 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 10551811 t gcesareni "The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71." SIGNOR-72104 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000011 8754811 f ggiuliani "Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells." SIGNOR-255963 SRC protein P12931 UNIPROT CORO7 protein P57737 UNIPROT "up-regulates activity" phosphorylation Tyr758 GDTRVFLyELLPESP -1 18581049 t done miannu "We establish that Src activity is indispensable for the interaction of Crn7 with Golgi membranes. Crn7 binds Src in vivo and can be phosphorylated by recombinant Src in vitro. We demonstrate that tyrosine-758 is the major Src phosphorylation site. " SIGNOR-274005 FOXO proteinfamily SIGNOR-PF27 SIGNOR NOTCH3 protein Q9UM47 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 24749067 f gcesareni "We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration." SIGNOR-252941 UCK2 protein Q9BZX2 UNIPROT "cytidine 5'-monophosphate(2-)" smallmolecule CHEBI:60377 ChEBI "up-regulates quantity" "chemical modification" 11306702 t lperfetto "Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides." SIGNOR-275861 TRIM26 protein Q12899 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys70 AYVPGRDkPDLPTWK 9606 25763818 t miannu "To investigate whether TRIM26 promotes IRF3 ubiquitination through K70 and K87, IRF3 mutant K70/87A was transfected into HEK293 cells together with Flag-TRIM26.|All together, these data indicated that active IRF3 was ubiquitinated and degraded by TRIM26 in nucleus." SIGNOR-278534 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr826 LPTPTKMtPRSRILV 9606 SIGNOR-C18 9139732 t miannu "We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein." SIGNOR-47899 FOXN3 protein O00409 UNIPROT PIM2 protein Q9P1W9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002552 24403608 t Luana "CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis." SIGNOR-261607 TNFRSF17 protein Q02223 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79501 PRKG1 protein Q13976 UNIPROT SEPTIN3 protein Q9UH03 UNIPROT "up-regulates activity" phosphorylation Ser91 SQVSRKAsSWNREEK -1 15107017 t miannu "Mutation of Ser-91 to Ala in recombinant Sept3 also abolished PKG phosphorylation, confirming that Ser-91 is the major site in vitro. Therefore Sept3 is phosphorylated on Ser-91 in nerve terminals and its phosphorylation may contribute to the regulation of its subcellular localization in neurons." SIGNOR-263183 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI "up-regulates quantity" "precursor of" 9606 27487822 t miannu "In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions." SIGNOR-266265 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB5 protein Q9Y5G0 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265692 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 8384556 t gcesareni "The nerve growth factor (ngf) receptor/trk associated with and phosphorylated phospholipase c gamma (plc gamma)" SIGNOR-38538 BTK protein Q06187 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation Tyr694 LAKAVDGyVKPQIKQ -1 11413148 t llicata "Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity." SIGNOR-250603 GRIA3 protein P42263 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264949 SNAI1 protein O95863 UNIPROT PXDN protein Q92626 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 29305973 t miannu "TGF-β1 induced Snai1 binding to the PXDN promoter (as assessed by chromatin immunoprecipitation-PCR) and significantly repressed luciferase reporter gene expression, as did Snai1 overexpression." SIGNOR-265249 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-251072 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12777400 t Manara "These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386" SIGNOR-260769 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 t lperfetto "We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function." SIGNOR-249028 PRKACA protein P17612 UNIPROT STMN2 protein Q93045 UNIPROT "down-regulates activity" phosphorylation Ser97 AAEERRKsQEAQVLK 9534 BTO:0000298 9525956 t miannu "Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation" SIGNOR-250057 L-dopa smallmolecule CHEBI:15765 ChEBI dopamine smallmolecule CHEBI:18243 ChEBI "up-regulates quantity" "precursor of" 9606 NBK536726 t brain lperfetto "Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal" SIGNOR-264174 2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide chemical CID:121427831 PUBCHEM BRD2 protein P25440 UNIPROT "down-regulates quantity" "chemical inhibition" 9606 29764999 t Monia "DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells" SIGNOR-261095 FZR1 protein Q9UM11 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 12234927 t miannu "We found that Cdc25 A degradation during mitotic exit and in early G(1) is mediated by the anaphase-promoting complex or cyclosome (APC/C)(Cdh1) ligase, and that a KEN-box motif in the N-terminus of the protein is required for its targeted degradation." SIGNOR-271388 FOXO6 protein A8MYZ6 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260103 ACD protein Q96AP0 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 17237768 t miannu "We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme." SIGNOR-152321 DCC protein P43146 UNIPROT CACNA1C protein Q13936 UNIPROT "up-regulates activity" 9606 12827203 t miannu "DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER." SIGNOR-268291 ABL1 protein P00519 UNIPROT CRKL protein P46109 UNIPROT down-regulates 9606 21779437 f lperfetto "Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl" SIGNOR-175138 NEUROG1 protein Q92886 UNIPROT NEUROD2 protein Q15784 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000596 10814830 t Luana "Based on these results, we concluded that the transactivation of the NDRF gene by ngn1 is mediated through the E4 box, suggesting that the E4 box and its binding bHLH protein(s) may play an important role in the transcriptional regulation of the NDRF gene." SIGNOR-266235 SMO protein Q99835 UNIPROT SUFU protein Q9UMX1 UNIPROT "down-regulates activity" binding 9606 BTO:0000452 22114142 t lperfetto "In addition to activating g(i), smo signals through its c-terminal tail to inhibit suppressor of fused, resulting in stabilization and activation of the gli family of transcription factors, which execute a transcriptional response to so-called canonical hh signaling." SIGNOR-177656 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" gcesareni "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-138940 MAPK1 protein P28482 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-203286 AKT2 protein P31751 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C7 17964260 t gcesareni "Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300." SIGNOR-158627 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser366 GSYAKLPsPEPSMSP -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265960 PRKACA protein P17612 UNIPROT PPP2R5D protein Q14738 UNIPROT up-regulates phosphorylation Ser573 KVLLRRKsELPQDVY 9606 17301223 t gcesareni "Protein kinase a activates protein phosphatase 2a by phosphorylation of the b56delta subunit." SIGNOR-153218 "PB28 dihydrochloride" chemical CID:46861545 PUBCHEM TMEM97 protein Q5BJF2 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000093 16891467 t Federica "Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer" SIGNOR-261110 SP1 protein P08047 UNIPROT CHGA protein P10645 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12456801 t "Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation." SIGNOR-254273 NPBWR1 protein P48145 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256675 PRKCD protein Q05655 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Ser318 GDKILQVsFKTNKSH 9606 20086103 t lperfetto "Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur." SIGNOR-163528 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT "up-regulates activity" phosphorylation Tyr151 KKDGLKFyTDPSYFF 9606 BTO:0000815 17623672 t "WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3." SIGNOR-262299 DOK7 protein Q18PE1 UNIPROT CRKL protein P46109 UNIPROT "up-regulates activity" binding 10090 BTO:0000165 20603078 t miannu "Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7." SIGNOR-273848 HSPA8 protein P11142 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "down-regulates quantity by destabilization" binding 24789820 t lperfetto "Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane." SIGNOR-260718 "propionic acid" chemical CHEBI:30768 ChEBI FFAR2 protein O15552 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257489 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 BTO:0000887;BTO:0001260 8702756 t gcesareni "Rho-kinase phosphorylates the mlc of intact myosin and activates its mgatpase activity in a gtp_?Rho-dependent manner." SIGNOR-43031 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2647 QQHDFTLtQTADGRS 9606 BTO:0000773 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249160 IFNAR complex SIGNOR-C243 SIGNOR TYK2 protein P29597 UNIPROT "up-regulates activity" binding 9606 15120645 t miannu "Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48)." SIGNOR-260146 PRKD1 protein Q15139 UNIPROT FAM83G protein A6ND36 UNIPROT "up-regulates activity" phosphorylation Ser356 YALVKAKsVDEIAKI 10029 32570757 t lperfetto "Taken together, these data demonstrate that FAM83G S356 phosphorylation modulates HSP27 phosphorylation and apoptosis regulation and that HSP27 is a counterpart of FAM83G.|an active form of PKD1/PKCm could phosphorylate the FAM83G peptide, including the S356 portion.|We also demonstrated that the phosphorylation of the FAM83G S356 residue was required for the reduction of the live cell number, as the CHO cells were unaffected upon the overexpression of a FAM83G S356A mutant resistant to S356 phosphorylation." SIGNOR-264764 ITGB1BP1 protein O14713 UNIPROT ITGB4 protein P16144 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257658 PAK1 protein Q13153 UNIPROT PGM1 protein P36871 UNIPROT up-regulates phosphorylation Thr467 SANDKVYtVEKADNF 9606 BTO:0001271 15378030 t gcesareni "The signaling kinase p21-activated kinase 1 (pak1) binds to, phosphorylates and enhances the enzymatic activity of phosphoglucomutase 1 (pgm)," SIGNOR-127135 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191409 DYRK1A protein Q13627 UNIPROT PLK2 protein Q9NYY3 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser358 VPDFHLSsPAKNFFK 9606 BTO:0000007 37387444 t miannu " In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability. " SIGNOR-277805 DNMT3A protein Q9Y6K1 UNIPROT MEIS1 protein O00470 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 28288143 f miannu "Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia." SIGNOR-256125 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269382 MCC complex SIGNOR-C382 SIGNOR APC-c complex SIGNOR-C150 SIGNOR "down-regulates activity" binding 9606 BTO:0000567 25092294 t miannu "The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20." SIGNOR-265977 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR SOX2 protein P48431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269253 "2-deoxy-D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:62877 ChEBI "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "precursor of" 9606 25229427 t miannu "Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase." SIGNOR-267096 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT "down-regulates quantity by destabilization" phosphorylation 10090 15767683 t miannu "The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2." SIGNOR-267995 RAI1 protein Q7Z5J4 UNIPROT CRY1 protein Q16526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000614 22578325 f miannu "Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others." SIGNOR-266842 AURKA protein O14965 UNIPROT LDHB protein P07195 UNIPROT "up-regulates activity" phosphorylation Ser162 PKHRVIGsGCNLDSA 9606 BTO:0000567 31804482 t miannu "Aurora-A-mediated phosphorylation of LDHB serine 162 significantly increases its activity in reducing pyruvate to lactate, which efficiently promotes NAD+ regeneration, glycolytic flux, lactate production and bio-synthesis with glycolytic intermediates. " SIGNOR-277493 HERC3 protein Q15034 UNIPROT RELA protein Q04206 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 26476452 t miannu "Our data so far suggest that HERC3 reduces NF-kappaB transcriptional activity by binding to the proteasome and delivering RelA for degradation.|We show that HERC3 mediates ubiquitination of RelA on two distinct lysine residues, K195 and K315." SIGNOR-278546 NFIX protein Q14938 UNIPROT WNT5A protein P41221 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268889 SL-327 chemical CHEBI:92211 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni "Pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity (impey et al., 1999) and neuronal survival (villalba and journot, 1997;meyerfranke et al., 1998;skaper et al., 1998;anderson and tolkovsky, 1999;singer et al., 1999;bi et al., 2000). Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors, (kamakura et al., 1999), suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2." SIGNOR-104936 FARSB protein Q9NSD9 UNIPROT "Phenylalanyl-tRNA synthetase" complex SIGNOR-C473 SIGNOR "form complex" binding 9606 20223217 t miannu "Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers." SIGNOR-270435 NLK protein Q9UBE8 UNIPROT TCF4 protein P15884 UNIPROT down-regulates phosphorylation 9606 2861485 t gcesareni "Whereas lef-1 and tcf-4 phosphorylation by nlk (nemo-like kinase) leads to less lef/tcf/beta-catenin complex binding to dna and to lef-1/tcf-4 degradation" SIGNOR-24147 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates 9606 22298955 f gcesareni "Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro." SIGNOR-254335 MARCHF5 protein Q9NX47 UNIPROT PRKN protein O60260 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys220 GAHPTSDkETSVALH 9606 33565245 t miannu "MITOL promotes cell survival by degrading Parkin during mitophagy.|Mechanistically, MITOL mediates ubiquitination of Parkin at lysine 220 residue, which promotes its proteasomal degradation, and thereby fine-tunes mitophagy by controlling the quantity of Parkin." SIGNOR-278554 SRC protein P12931 UNIPROT PTTG1IP protein P53801 UNIPROT "up-regulates activity" phosphorylation Tyr174 LFKEENPyARFENN 9534 BTO:0000298 23678037 t done miannu "Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in PM retention and a markedly reduced ability to bind NIS. " SIGNOR-273810 PSMA7 protein O14818 UNIPROT XBP1 protein P17861 UNIPROT "down-regulates quantity by destabilization" binding -1 19941857 t 1 miannu "We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination." SIGNOR-239042 NCOR1 protein O75376 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18588516 f miannu "The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor)." SIGNOR-254229 AURKB protein Q96GD4 UNIPROT ATM protein Q13315 UNIPROT up-regulates phosphorylation Ser1403 CHKTKLKsILEILSK 9606 22099307 t lperfetto "Aurora-b mediated atm serine 1403 phosphorylation is required for mitotic atm activation and the spindle checkpoint" SIGNOR-177280 BLOC-3 complex SIGNOR-C253 SIGNOR RAB32 protein Q13637 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 23174301 t lperfetto "HPS1/HPS4 was active exclusively for RAB32 and RAB38. Moreover, when overexpressed with HPS1 in HeLa cells, a mitochondrially restricted form of HPS4 preferentially recruited GFP-tagged RAB32 or RAB38 – but not the related RAB7 or RAB9 – to mitochondria. Activity in both assays required both HPS1 and HPS4. Finally, depletion of HPS1 or HPS4 by siRNA in a pigmented human melanoma cell line, MNT-1, resulted in the mislocalization of RAB32. These data provide strong evidence that BLOC-3 is a selective GEF for RAB32 and RAB38 " SIGNOR-260693 MFGE8 protein Q08431 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21901532 f miannu "In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production" SIGNOR-260653 POMC protein P01189 UNIPROT MC1R protein Q01726 UNIPROT "up-regulates activity" binding 9606 BTO:0000847 19656324 t miannu "Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses." SIGNOR-252370 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser408 GPLPRAPsISTVEPK 26190112 t "Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-253541 HCK protein P08631 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" phosphorylation Tyr394 LNTIGLIyEKISLPK 9606 BTO:0002181 28618271 t miannu "The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. " SIGNOR-276727 FZD9 protein O00144 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0003006 15705594 f "Transfected Wnt-7a and Fzd-9 inhibit proliferation of NSCLC cells." SIGNOR-278115 RAB6B protein Q9NRW1 UNIPROT VPS13B protein Q7Z7G8 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 25492866 t miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues" SIGNOR-269205 AURKA protein O14965 UNIPROT FANCA protein O15360 UNIPROT "up-regulates activity" phosphorylation Ser165 HSMFSRLsFCQELWK 9606 BTO:0002181 27398318 t miannu "E detected interactions between Aurora A kinase and FANCA protein, one of the components of the FA nuclear core complex. These results suggest that S165 phosphorylation by Aurora A kinase is required for proper activation of the FA/BRCA pathway in response to DNA damage." SIGNOR-277263 porfimer chemical CHEBI:60652 ChEBI LDLR protein P01130 UNIPROT "up-regulates activity" "chemical activation" 9606 1450993 t miannu "Porphyrins are transported in blood mainly by lipoproteins, and the low density lipoprotein (LDL) receptor-mediated pathway is probably one of the important factors involved in the selective accumulation of porphyrins by tumor tissues, as cancer cells generally express much more LDL receptors than normal cells." SIGNOR-259302 PIK3CD protein O00329 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242655 CFAP53 protein Q96M91 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR "up-regulates activity" binding 10090 BTO:0000379 33347437 t miannu "CFAP53 associates with axonemal microtubules of tracheal cilia and interacts with dynein proteins and the docking complex (DC)" SIGNOR-265547 SRC protein P12931 UNIPROT DNM1 protein Q05193 UNIPROT "up-regulates activity" phosphorylation Tyr597 NTEQRNVyKDYRQLE 9534 BTO:0004055 12011079 t lperfetto "Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. Electron microscopic analyses reveal that tyrosine-phosphorylated dynamin I spontaneously self-assembles into large stacks of rings. Tyrosine 597 was identified as being phosphorylated both in vitro and in cultured cells following epidermal growth factor receptor stimulation." SIGNOR-247129 PITX1 protein P78337 UNIPROT POU1F1 protein P28069 UNIPROT "up-regulates activity" binding -1 8755540 t miannu "A novel OTX-related homeodomain transcription factor has been identified on the basis of its ability to interact with the transactivation domain of the pituitary-specific POU domain protein, Pit-1. P-OTX is able to independently activate and to synergize with Pit-1 on pituitary-specific target gene promoters." SIGNOR-219740 MAP2K3 protein P46734 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation 9606 BTO:0000887;BTO:0001103 11980910 t amattioni "Mkk3 enhanced mirk kinase activity. Mkk3 possibly activates mirk by phosphorylating it." SIGNOR-86731 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates phosphorylation Tyr500 TSLGSQSyEDMRGIL 9606 10933394 t llicata "Experiments with purified proteins demonstrated that cd19-y513 was lyn's initial phosphorylation and binding site. This led to processive phosphorylation of cd19-y482, which recruited a second lyn molecule, allowing for transphosphorylation and amplification of lyn activation." SIGNOR-80290 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr681 QRHKRTHtGEKKFAC 9606 BTO:0000887;BTO:0001260 18258854 t llicata "Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter." SIGNOR-160774 TRIM65 protein Q6PJ69 UNIPROT NLRP3 protein Q96P20 UNIPROT "down-regulates activity" ubiquitination 9606 34512673 t miannu "These results suggest that TRIM65 could inhibit the activation of the NLRP3 inflammasome in response to multiple agonists.|Thus, TRIM65 deficiency impairs NLRP3 ubiquitination and enhances NLRP3 inflammasome activation, but has no effects on AIM2 or IPAF inflammasome activation." SIGNOR-278566 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2A protein Q9UQM7 UNIPROT "up-regulates activity" "chemical activation" 15621017 t "It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK." SIGNOR-255491 NEDD4 protein P46934 UNIPROT GRIA1 protein P42261 UNIPROT "down-regulates quantity" ubiquitination 9606 21148011 t miannu "Finally, we show that ubiquitination of GluA1 by Nedd4-1 becomes more prevalent as neurons mature.|The ability of Nedd4-1 to reduce surface GluA1 levels required its ligase activity, since co-expression of a catalytically-inactive version of Nedd4-1 (Nedd4-1 CS) did not decrease surface GluA1 levels ." SIGNOR-278572 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser283 NLQMLPEsEDEESYD 9606 BTO:0000782 8622692 t llicata "Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation." SIGNOR-40502 LCK protein P06239 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 BTO:0000150;BTO:0000567 9500442 t gcesareni "On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation." SIGNOR-55853 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CCND3 protein P30281 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000018 22024926 t miannu "Here, we show that a relatively new E3 ligase component belonging to the SCF (Skip-Cullin1-F-box protein) E3 ligase family, SCF (FBXL2) , impairs cell proliferation by mediating cyclin D3 polyubiquitination and degradation. " SIGNOR-271888 PHLPP2 protein Q6ZVD8 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 BTO:0001544 19261608 t "The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells." SIGNOR-248731 SLBP protein Q14493 UNIPROT H2AB1 protein P0C5Y9 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265411 SRC protein P12931 UNIPROT PBK protein Q96KB5 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr74 NPICNDHyRSVYQKR 9606 BTO:0000038 27016416 t miannu "Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon" SIGNOR-277218 CHEK1 protein O14757 UNIPROT E2F6 protein O75461 UNIPROT "down-regulates activity" phosphorylation Ser52 EDNVQYVsMRKALKV -1 23954429 t miannu "the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters." SIGNOR-266371 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol chemical CHEBI:75722 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258149 F2RL1 protein P55085 UNIPROT WWOX protein Q9NZC7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254854 OSM protein P13725 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 t gcesareni "Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2." SIGNOR-48114 RPS6KA5 protein O75582 UNIPROT PLA2G4A protein P47712 UNIPROT "up-regulates activity" phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007 10978317 t lperfetto "Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases." SIGNOR-249051 POU5F1 protein Q01860 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 19968627 f miannu "p21 protein levels were repressed by Oct-4 and were induced by the down-regulation of Oct-4 in ZHBTc4 ES cells." SIGNOR-255043 ADP chemical CHEBI:16761 ChEBI P2RY1 protein P47900 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257557 CSNK2A1 protein P68400 UNIPROT CAV2 protein P51636 UNIPROT "up-regulates activity" phosphorylation Ser23 DDSYSHHsGLEYADP 9606 BTO:0001130 12743374 t lperfetto "We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae" SIGNOR-101106 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK6 protein Q00534 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192470 DUSP3 protein P51452 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates activity" dephosphorylation Tyr1221 SPAFDNLyYWDQDPP 9606 BTO:0002552 21262974 t "Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2." SIGNOR-248534 PRKCA protein P17252 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275441 KIT protein P10721 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 22806893 t irozzo "SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation." SIGNOR-256140 AR protein P10275 UNIPROT ARG2 protein P78540 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20711410 f "The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry." SIGNOR-253671 AURKA protein O14965 UNIPROT LIMK1 protein P53667 UNIPROT "up-regulates activity" phosphorylation Ser307 DRSPGAGsLGSPASQ -1 22214762 t miannu "Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology. " SIGNOR-276399 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:RBR_E3 complex SIGNOR-C520 SIGNOR "form complex" binding 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag." SIGNOR-271381 FFAR4 protein Q5NUL3 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256773 TLN1 protein Q9Y490 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257634 CDK1 protein P06493 UNIPROT KIF22 protein Q14807 UNIPROT "up-regulates activity" phosphorylation Thr463 QGAPLLStPKRERMV 9606 SIGNOR-C17 12727876 t lperfetto "Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes" SIGNOR-100964 "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR CDK1 protein P06493 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000011 25533466 f miannu "We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis." SIGNOR-252249 HUWE1 protein Q7Z6Z7 UNIPROT BRCA1 protein P38398 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 24472556 t miannu "Collectively, these data indicate that HUWE1 targets BRCA1, but not BARD1, for polyubiquitination and degradation.Because HUWE1 promotes BRCA1 ubiquitination and degradation, we wondered whether it might contribute to the reduced BRCA1 protein levels in sporadic breast cancer." SIGNOR-278583 LATS2 protein Q9NRM7 UNIPROT PRPS1 protein P60891 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser285 EDKMKHCsKIQVIDI -1 34465890 t miannu " Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness." SIGNOR-276504 CDK7 protein P50613 UNIPROT RARA protein P10276 UNIPROT up-regulates phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 BTO:0000567 9230306 t llicata "However, only the coexpression of cdk7 stimulated ser-77 phosphorylation in vivo and enhanced transactivation by rar alpha, but not by a s77a rar mutant." SIGNOR-49693 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM67 protein Q6ZTA4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271177 CENPN protein Q96H22 UNIPROT "CCAN complex" complex SIGNOR-C365 SIGNOR "form complex" binding 9606 BTO:0000567 18007590 t lperfetto "CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S)." SIGNOR-265210 5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin chemical CID:122187 PUBCHEM HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258865 CLCC1 protein Q96S66 UNIPROT PIGBOS1 protein A0A0B4J2F0 UNIPROT "up-regulates activity" binding 9606 31653868 t Simone "The PIGBOS microprotein interacts with the ER protein CLCC1. PIGBOS localizes to the mitochondrial outer membrane where itinteracts with the ER protein CLCC1 at ER–mitochondria contact sites. PIGBOS-CLCC1 interaction is necessary for PIGBOS function" SIGNOR-261040 ADAM10 protein O14672 UNIPROT CD44 protein P16070 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin." SIGNOR-259847 MARCHF5 protein Q9NX47 UNIPROT MFN2 protein O95140 UNIPROT "up-regulates activity" ubiquitination 9606 23727017 t miannu "Taken together, these results suggested that MITOL regulates endoplasmic reticulum tethering to mitochondria by activating Mfn2 via K192 ubiquitination.|Therefore, MITOL specifically ubiquitinates mitochondrial Mfn2." SIGNOR-278553 KAT2B protein Q92831 UNIPROT H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269625 DOK1 protein Q99704 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257688 FZR1 protein Q9UM11 UNIPROT REV1 protein Q9UBZ9 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23287467 t miannu " Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1." SIGNOR-272893 sapitinib chemical CHEBI:132986 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR down-regulates "chemical inhibition" 9606 BTO:0000551 20145185 t "AZD8931 has a unique pharmacologic profile providing equipotent EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models." gcesareni "In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation." SIGNOR-269874 TRPM7 protein Q96QT4 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser78 SSGSPANsFHFKEAW 9606 BTO:0000007 21112387 t miannu "TRPM7 interacts with, and phosphorylates mouse eEF2-k at serine site 77" SIGNOR-277923 2-Amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7-(naphthalen-1-YL)-5-oxo-4H-chromene-3-carbonitrile chemical CID:25223366 PUBCHEM SLC1A3 protein P43003 UNIPROT "down-regulates activity" "chemical inhibition" 9606 19161278 t Federica "The most potent analogue in the series, 1o, displayed high nanomolar inhibitory activity (IC50) 0.66μM) at EAAT1, with more than 400-foldselectivity compared to EAAT2 and EAAT3." SIGNOR-261108 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Thr288 QCPVGFNtLAFPSMK -1 19264966 t miannu "The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites." SIGNOR-276129 TIMM23 protein O14925 UNIPROT "TIM23 complex" complex SIGNOR-C423 SIGNOR "form complex" binding 32074073 t lperfetto "The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE." SIGNOR-267697 ARNTL protein O00327 UNIPROT PER2 protein O15055 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 22750052 f "Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins." SIGNOR-253629 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates 9606 22972936 t milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-192042 RPL7A protein P62424 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262454 EGR2 protein P11161 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 BTO:0001412 1864967 f irozzo "Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes." SIGNOR-256089 SEC24A protein O95486 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265295 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni "Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation" SIGNOR-56827 FN1 protein P02751 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "up-regulates activity" binding 9606 BTO:0000664 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253250 MDM2 protein Q00987 UNIPROT IRF1 protein P10914 UNIPROT "down-regulates quantity" ubiquitination 9606 27795392 t miannu "HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation.|IRF-1 ubiquitination by HDM2 is specifically increased during HIV-1 infection in the presence of increasing amounts of Tat and is mediated by the formation of a trimeric complex between Tat, IRF-1, and HDM2, as demonstrated by coimmunoprecipitation analysis (XREF_FIG)." SIGNOR-278590 IFNGR2 protein P38484 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "form complex" binding 9606 BTO:0000801 19041276 t lperfetto "The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process." SIGNOR-249486 RNF2 protein Q99496 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys45 RWMKWEGkRVELPDS 9606 24980959 t miannu "RNF2 ubiquitinates AMBRA1 at lysine 45.|These data indicate that RNF2 directly accelerates the degradation of AMBRA1." SIGNOR-278596 hsa-miR-520a-5p mirna URS0000534239_9606 RNAcentral LAMTOR5 protein O43504 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000093 21343296 t Parnian "These data suggest that miR-520b is able to regulate breast cancer cell migration by directly targeting HBXIP." SIGNOR-278014 CSNK2A1 protein P68400 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser529 GLPNGLLsGDEDFSS 9606 10938077 t gcesareni "Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II.|Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential." SIGNOR-149635 YARS1 protein P54577 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 16429158 t miannu "YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr" SIGNOR-270519 ARID5B protein Q14865 UNIPROT MYB protein P10242 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29326336 f miannu "We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F)." SIGNOR-256160 MDM2 protein Q00987 UNIPROT DDX24 protein Q9GZR7 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0001109 24980433 t miannu "MDM2 mediates nonproteolytic polyubiquitylation of the DEAD-Box RNA helicase DDX24. Unexpectedly, however, the polyubiquitylation of DDX24 did not elicit its proteasomal degradation but rather promoted its association with preribosomal ribonucleoprotein (pre-rRNP) processing complexes that are required for the early steps of pre-rRNA processing." SIGNOR-272845 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1310351 f gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16469 PTPRF protein P10586 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation 9606 12018405 t lperfetto "Some 10 years ago, Hashimoto et al. (87) had shown that the LAR catalytic domain can dephosphorylate the EGFR receptor in vitro, and more recently, Kulas and colleagues (88) have demonstrated that the antisense mediated suppression of LAR can enhance the growth factor induced activation of EGFR in rat hepatoma cells.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types." SIGNOR-277029 CASC3 protein O15234 UNIPROT "Exon junction complex" complex SIGNOR-C369 SIGNOR "form complex" binding -1 16923391 t miannu "The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP." SIGNOR-265241 TRAF6 protein Q9Y4K3 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates quantity by stabilization" ubiquitination 9606 23707529 t miannu "We have also observed that ubiquitination of PS1 by TRAF6 increases the stability of PS1 holoprotein, and TRAF6-deficiency coincides with reduced endogenous PS1 and PS2 levels." SIGNOR-278601 sufentanil chemical CHEBI:9316 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10030 21215785 t Luana "Experiments were conducted to obtain K(i)'s for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. The K(i) values obtained ranged from 0.1380 nM (sufentanil) to 12.486 μM (tramadol). " SIGNOR-257890 (5Z)-5-(quinoxalin-6-ylmethylidene)-1,3-thiazolidine-2,4-dione chemical CHEBI:45302 ChEBI PIK3CG protein P48736 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000099 31195053 t miannu "We identified the protective effect of the PI3Kγ inhibitor AS605240 against stroke-related injury in the mouse model of transient intraluminal middle cerebral artery occlusion (tMCAO). in this study, the effects of AS605240 on astrocytes were studied in cell cultures." SIGNOR-262224 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr112 EGMQIPStQFDAAHP -1 12432063 t miannu "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin. " SIGNOR-275994 PIK3CA protein P42336 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000899 10201980 t lperfetto "Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation" SIGNOR-249610 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 21349850 t gcesareni "Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth." SIGNOR-172235 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249001 UHRF1 protein Q96T88 UNIPROT LRIF1 protein Q5T3J3 UNIPROT "down-regulates activity" ubiquitination 9606 26727879 t miannu "In our study, we found the UHRF1 is sufficient to suppress RIF1 accumulation at DSBs in S phase and CtIP functions as a negative regulator of RIF1 only in G2 phase (XREF_FIG; XREF_SUPPLEMENTARY).|UHRF1 ubiquitinates RIF1." SIGNOR-278604 FBXW11 protein Q9UKB1 UNIPROT PER1 protein O15534 UNIPROT down-regulates ubiquitination 9606 15917223 t miannu "We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1" SIGNOR-137758 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252440 CENPK protein Q9BS16 UNIPROT SOX6 protein P35712 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 10996314 t miannu "Here we report the cloning of a novel cDNA, termed Solt, from a mouse testis cDNA library. Its gene product, Solt, interacts with the leucine zipper region of SoxLZ/Sox6. In transient transfection assays with SoxLZ/Sox6 containing the transactivation domain of herpes simplex virus VP16, the expression of a luciferase reporter gene under the control of a promoter containing a synthetic cis element that is bound by the HMG box of SoxLZ/Sox6 was poorly enhanced in the presence of Solt." SIGNOR-221820 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 20219869 f apalma "Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6." SIGNOR-255354 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr502 TPGTGLGtSPALAGD -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-250906 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM51 protein Q9BSJ1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270962 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR SMURF1 protein Q9HCE7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272443 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto "Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export." SIGNOR-236163 PAX3 protein P23760 UNIPROT PITX2 protein Q99697 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21143873 f gcesareni "Pitx genes, such as pitx2, which is positively regulated by pax3, have been implicated in myogenesis." SIGNOR-170343 IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 19029956 t lperfetto "At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family." SIGNOR-182484 MAPK1 protein P28482 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 9606 11741541 t lperfetto "Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna" SIGNOR-112805 BMP2 protein P12643 UNIPROT OMD protein Q99983 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16970923 f miannu "Bmp-2 up regulates osad" SIGNOR-149562 CBP/p300 complex SIGNOR-C6 SIGNOR H3-3A protein P84243 UNIPROT "down-regulates activity" acetylation Lys28 LATKAARkSAPSTGG 9606 21131905 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription." SIGNOR-217214 DBP protein Q10586 UNIPROT CYP3A4 protein P08684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 18004209 f miannu "The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock." SIGNOR-253835 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK2 protein O96017 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm)." SIGNOR-163234 GRIK5 protein Q16478 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264946 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr243 ARRLCDLyYINSPEL 9606 22195962 t llicata "Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1" SIGNOR-191723 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-66767 NR0B2 protein Q15466 UNIPROT AR protein P10275 UNIPROT down-regulates binding 9606 11735420 t gcesareni "We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation" SIGNOR-112589 PPP2CB protein P62714 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates activity" dephosphorylation Thr500 WDGVTTKtFCGTPDY 10116 8749392 t "Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme." SIGNOR-248585 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248398 domperidone chemical CHEBI:31515 ChEBI DRD3 protein P35462 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 1975644 t miannu "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells." SIGNOR-258381 PTPRG protein P23470 UNIPROT CTTN protein Q14247 UNIPROT "down-regulates activity" dephosphorylation Tyr470 AYATEAVyESAEAPG -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254696 RAD18 protein Q9NS91 UNIPROT PCNA protein P12004 UNIPROT "up-regulates activity" ubiquitination Lys164 AVVISCAkDGVKFSA 9606 20937699 t miannu "Second, these findings suggest the following model (XREF_FIG) : upon replication fork stalling at cisplatin induced DNA lesions, the RAD18 and RAD6 complex ubiquitylates PCNA on Lys164.|The DNA damage-activated E3 ubiquitin ligase RAD18 promotes repair of interstrand DNA cross-links by ubiquitylating PCNA and recruiting FANCL to chromatin." SIGNOR-278612 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257999 JAK3 protein P52333 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 28821617 t miannu "Jak3 phosphorylates Tyr 30, Tyr 64, and Tyr 86 of beta-catenin in intestinal epithelial cells." SIGNOR-278180 HOXD12 protein P35452 UNIPROT MAFF protein Q9ULX9 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221884 CAD protein P27708 UNIPROT "carbamoyl phosphate(2-)" smallmolecule CHEBI:58228 ChEBI "down-regulates quantity" "chemical modification" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-268092 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM4 protein Q9C037 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271218 ATM protein Q13315 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser31 ALRLLDSsQIVIISA 10090 11459832 t lperfetto "Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes." SIGNOR-109416 HTR6 protein P50406 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256944 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Thr895 KLSFRRRtDKDTEQP 9606 10488078 t lperfetto "Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)" SIGNOR-70730 ILK protein Q13418 UNIPROT NACA protein Q13765 UNIPROT up-regulates phosphorylation Ser43 PELEEQDsTQATTQQ 9606 15299025 t lperfetto "Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase." SIGNOR-127694 naproxen chemical CHEBI:7476 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" -1 9057869 t miannu "Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM)." SIGNOR-258602 morphine chemical CHEBI:17303 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258931 "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 25533466 f miannu "We show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR." SIGNOR-252248 SREBF2 protein Q12772 UNIPROT LRP1 protein Q07954 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20980003 f miannu "In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression." SIGNOR-254461 N2,N4-Dibenzylquinazoline-2,4-diamine chemical CID:676352 PUBCHEM VCP protein P55072 UNIPROT "down-regulates activity" "chemical inhibition" -1 21383145 t Monia "DBeQ (1) is a reversible and selective inhibitor of p97" SIGNOR-261100 "erlotinib hydrochloride" chemical CHEBI:53509 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271 17178722 t "JAK2(V617F), a mutant of tyrosine kinase JAK2. Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor." gcesareni "This study shows that the anti-cancer drug erlotinib (tarceva) is a potent inhibitor of jak2(v617f) activity." SIGNOR-151271 3-[(4-Bromophenyl)methyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one chemical CID:10248127 PUBCHEM ACHE protein P22303 UNIPROT "down-regulates activity" "chemical inhibition" 9606 17888667 t Luana "AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE." SIGNOR-257761 WNK3 protein Q9BYP7 UNIPROT SLC12A3 protein P55017 UNIPROT "up-regulates activity" phosphorylation 21613606 t lperfetto "We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs" SIGNOR-264624 ATR protein Q13535 UNIPROT MCC protein P23508 UNIPROT "up-regulates activity" phosphorylation Ser120 LRSELSQsQHEVNED 9606 BTO:0001109 21779472 t miannu "MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity." SIGNOR-273515 MCU_MICU3_variant complex SIGNOR-C501 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270873 STOM protein P27105 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266040 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 8335191 t "Crohn's Disease" gcesareni SIGNOR-251701 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT "down-regulates activity" binding 9534 16757346 t miannu "We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ" SIGNOR-261707 FYN protein P06241 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Tyr1038 ESWIRAKyEQLLFLA 9606 16841086 t llicata "We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival." SIGNOR-147932 PES1 protein O00541 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0002882 15169904 f miannu "Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development." SIGNOR-260078 PRKD3 protein O94806 UNIPROT PAK4 protein O96013 UNIPROT "up-regulates activity" phosphorylation Ser474 KEVPRRKsLVGTPYW 23841590 t lperfetto "PAK4 activity is regulated by an autoinhibitory domain that is released upon RhoGTPase binding as well as phosphorylation at Ser474 in the activation loop of the kinase domain. In the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1)" SIGNOR-275931 TRIM56 protein Q9BRZ2 UNIPROT STING1 protein Q86WV6 UNIPROT "up-regulates activity" ubiquitination 9606 21074459 t miannu "In contrast, we found that TRIM56 preferentially promoted K63 linked ubiquitination of the same lysine residue of STING that was important for the dimer formation and TBK1 activation.|Specifically, TRIM56 induces STING dimerization during dsDNA triggered signaling to potentiate antiviral responses while RNF5 may induce degradation of mitochondrial STING to suppress RLR induced antiviral responses.The findings that TRIM56 failed to interact with dsDNA and that there was no colocalization between TRIM56 and dsDNA within cells suggest that TRIM56 is unlikely to be a dsDNA sensor, and instead facilitates the STING function by ubiquitination." SIGNOR-278621 NCOA2 protein Q15596 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11851396 t gcesareni "Here, it is demonstrated that mutation of the h11 phenylalanine residues diminishes the ability of rxr to associate with the p160 coactivators tif2 and p/cip, but has little effect on ligand-dependent interactions of the receptor with the unrelated coactivator tif1." SIGNOR-114847 PKC proteinfamily SIGNOR-PF53 SIGNOR SCN2A protein Q99250 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 32599005 t lperfetto "For example, protein kinase A (PKA) and protein kinase C (PKC) have been shown to phosphorylate multiple serine residues on the interdomain I-II and III-IV linkers of Nav1.2, significantly reducing current and increasing firing thresholds" SIGNOR-275750 CASP8 protein Q14790 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 t lperfetto "Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis." SIGNOR-261754 ITGB7 protein P26010 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253292 LNX1 protein Q8TBB1 UNIPROT SUFU protein Q9UMX1 UNIPROT "down-regulates quantity" ubiquitination Lys59 LQVTAIVkYWLGGPD 9606 33608498 t miannu "Indeed, they target different lysine residues in the SuFu protein, as LNX1 ubiquitinates SuFu at K59 and K470, and SCF Fbxl17 acts at K257, while Itch ubiquitinates at K321 and K457.|XREF_FIG, ectopic LNX1 expression reduced SuFu protein levels in HEK-293T cells, while shRNA mediated knockdown of LNX1 increased these levels." SIGNOR-278627 PTCRA protein Q6ISU1 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" binding 9606 20626350 t lperfetto "However, non-canonical mechanisms of p38alfa activation have been also described. One is apparently specific to antigen receptor stimulated t-lymphocytes. This involves phosphorylation of p38alfa on tyr323 by the tcr-proximal tyrosine kinase zap70 and p56lck." SIGNOR-166658 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser266 SLPLTPEsPNDPKGS 9606 BTO:0000887 11741533 t gcesareni "Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298" SIGNOR-112766 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser329 STISGRLsPIMTEQD 9606 11311120 t lperfetto "The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus" SIGNOR-252909 MAPK14 protein Q16539 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT "up-regulates activity" phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 t lperfetto "In hela cells, prak was activated in response to cellular stress and proinflammatory cytokines. Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site." SIGNOR-58135 calcium(2+) smallmolecule CHEBI:29108 ChEBI Cadherins proteinfamily SIGNOR-PF71 SIGNOR "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265811 MIB1 protein Q86YT6 UNIPROT SNRPN protein P63162 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23615451 t miannu "These data indicate that Mib1 reduces SMN protein stability by targeting it for degradation by the proteasome and represents a new modifier of the SMA phenotype.|Through this study, we provide evidence that the E3 ligase Mib1 ubiquitinates and catalyzes SMN protein degradation." SIGNOR-278632 ATP6V0E1 protein O15342 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR "form complex" binding 9606 33065002 t miannu "Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes." SIGNOR-277747 NEDD4 protein P46934 UNIPROT APOBEC3G protein Q9HC16 UNIPROT "up-regulates activity" ubiquitination 9606 15581898 t miannu "APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles|This could be explained in at least two ways : first, endogenous Nedd4 is naturally expressed at a level largely sufficient to target APOBEC3G into the VLP or virions." SIGNOR-278635 NEDD4 protein P46934 UNIPROT GRIN2D protein O15399 UNIPROT "down-regulates activity" ubiquitination 9606 23639431 t miannu "Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses.|This suggests that Nedd4 association reduces GluN2D function, mostly likely by promoting GluN2D ubiquitination and internalization." SIGNOR-278636 VEGFA protein P15692 UNIPROT FLT1 protein P17948 UNIPROT up-regulates binding 9606 BTO:0004980 14704231 t gcesareni "Vegf exerts its action by binding to vegfr-1 and vegfr-2." SIGNOR-121132 CDK1 protein P06493 UNIPROT PPP1R13L protein Q8WUF5 UNIPROT "up-regulates activity" phosphorylation Ser84 EPFGSRGsPRKAATD 9606 30105797 t done miannu "Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53. " SIGNOR-273585 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 t lperfetto "We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity" SIGNOR-232146 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" 9606 31908417 t miannu "The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs." SIGNOR-262250 PAK4 protein O96013 UNIPROT NFE2L2 protein Q16236 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr369 ESSSYGDtLLGLSDS 10090 BTO:0000575 35108418 t miannu "PAK4 directly phosphorylated Nrf2 at T369, and it led to its nuclear export and proteasomal degradation, all of which impaired antioxidant responses in hepatocytes." SIGNOR-277583 TAF1C protein Q15572 UNIPROT "SL1 complex" complex SIGNOR-C464 SIGNOR "form complex" binding 9606 30693017 t lperfetto "SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation." SIGNOR-269564 methylnaltrexone chemical CHEBI:136007 ChEBI OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258147 E2F1 protein Q01094 UNIPROT TYMS protein P04818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253863 FGF9 protein P31371 UNIPROT BMP2 protein P12643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15780951 f "FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1." gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts." SIGNOR-134794 sirolimus chemical CHEBI:9168 ChEBI LILRB2 protein Q8N423 UNIPROT "down-regulates quantity by repression" 9606 18652845 f miannu "Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells." SIGNOR-255477 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164633 NANOG protein Q9H9S0 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086;BTO:0005511 15983365 f miannu "Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta." SIGNOR-254625 RLN2 protein P04090 UNIPROT RXFP1 protein Q9HBX9 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 t gcesareni "Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway" SIGNOR-114549 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser448 HRSIRHSsIQE 9606 BTO:0000782 20697158 t miannu "Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells." SIGNOR-167471 dexamethasone chemical CHEBI:41879 ChEBI SCNN1A protein P37088 UNIPROT up-regulates 9606 BTO:0000018 10722699 f "Regulation of expression" miannu "Dexamethasone induces α-ENaCmRNA expression in lung epithelial A549 cells" SIGNOR-251945 Guanabenz chemical CHEBI:5553 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258909 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "down-regulates activity" phosphorylation Ser146 MEPERRDsQDGSSYR 9606 22665060 t llicata "Phosphorylation of lasp-1 by pka at serine 146 induces translocation of the lasp-1/zo-2 complex from the cytoplasm to the nucleus. Interaction occurs within the carboxyterminal proline-rich motif of zo-2 and the sh3 domain in lasp-1." SIGNOR-197720 PRKACA protein P17612 UNIPROT PARP1 protein P09874 UNIPROT "up-regulates activity" phosphorylation Ser465 FLQDVSAsTKSLQEL 9606 BTO:0001412 25069723 t miannu " In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). " SIGNOR-276651 BACH1 protein O14867 UNIPROT GAPDH protein P04406 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 31257027 t "BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells." SIGNOR-259339 HEY1 protein Q9Y5J3 UNIPROT MYOG protein P15173 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 19917614 f lperfetto "Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis." SIGNOR-235822 MLLT11 protein Q13015 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0003295 21715312 f irozzo "Our results indicate that AF1q cooperates with the Notch signaling pathway to foster the emergence of BM prothymocytes and drive subsequent intrathymic specification toward the T-cell lineage." SIGNOR-259201 TARDBP protein Q13148 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR "up-regulates quantity" 9606 BTO:0000312 22051914 f lperfetto "Pathological protein aggregates, identified as compact or skein-like ubiquitinated inclusions, are a cardinal feature of ALS.4–6 The identification of TDP-43 as the major protein constituent of these inclusions initi- ated a major shift in our understanding of the patho- biology of ALS" SIGNOR-262278 AKT proteinfamily SIGNOR-PF24 SIGNOR CELF1 protein Q92879 UNIPROT "up-regulates activity" phosphorylation Ser28 GQVPRTWsEKDLREL 10090 BTO:0000165 18570922 t miannu "CUG repeat binding protein, CUGBP1, is a key regulator of translation of proteins that are involved in muscle development and differentiation. In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA." SIGNOR-262615 BZLF2 protein P03205 UNIPROT "EBV gH:gL:gp42" complex SIGNOR-C403 SIGNOR "form complex" binding 9606 BTO:0000776 9151859 t scontino "Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR." SIGNOR-266625 gL protein P03212 UNIPROT "EBV gH:gL:gp42" complex SIGNOR-C403 SIGNOR "form complex" binding 9606 BTO:0000776 9151859 t scontino "Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR." SIGNOR-266627 gH protein P03231 UNIPROT "EBV gH:gL:gp42" complex SIGNOR-C403 SIGNOR "form complex" binding 9606 BTO:0000776 9151859 t scontino "Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR." SIGNOR-266626 F2R protein P25116 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256732 CHRM5 protein P08912 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257351 NCKAP1 protein Q9Y2A7 UNIPROT NHS protein Q6T4R5 UNIPROT "up-regulates activity" binding 9606 20332100 t miannu "We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge." SIGNOR-253576 SLBP protein Q14493 UNIPROT "Histone H2A" proteinfamily SIGNOR-PF70 SIGNOR "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265374 "albuterol sulfate" chemical CHEBI:2550 ChEBI ADRB2 protein P07550 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-206682 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT "down-regulates activity" phosphorylation Thr276 DGIMYYLtPQWDKIL 9823 21864610 t miannu "We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity." SIGNOR-262920 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD3 protein O94806 UNIPROT "up-regulates activity" phosphorylation Ser731 ARIIGEKsFRRSVVG 18692497 t lperfetto "The results presented in this study indicate that during mitosis, PKD3 and PKD are phosphorylated at Ser(731) and Ser(744) within their activation loop by a mechanism that requires protein kinase C. Mitosis-associated PKD3 Ser(731) and PKD Ser(744) phosphorylation is related to the catalytic activation of these kinases as evidenced by in vivo phosphorylation of histone deacetylase 5, a substrate of PKD and PKD3." SIGNOR-275924 MAPK3 protein P27361 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" phosphorylation Ser59 EGSNPPAsPLQDNLV 9606 BTO:0000567 8618896 t lperfetto "Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation." SIGNOR-249469 STAT5A protein P42229 UNIPROT CISH protein Q9NSE2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15769897 t "The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD" SIGNOR-261544 BRCA1 protein P38398 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 16331276 f miannu "We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1." SIGNOR-142888 CSNK2A1 protein P68400 UNIPROT ACACA protein Q13085 UNIPROT unknown phosphorylation Ser29 GSVSEDNsEDEISNL -1 2900140 t llicata "These results show that casein kinase-2 phosphorylates site 6 exclusively" SIGNOR-250823 CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1270 YQQKPYPsPKTIEDL 9606 11584018 t lperfetto "Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter." SIGNOR-110912 PRKN protein O60260 UNIPROT LTF protein P02788 UNIPROT "down-regulates activity" ubiquitination Lys649 NGSDCPDkFCLFQSE 9606 32786404 t miannu "We propose that Parkin ubiquitylation of LTF at K649 perturbs LTF\u2019s ability to accumulate intracellular iron levels and that depletion of Parkin, or substitution of K649 on LTF, allows LTF to accumulate intracellular iron levels.|Parkin dependent ubiquitylation of LTF occurred most often on lysines (K) 182 and 649." SIGNOR-278641 RNF41 protein Q9H4P4 UNIPROT PRKN protein O60260 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 18541373 t miannu "Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage dependent and proteasome dependent manner.|More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate." SIGNOR-278644 "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "up-regulates quantity" "precursor of" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-268134 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR GADD45B protein O75293 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11713530 f gcesareni "Here we report that nf-kappab complexes downregulate the c-jun amino-terminal kinase (jnk) cascade, thus establishing a link between the nf-kappab and the jnk pathways. This link involves the transcriptional upregulation of gadd45beta/myd118, which downregulates jnk induced by the tnf receptor (tnf-r)." SIGNOR-111963 NSD1 protein Q96L73 UNIPROT PRB4 protein P10163 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003233 29156722 t miannu "We here demonstrate that NSD1 could bind to the promoter regions of PRB4 and activate promoter activity by reducing the binding of H3K27me2 and increasing the binding of H3K36me2 on PRB4 promoter." SIGNOR-268459 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser487 AQLAGSDsDLDSDDE 9606 20864032 t lperfetto "Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)" SIGNOR-168036 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8422248 t lperfetto "These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III." SIGNOR-248930 FYN protein P06241 UNIPROT CLIC5 protein Q9NZA1 UNIPROT "up-regulates activity" phosphorylation Tyr33 EENESPHyDDVHEYL 9606 BTO:0000567 10930415 t miannu "In this paper, we demonstrate that p64 becomes tyrosine phosphorylated when co-expressed with p59(fyn) in HeLa cells." SIGNOR-274006 U50488 chemical CHEBI:73358 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 9262330 t miannu "We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine." SIGNOR-258666 TLE4 protein Q04727 UNIPROT PAX2/TLE4 complex SIGNOR-C152 SIGNOR "form complex" binding 9606 16631587 t miannu "Several Pax proteins are able to interact with groucho (TLE) family members. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1." SIGNOR-256360 STUB1 protein Q9UNE7 UNIPROT INO80 protein Q9ULG1 UNIPROT "up-regulates activity" ubiquitination 9606 33658435 t miannu "Then, by an in vivo ubiquitination assay under denaturing conditions (hereafter, all in vivo ubiquitination assays were carried out under denaturing conditions), we determined whether CHIP ubiquitinates Ino80.|We also show that CHIP works together with BAP1 to enhance the stabilization of Ino80, leading to its chromatin binding." SIGNOR-278646 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser188 RKRHKSDsISLSFDE 9606 BTO:0000671 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188)" SIGNOR-124953 CDK5 protein Q00535 UNIPROT TRIM59 protein Q8IWR1 UNIPROT "up-regulates activity" phosphorylation Ser308 LIPKMKIsPKRMSCS 31488827 t miannu " Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation." SIGNOR-272929 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20308527 t lperfetto "We demonstrate that CHD8 directly associates with AR and that CHD8 and AR simultaneously localize to the TMPRSS2 enhancer after androgen treatment. In the LNCaP cell line, reduction of CHD8 levels by small interfering RNA treatment severely diminishes androgen-dependent activation of the TMPRSS2 gene. We demonstrate that the recruitment of AR to the TMPRSS2 promoter in response to androgen treatment requires CHD8" SIGNOR-253686 RPS6KA3 protein P51812 UNIPROT FOXN2 protein P32314 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser365 EDDPLGDsGYASQPC 9606 BTO:0002552 29396548 t done miannu "Importantly, we identified RSK2 kinase as the upstream kinase for the FOXN2 phosphodegron. The Ser365 and Ser369 sites in a conserved DSGYAS motif are responsible for the ubiquitination of FOXN2 by β-Trcp. " SIGNOR-273840 HSP90AB1 protein P08238 UNIPROT NOD2 protein Q9HC29 UNIPROT "up-regulates quantity by stabilization" binding 9606 23019338 t miannu "Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation." SIGNOR-252415 calcium(2+) smallmolecule CHEBI:29108 ChEBI PPP3CA protein Q08209 UNIPROT up-regulates "chemical activation" 9606 22944199 t lperfetto "Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell)." SIGNOR-198819 RUSC1 protein Q9BVN2 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000007 19365808 t miannu "NESCA interacts with the IKK complex by the N-terminal region of NEMO. This experiment revealed that the overexpression of NESCA completely abolished the TRAF6-mediated polyubiquitination of NEMO, as it appears by using either anti-HA (Fig. 5A) or anti-NEMO (Fig. 5B) antibodies on immunoprecipitated extracts." SIGNOR-272775 CSNK2A1 protein P68400 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" phosphorylation Ser59 NKLFQYAsTDMDKVL -1 8663403 t llicata "We show that serine 59 located between the MADS and MEF2 domains of MEF2C is phosphorylated in vivo and can be phosphorylated in vitro by casein kinase-II (CKII). Phosphorylation of this site enhanced the DNA binding and transcriptional activity of MEF2C by increasing its DNA binding activity 5-fold." SIGNOR-250914 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser285 SSASPALsRRGSLGE 10090 17213202 t lperfetto "Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo." SIGNOR-234469 EPAS1 protein Q99814 UNIPROT KDM5B protein Q9UGL1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271578 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR peptide smallmolecule CHEBI:16670 ChEBI "up-regulates quantity" "chemical modification" 9606 20025795 t miannu "In the initial binding state, referred to as A/T state, this aa-tRNA is in a ternary complex with the GTPase EF-Tu (eEF1A in eukaryotes) and GTP. When a Watson–Crick codon–anticodon match is recognized by the ribosome, a signal is transmitted to EF-Tu that triggers GTP hydrolysis and thereby causes the dissociation of EF-Tu from the ribosome. The subsequent accommodation of the 3′ acceptor arm of the tRNA in the PTC of the large subunit leads to a rapid peptide bond transfer" SIGNOR-270811 LATS1 protein O95835 UNIPROT MTF1 protein Q14872 UNIPROT "down-regulates activity" phosphorylation Ser152 EGCPRTYsTAGNLRT 35027733 t lperfetto "The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression" SIGNOR-275473 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR RHOA protein P61586 UNIPROT "down-regulates activity" phosphorylation Tyr66 DTAGQEDyDRLRPLS 9606 BTO:0000567 23027962 t lperfetto "When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity" SIGNOR-271699 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Thr509 LKRKRRPtSGLHPED 9606 BTO:0000150 17428466 t lperfetto "Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation" SIGNOR-154312 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser447 YHRSIRHsSIQE 9606 BTO:0000782 20697158 t miannu "Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells." SIGNOR-167467 DAB2 protein P98082 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 22491013 t gcesareni "Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin." SIGNOR-196925 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT "up-regulates activity" phosphorylation Ser326 SSVDTLLsPTALIDS 9606 35080342 t miannu "AKT1 and AKT2 phosphorylate HSF1 at S326 but only AKT1 activates HSF1.|Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not." SIGNOR-278374 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT "down-regulates activity" phosphorylation Ser100 QPQDKVIsGIAREKL 9534 BTO:0000298 10759890 t miannu "IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex" SIGNOR-262713 MECP2 protein P51608 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000452 19820693 f Luana "We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner." SIGNOR-264550 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190179 TRIM21 protein P19474 UNIPROT IRF8 protein Q02556 UNIPROT "down-regulates quantity" ubiquitination 9606 28592884 t miannu "From these results, we concluded that TRIM21 down-regulated IRF8 and enhanced the secretion of IL-12/23p40 in BD monocytes.|IRF8 is ubiquitinated by TRIM21, which promotes secretion of IL-12/23p40 after TLR/IFN-\u03b3 stimulation xref ." SIGNOR-278791 GGCX protein P38435 UNIPROT SMAD7 protein O15105 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261233 CBX3 protein Q13185 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264494 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0002181 22012064 t irozzo "Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels" SIGNOR-255707 PBRM1 protein Q86U86 UNIPROT S100A13 protein Q99584 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000562 15601824 f miannu "We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues." SIGNOR-132431 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 10037602 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-64972 AMBRA1 protein Q9C0C7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 dephosphorylation:Ser52 KRVELPDsPRSTFLL 23524951 t lperfetto "In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function." SIGNOR-272963 indometacin chemical CHEBI:49662 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" -1 9057869 t miannu "Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM)." SIGNOR-258607 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 17827393 t gcesareni "Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K)." SIGNOR-157734 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser297 GLRYNRLsAIPRSLA 29383184 t lperfetto "PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8." SIGNOR-275567 HTR4 protein Q13639 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257242 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Ser281 NRRQLAFsTVGTPDY 9606 BTO:0000007 16314523 t lperfetto "Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity." SIGNOR-142514 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity" phosphorylation Tyr102 YDLKLQEyQSAIKVE 10090 BTO:0000007;BTO:0000011 25368164 t "We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ." SIGNOR-262297 MTCH2 protein Q9Y6C9 UNIPROT BID protein P55957 UNIPROT up-regulates relocalization 9606 20436477 t "In the experiment they use a truncated BID (tBID)-interacting protein." gcesareni "Mtch2/mimp (mitochondrial carrier homologue 2/met-induced mitochondrial protein), a novel truncated bid (tbid)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tbid to mitochondria" SIGNOR-165081 NR2F2 protein P24468 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 t gcesareni "Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site." SIGNOR-79443 MAPK8 protein P45983 UNIPROT SYT4 protein Q9H2B2 UNIPROT "up-regulates activity" phosphorylation Ser135 EGEKESVsPESLKSS 10116 BTO:0001009 18046461 t done miannu "JNK phosphorylates Syt 4 at Ser135 in vitro and in vivo." SIGNOR-273673 TGFB1 protein P01137 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 19114990 t lperfetto "While association of the TGF_RI receptor with p85 requires TGF-_ stimulation." SIGNOR-252729 ARID1B protein Q8NFD5 UNIPROT "Muscle cell-specific SWI/SNF ARID1B variant" complex SIGNOR-C482 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270702 SMARCA2 protein P51531 UNIPROT "Neural progenitor-specific SWI/SNF" complex SIGNOR-C477 SIGNOR "form complex" binding 9606 25195934 t miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270610 NANOG protein Q9H9S0 UNIPROT "CGB Family" proteinfamily SIGNOR-PF108 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086;BTO:0005511 15983365 f miannu "Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta." SIGNOR-254624 PIP3 smallmolecule CHEBI:16618 ChEBI ZFYVE26 protein Q68DK2 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000567 20208530 t miannu "We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis." SIGNOR-265537 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser688 QFHSPVGsPLKSIQA 9606 SIGNOR-C17 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-164491 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser696 EKNYALPsPATTEGG 9606 BTO:0000007 SIGNOR-C3 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-169526 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser392 FKTEGPDsD 9606 23603988 t gcesareni "We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation" SIGNOR-201931 ECM stimulus SIGNOR-ST20 SIGNOR "A9/b1 integrin" complex SIGNOR-C166 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259048 HIC1 protein Q14526 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 19486893 f miannu "HIC1 is also implicated in growth control since it recruits BRG1, one of the two alternative ATPases (BRM or BRG1) of SWI/SNF chromatin-remodeling complexes to repress transcription of E2F1 in quiescent fibroblasts." SIGNOR-254239 CSNK2A1 protein P68400 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata "Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. " SIGNOR-250952 KISS1R protein Q969F8 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256750 PRKACB protein P22694 UNIPROT TENT2 protein Q6PIY7 UNIPROT "down-regulates activity" phosphorylation Ser116 LSGERRYsMPPLFHT 9606 31057087 t miannu "We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition." SIGNOR-259403 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR AKT1 protein P31749 UNIPROT "down-regulates activity" cleavage -1 10579725 t lperfetto "P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro" SIGNOR-256447 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica "Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ" SIGNOR-201165 POLR2L protein P62875 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 9606 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266151 "folic acid" smallmolecule CHEBI:27470 ChEBI dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000575 19706381 t lperfetto "However, since the synthesis of folic acid (FA, pteroylglutamic acid) as a provitamin in 1945, DHFR has taken on another role: reduction of FA to 7,8-DHF (Fig. 1)" SIGNOR-268263 ENO1 protein P06733 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9534 BTO:0000318 2005901 t Luana "This result suggests that MBP-1 in vivo acts as a sequence-specific repressor." SIGNOR-261594 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SNAI2 protein O43623 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser54 ILSSGAYsPITVWTT 9606 24662826 t miannu "At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation." SIGNOR-276628 ODC1 protein P11926 UNIPROT spermidine smallmolecule CHEBI:16610 ChEBI "up-regulates quantity" "chemical modification" 9606 14617280 t miannu "Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)" SIGNOR-256038 CBX3 protein Q13185 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "up-regulates activity" binding 9606 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-265324 GSK3A protein P49840 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser509 GVHSPMAsSGNTGNH 9606 BTO:0000093 17574025 t miannu "GSK3 Phosphorylates SRC-3 on S505.In this report, we identified GSK3 as a kinase that phosphorylates SRC-3 on S505 and demonstrated that this phosphorylation modulates SRC-3 transcriptional function and turnover." SIGNOR-276067 AMPK complex SIGNOR-C15 SIGNOR CTH protein P32929 UNIPROT "up-regulates activity" phosphorylation Thr355 AELPAIMtHASVLKN 9606 BTO:0000007 37922764 t miannu " Here we define an important mechanism of increased persulfide and polysulfide production involving cystathionine gamma lyase (CSE) phosphorylation at serine 346 and threonine 355 in a substrate specific manner, under acute hypoxic conditions. Hypoxic phosphorylation of CSE occurs in an AMP kinase dependent manner increasing enzyme activity involving unique inter- and intramolecular interactions within the tetramer. " SIGNOR-277793 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "precursor of" 9913 11254391 t miannu "Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate." SIGNOR-266915 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." SIGNOR-255972 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Ser187 RIMEKADsNKTRIDE 9606 12459461 t lperfetto "This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C" SIGNOR-249178 IRX1 protein P78414 UNIPROT INHBA protein P08476 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20440264 f Luana "We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed." SIGNOR-261666 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 21808241 t "The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction." SIGNOR-175813 CDK1 protein P06493 UNIPROT STIL protein Q15468 UNIPROT "down-regulates activity" phosphorylation 9606 27112295 t miannu "Importantly, we show that CDK1 and CyclinB phosphorylates the N-terminal domain of STIL, but not the region encompassing the CC or STAN motifs." SIGNOR-279145 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273922 CDK6 protein Q00534 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser325 STVSGRLsPIMASTE 9606 28778953 t miannu "CDK6 and cyclin D3 complex phosphorylates FOXO3 on S325.|Using cycloheximide (CHX), we observed that CDK6 knockdown decreased FOXO3 stability, particularly in platinum treated cells (Fig XREF_FIG A) and that, following platinum treatment, FOXO3 WT was more stable than the non phosphorylatable mutant FOXO3 S325A (Fig XREF_FIG B)." SIGNOR-279023 USF1 protein P22415 UNIPROT S100A6 protein P06703 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11118618 f miannu "The results indicate that USF1 binds to an E-box sequence of the calcyclin gene promoter and enhances its transcription activity." SIGNOR-255598 NLGN4Y protein Q8NFZ3 UNIPROT NRXN2 protein Q9P2S2 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264153 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr77 DPCSLIPtPDKEDDD 9606 14536078 t gcesareni "Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380" SIGNOR-118563 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10074433 t gcesareni "We conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin. we found that the binding of beta-trcp to beta-catenin was direct." SIGNOR-65429 GSK3B protein P49841 UNIPROT DDIT4 protein Q9NX09 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr23 SPSSLPRtPTPDRPP 9606 23717519 t miannu "It has been reported that GSK3beta phosphorylates REDD1 at residues Thr23 and Thr25, resulting in REDD1 recruitment to the Cullin 4a-beta-Trcp E3 ligase complex." SIGNOR-279525 MAP3K8 protein P41279 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000007 15466476 t lperfetto "Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases." SIGNOR-129698 Ub:E2 complex SIGNOR-C497 SIGNOR RNF208 protein Q9H0X6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271013 TP53 protein P04637 UNIPROT SCO2 protein O43819 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27692180 t miannu "P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway." SIGNOR-267463 CAD protein P27708 UNIPROT CAD protein P27708 UNIPROT "up-regulates activity" phosphorylation Thr1037 QQCRVLGtSPEAIDS -1 11986331 t llicata "Autophosphorylation resulted in a 2-fold increase in CPSase activity, an increased sensitivity to the feedback inhibitor UTP, and decreased allosteric activation by 5-phosphoribosyl-1-pyrophosphate" SIGNOR-250610 KAT2B protein Q92831 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates acetylation Lys19 VKRLLGWkKSAGGSG 9606 SIGNOR-C7 17074756 t gcesareni "We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. Smad2 is also acetylated by p/caf. The acetylation of smad2 was significantly higher than that of smad3. Lys(19) in the mh1 domain was identified as the major acetylated residue in both the long and short isoform of smad2.....acetylation of the short isoform of smad2 improves its dna binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity" SIGNOR-150273 RPS6KA4 protein O75676 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12773393 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-249211 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191433 SRC protein P12931 UNIPROT PANX1 protein Q96RD7 UNIPROT "up-regulates activity" phosphorylation Tyr199 KYPIVEQyLKTKKNS 9606 BTO:0004578 30814251 t miannu "We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198" SIGNOR-277817 SERPINC1 protein P01008 UNIPROT F2 protein P00734 UNIPROT "down-regulates activity" cleavage 31030036 t lperfetto "Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1" SIGNOR-264136 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT "up-regulates activity" phosphorylation Thr103 LIDATGDtPGAEDDE 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250128 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr225 IKGRAQPyDPNFYDE 9606 12052863 t lperfetto "We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown)." SIGNOR-88899 XRCC3 protein O43542 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" 9606 BTO:0000567 23438602 f lperfetto "Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation." SIGNOR-263261 TUBGCP2 protein Q9BSJ2 UNIPROT "g-TuRC complex" complex SIGNOR-C282 SIGNOR "form complex" binding -1 31862189 t lperfetto "Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.”" SIGNOR-262326 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9534 BTO:0004055 14993270 t lperfetto "We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling." SIGNOR-244862 MAPK3 protein P27361 UNIPROT PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation Ser21 LEAGDLEsPLSEEFL 9606 BTO:0000599 10187842 t lperfetto "We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution." SIGNOR-249474 PRKACA protein P17612 UNIPROT TRPC5 protein Q9UL62 UNIPROT "down-regulates quantity" phosphorylation Ser794 SGGARAKsKSVSFNL 9606 BTO:0000007 21734191 t miannu "Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A)." SIGNOR-277823 FNTB protein P49356 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242565 ADNP protein Q9H2P0 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 12888219 f miannu "Mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment." SIGNOR-266758 CDK1 protein P06493 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" phosphorylation Ser460 STSVLHSsPLNVFMG 21690413 t lperfetto "Mechanistically, we demonstrated that Cdc2-dependent phosphorylation on a γ-tubulin ring complex (γ-TuRC) recruitment protein, Nedd1/GCP-WD, at the previously uncharacterized S460 residue induces the Nedd1-Plk1 interaction" SIGNOR-272972 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR CEBPD protein P49716 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000527 25303533 t miannu "KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ." SIGNOR-272457 CSNK2A1 protein P68400 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser172 GDVDVSDsDDEDDNL 9606 18559419 t llicata "Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation." SIGNOR-178943 DMTF1 protein Q9Y222 UNIPROT JUNB protein P17275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004532 19816943 t Luana " Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. " SIGNOR-261585 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCQ protein Q04759 UNIPROT "up-regulates activity" binding 9606 14967450 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." lperfetto "The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified." SIGNOR-242596 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273101 "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 24832651 f lperfetto "The exact function of the BRCC complex in HR is not entirely elucidated, but its E3 ligase activity may promote the mobilization and stabilization of the complex at broken chromatin sites were the complex can stabilize the formation of RAD51 filaments thus facilitating the repair process" SIGNOR-263204 SEC23B protein Q15437 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265288 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 SIGNOR-C17 10864927 t gcesareni "Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b." SIGNOR-78428 PTPRB protein P23467 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" dephosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 t miannu "VE-PTP interacts with eNOS and dephosphorylates Tyr81" SIGNOR-277521 CSF1R protein P07333 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr228 YPGGSDNyGSLSRVT 9606 21049007 t miannu "In our study, CSF-1R induced the tyrosine phosphorylation of p120 Y904 and Y228 in a SRC-dependent manner ( xref )." SIGNOR-278928 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." SIGNOR-236475 S1PR3 protein Q99500 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256790 CSNK2A1 protein P68400 UNIPROT CERS5 protein Q8N5B7 UNIPROT "up-regulates activity" phosphorylation Ser356 RSDVESSsEEEDVTT 9606 BTO:0000007 26887952 t miannu "Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. " SIGNOR-273986 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 17110930 t Barakat "Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK" SIGNOR-274148 "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268600 WNT7A protein O00755 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131897 POU5F1 protein Q01860 UNIPROT LEFTY1 protein O75610 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254938 MAPK8IP2 protein Q13387 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10490659 t gcesareni "Both jip1 and jip2 selectively bind the mapkk isoform mkk7." SIGNOR-70857 GRM2 protein Q14416 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264933 DUSP9 protein Q99956 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates binding 9606 21908610 t "inferred from 70% of family members" gcesareni "Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein." SIGNOR-269902 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr1253 EGSFESRyQQPFEDF 9606 BTO:0000142 1689310 t llicata "We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation." SIGNOR-20976 AKT1 protein P31749 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251622 AKT1 protein P31749 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 9415393 f "Translocation from intracellular compartment to cell surface in muscle and adipose tissue" gcesareni "Akt is not only capable of stimulating the translocation of glut4 to the cell surface. Endogenous akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue" SIGNOR-252580 CLSPN protein Q9HAW4 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates binding 9606 11090622 t gcesareni "Binding of claspin to xchk1 is highly elevated in the presence of dna templates that trigger a checkpoint arrest of the cell cycle in xenopus egg extracts" SIGNOR-84474 ILF3 protein Q12906 UNIPROT NF90-NF45 complex SIGNOR-C443 SIGNOR "form complex" binding -1 18458058 t miannu "Nuclear factor 90 (NF90) and its C-terminally extended isoform, NF110, have been isolated as DNA- and RNA-binding proteins together with the less-studied protein NF45. These complexes have been implicated in gene regulation, but little is known about their cellular roles and whether they are redundant or functionally distinct. We show that heterodimeric core complexes, NF90-NF45 and NF110-NF45, exist within larger complexes that are more labile and contain multiple NF90/110 isoforms and additional proteins. This study identified NF45 as an unstable regulatory subunit of NF90-NF45 complexes and uncovered their critical role in normal cell division. Furthermore, the study revealed that NF90 is functionally distinct from NF110 and is more important for cell growth." SIGNOR-268488 IFNG protein P01579 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 10090 23667107 f "Early inhibition of IL-1β expression by IFN-γ is mediated by impaired binding of NF-κB to the IL-1β promoter but is independent of nitric oxide." SIGNOR-255937 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT "down-regulates activity" phosphorylation Ser787 KAPEKRAsPSKPASA 9606 BTO:0000567 10791892 t miannu "We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region. Mutation of Ser787 to Glu strikingly reduced the MAP4's MT-polymerization activity, while Glu-mutation at Ser696 did not. These results suggest that Ser787 could be the critical phosphorylation site causing MTs to be dynamic at mitosis." SIGNOR-277459 NFKB1 protein P19838 UNIPROT THBD protein P07204 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17211835 f miannu "Blocking the transcriptional activation of NF-kappaB prevented the TNFalpha-induced downregulation of TM." SIGNOR-254811 LRRK2 protein Q5S007 UNIPROT PRDX3 protein P30048 UNIPROT "down-regulates activity" phosphorylation Thr146 SHLAWINtPRKNGGL 9606 BTO:0000793 21850687 t miannu "Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells." SIGNOR-262891 SMURF2 protein Q9HAU4 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-192898 SRC protein P12931 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 12810717 t gcesareni "Tiam1 cooperated with src to induce activation of rac1 in vivo and the formation of membrane ruffles." SIGNOR-102354 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 10521487 t gcesareni "Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b." SIGNOR-252584 MACF1 protein Q9UPN3 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 BTO:0000938 16815997 f flangone "Macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane." SIGNOR-147457 NFE2L2 protein Q16236 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 26194347 f irozzo "Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes." SIGNOR-256652 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 11062067 t lperfetto "Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)." SIGNOR-83729 ARHGAP22 protein Q7Z5H3 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260476 NOS1 protein P29475 UNIPROT "nitric oxide" smallmolecule CHEBI:16480 ChEBI "up-regulates quantity" "chemical modification" 9606 21890489 t gcesareni "Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates" SIGNOR-243957 MKNK2 protein Q9HBH9 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 t lperfetto "Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes." SIGNOR-157537 HRH1 protein P35367 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257251 HIF1A protein Q16665 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 17415528 f "HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate" SIGNOR-259381 DOCK7 protein Q96N67 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10090 BTO:0000132 29187380 t lperfetto "As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover." SIGNOR-261886 MAPK7 protein Q13164 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000007 12637502 t miannu "Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC." SIGNOR-250115 NAE complex SIGNOR-C131 SIGNOR CUL3 protein Q13618 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243157 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-34653 "EEF1B complex" complex SIGNOR-C460 SIGNOR EEF1A2 protein Q05639 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A." SIGNOR-269388 pipamperone chemical CHEBI:78549 ChEBI HTR1D protein P28221 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000529 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258574 XIAP protein P98170 UNIPROT RIPK4 protein P57078 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 21931591 t miannu "In this study, we report that in addition to RIP1 and RIP2, also RIP3 and RIP4 directly interact with XIAP, cIAP1 and cIAP2. When comparing the ability of these IAPs to directly conjugate RIP1–RIP4 with ubiquitin chains, we found that cIAP1 was the most effective E3 and was capable of ubiquitinating all four RIPs in the presence of the E2 component UbcH5a. On the contrary, XIAP was only capable of inducing weak ubiquitination of RIP4." SIGNOR-272716 CYP2R1 protein Q6VVX0 UNIPROT "vitamin D" smallmolecule CHEBI:27300 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000759 30080183 t lperfetto "Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D." SIGNOR-270569 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr267 SQYGQEVyDTPPMAV 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246401 GPHN protein Q9NQX3 UNIPROT ARHGEF9 protein O43307 UNIPROT "up-regulates activity" binding 9606 25882190 t miannu "Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses." SIGNOR-264973 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT "up-regulates activity" phosphorylation Thr342 ASEKFAQtVMTSRIV 9606 BTO:0000007 17141195 t lperfetto "The present data indicate that the kinase activity of irak-4 is dependent on the autophosphorylations at t342" SIGNOR-151006 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t "inferred from 70% family members" gcesareni "Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity." SIGNOR-270204 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser149 SNSLKKSsAELKKIL 9606 BTO:0000671 12628002 t lperfetto "Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)" SIGNOR-99139 Ub:E2 complex SIGNOR-C497 SIGNOR MGRN1 protein O60291 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271144 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 24168260 f miannu "NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis" SIGNOR-260445 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm)." SIGNOR-163231 LSM-1231 chemical CHEBI:91471 ChEBI NTRK1 protein P04629 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258238 ATF4 protein P18848 UNIPROT SARS1 protein P49591 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269424 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr19 LFMDDDSySHHSGLE 9606 12091389 t lperfetto "We show that caveolin-2 undergoes src-induced phosphorylation on tyrosine 19. we conclude that the tyrosine phosphorylation of caveolin-2 (tyr(p)(19)) may function as a signal that is recognized by the cellular machinery to induce the dissociation of caveolin-2 from caveolin-1 oligomers" SIGNOR-90225 WDR18 protein Q9BV38 UNIPROT "Rix1 complex" complex SIGNOR-C373 SIGNOR "form complex" binding 9606 BTO:0000007 22190735 t miannu "LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes." SIGNOR-265471 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR CREB3L1 protein Q96BA8 UNIPROT up-regulates 9606 16417584 f miannu "Oasis (old astrocyte specifically induced substance) is an er stress transducer in astrocytes, a membrane-bound transcription factor that activates genes in the er stress response / when unfolded proteins accumulate in the er, oasis is cleaved at the membrane to release its cytoplasmic domain, which then enters the nucleus and activates target genes." SIGNOR-143823 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0000782 8325880 t gcesareni "Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase." SIGNOR-25826 SMO protein Q99835 UNIPROT GNG3 protein P63215 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-199186 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1063 FGLARDIyKDPDYVR 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165035 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Thr145 QKSKKHLtDNEFKDP -1 14523239 t lperfetto "We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. | Edman sequencing and scintillation counting delineated T144 as the in vitro PKC phosphorylation site" SIGNOR-249234 MC3R protein P41968 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268702 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK13 protein O15264 UNIPROT up-regulates "chemical activation" 9606 Other t "CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb" gcesareni SIGNOR-189696 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 14701756 t miannu "CHIP mediates the ubiquitination of Smad1. we demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process. " SIGNOR-272948 NUP214 protein P35658 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 SIGNOR-C9 12917407 t gcesareni "We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import." SIGNOR-117644 NMDA proteinfamily SIGNOR-PF56 SIGNOR DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11052931 t miannu "Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor" SIGNOR-264704 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 11062529 t gcesareni "The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c." SIGNOR-84041 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "The type i il-4 receptors result from association of IL-4R With the common ? Chain (?c), which is also a component of the receptors for il-2, il-7, il-9, and il-15." SIGNOR-100765 GGCX protein P38435 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265922 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t gcesareni "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" SIGNOR-78685 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI MET protein P08581 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258214 MARK4 protein Q96L34 UNIPROT TNK1 protein Q13470 UNIPROT "down-regulates activity" phosphorylation Ser502 RMKGISRsLESVLSL 9606 BTO:0000018 34504101 t miannu "We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.Phosphorylation of TNK1 at S502 within the proline rich domain is required for TNK1 binding to 14-3-3.MARKs mediate phosphorylation at S502 and 14-3-3 binding to TNK1, which restrains the movement of TNK1 into heavy membrane-associated clusters." SIGNOR-273865 CAMK4 protein Q16566 UNIPROT NOVA2 protein Q9UNW9 UNIPROT "up-regulates quantity" phosphorylation Ser25 EVVCTKRsNTGEEGE 9606 BTO:0000007 32492405 t miannu "CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. Conversely, Nova-2 with single or double mutations to alanine (2A and 1A2A) was predominantly nuclear, like the WT (Figures 5H and ​and5I).5I). In contrast, glutamate mutations at site 3 had no effect on Nova-2 localization (Figures 5H and ​and5I)5I) or on Nova-2 binding to RNA (Figure S5E). These results showed that active CaMKIV reduces Nova-2 nuclear localization by phosphorylating sites 1 and 2 (S25, T27)." SIGNOR-273521 bosutinib chemical CHEBI:39112 ChEBI SRC protein P12931 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190699 cabazitaxel chemical CHEBI:63584 ChEBI TUBB1 protein Q9H4B7 UNIPROT "down-regulates activity" "chemical inhibition" 9606 21770474 t miannu "Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization" SIGNOR-259341 P2RY6 protein Q15077 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256804 "dibutyl phthalate" chemical CHEBI:535597 ChEBI PPARA protein Q07869 UNIPROT "up-regulates activity" "chemical activation" 10116 33508418 t miannu "Both in vitro and in vivo experiments have proved that DBP is a real activator of PPARα. he current study proves that plasticizer DBP has severe hepatotoxicity and could induce liver dysfunction even at normal doses after prolonged exposure. DBP might accumulate in the liver for a long time to activate PPARα/SREBP-1c/FAS/GPAT/AMPK and result in the accumulation of triglycerides and cholesterol in the liver." SIGNOR-268748 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR -1 19494114 t llicata "Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases.|Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2." SIGNOR-248708 USP36 protein Q9P275 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "up-regulates quantity by stabilization" deubiquitination 22902402 t lperfetto "USP36, the human ortholog of Ubp10, complements the ubp10Δ allele for RNAPI stability, pre-rRNA processing, and cell growth in yeast, suggesting that deubiquitination of RNAPI may be conserved in eukaryotes. Our work implicates Ubp10/USP36 as a key regulator of rRNA production through control of RNAPI stability.|Human USP36 complements ubp10delta for RNA polymerase I deubiquitination and stability" SIGNOR-272292 PTPRC protein P08575 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 BTO:0000776;BTO:0003076 11994288 t gcesareni "These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3," SIGNOR-87157 AURKB protein Q96GD4 UNIPROT DIAPH2 protein O60879 UNIPROT up-regulates phosphorylation Ser196 SLTSNPVsWVNNFGH 9606 21397845 t lperfetto "The microtubule binding fh2 domain of mdia3 is phosphorylated by aurora b kinase in vitro, and cells expressing the nonphosphorylatable mdia3 mutant cannot position chromosomes at the metaphase plate" SIGNOR-172803 DDB1 protein Q16531 UNIPROT EDVP complex SIGNOR-C530 SIGNOR "form complex" binding 9606 BTO:0000007 19287380 t miannu "We named this E3 ligase complex containing EDD, DDB1 and VPRBP proteins as EDVP complex to distinguish it from the previously identified Cul4-Roc1-DDB1-VPRBP E3 ligase complex. " SIGNOR-271791 IL2 protein P60568 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 16477002 t miannu "Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c)." SIGNOR-144543 AVPR2 protein P30518 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256897 SRC protein P12931 UNIPROT YAP1 protein P46937-3 UNIPROT "up-regulates activity" phosphorylation Tyr394 QQNRFPDyLEAIPGT 10090 27013234 t done miannu "We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation." SIGNOR-274026 JAK2 protein O60674 UNIPROT CTLA4 protein P16410 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 10842319 t "Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules." SIGNOR-251346 "A3/b1 integrin" complex SIGNOR-C161 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu "Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing." SIGNOR-269010 HRH2 protein P25021 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257162 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 16943424 t lperfetto "Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm." SIGNOR-149296 GSK3A protein P49840 UNIPROT OSBP2 protein Q969R2 UNIPROT "up-regulates activity" phosphorylation 30925160 t lperfetto "CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes." SIGNOR-264875 HACD proteinfamily SIGNOR-PF86 SIGNOR "very long-chain (R)-3-hydroxyacyl-CoA(4-)" smallmolecule CHEBI:85440 ChEBI "down-regulates quantity" "chemical modification" 9606 18554507 t miannu "Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle." SIGNOR-267917 AMPA proteinfamily SIGNOR-PF58 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 15919192 f miannu "Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits." SIGNOR-264695 NR0B2 protein Q15466 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11369442 t gcesareni "Surprisingly, shp potentiated transcription by pparalpha/rxralpha heterodimers from the hd-ppre. This is the first demonstration of positive transcriptional activity attributable to shp. Together, these results suggest that shp can modulate pparalpha/rxralpha-mediated transcription in a response element-specific manner." SIGNOR-108252 AKT1 protein P31749 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation -1 16340011 t gcesareni "It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase." SIGNOR-252739 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 t lperfetto "We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity." SIGNOR-236455 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190404 MPO protein P05164 UNIPROT APOA1 protein P02647 UNIPROT "down-regulates activity" oxidation 9606 20043647 t miannu "When apolipoprotein A-I (apoA-I), the major HDL protein, was oxidized by MPO, its ability to promote cellular cholesterol efflux by ABCA1 was impaired. Moreover, oxidized apoA-I was unable to activate lecithin:cholesterol acyltransferase (LCAT), which rapidly converts free cholesterol to cholesteryl ester, a critical step in HDL maturation" SIGNOR-252102 DDX46 protein Q7L014 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270669 SMAD9 protein O15198 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 20957627 t gcesareni "Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus." SIGNOR-168740 AVPR1A protein P37288 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257077 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9550290 t miannu "Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists." SIGNOR-258887 DAAM1 protein Q9Y4D1 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 9606 23151663 f gcesareni "In pcp, dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58." SIGNOR-199381 GSK3B protein P49841 UNIPROT AREL1 protein O15033 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr783 IAAPTHStLPTAHTC 27162139 t lperfetto "These experiments suggested that GSK3beta phosphorylation of FIEL1 is required for PIAS4 targeting, and FIEL1 residues P779 and phosphorylated T783 are both required for PIAS4 interaction |FIEL1 T783A mutant overexpression completely failed to decrease PIAS4 protein level." SIGNOR-275528 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR PTGS2 protein P35354 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004850 23645839 f miannu "AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells." SIGNOR-255683 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys779 TKWMEHVkLERLKQV 9606 BTO:0000938 17283082 t lperfetto "Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage." SIGNOR-249576 SNCA protein P37840 UNIPROT Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR up-regulates 9606 12666095 f lperfetto "A key observation linking alpha-synuclein to PD was the demonstration that it is one of the principal components of Lewy bodies. Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein." SIGNOR-249700 PRPF19 protein Q9UMS4 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR "form complex" binding 9606 BTO:0000567 20176811 t miannu "In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27." SIGNOR-271968 CAMK1 protein Q14012 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates activity" phosphorylation Thr198 PGLRRRQt 10090 23707388 t Monia "We also demonstrate that i) CaMKI phosphorylates p27 at Thr157and Thr198 in human cells and at Thr170and Thr197in mouse cells to modulate its subcellular localization;|Collectively, these results suggest that CaMKI is involved in mediating G1 progression by promoting cyclin D1/cdk4 complex formation through site-specific p27 phosphorylation in human lung epithelia." SIGNOR-261194 SUCLG1 protein P53597 UNIPROT "Succinyl-CoA ATP variant" complex SIGNOR-C398 SIGNOR "form complex" binding 9606 32627745 t miannu "Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS)." SIGNOR-266261 CSNK1A1 protein P48729 UNIPROT JADE1 protein Q6IE81 UNIPROT "down-regulates activity" phosphorylation Ser20 SDDNGSLsTTWSQNS 9606 BTO:0000007 25100726 t done miannu "We demonstrate that the destruction complex component casein kinase 1α (CK1α) phosphorylates Jade-1 at a conserved SLS motif and reduces the ability of Jade-1 to inhibit β-catenin signaling. " SIGNOR-273617 KLF13 protein Q9Y2Y9 UNIPROT SIN3A protein Q96ST3 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 11438660 t miannu "detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A." SIGNOR-222437 PSMA6 protein P60900 UNIPROT XBP1 protein P17861 UNIPROT "down-regulates quantity by destabilization" binding -1 19941857 t 1 miannu "We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination." SIGNOR-239039 PRKACA protein P17612 UNIPROT SPTBN1 protein Q01082 UNIPROT "down-regulates activity" phosphorylation Thr2159 NGATEQRtSSKESSP -1 17088250 t miannu "Short C-terminal splice variant of betaII-spectrin (betaIISigma2) is a substrate for phosphorylation. protein kinase A phosphorylates Thr-2159. Mammalian alphaII- and betaII-spectrin subunits form dimers that associate head to head with high affinity to form tetramers In vitro, protein kinase A phosphorylation of an active fragment of betaIISigma2 greatly reduced its interaction with alphaII-spectrin at the tetramerization site." SIGNOR-250054 ATM protein Q13315 UNIPROT BLM protein P54132 UNIPROT up-regulates phosphorylation Thr99 NAPAGQEtQRGGSKS 9606 12034743 t lperfetto "Mitotic phosphorylation of blm was partially dependent on atm, and phosphorylation sites on blm were identified. A phosphospecific antibody against one of these sites (thr-99) revealed radiation-induced phosphorylation, which was defective in ataxia-telangiectasia cells. These data suggest that atm and blm function together in recognizing abnormal dna structures by direct interaction and that these phosphorylation sites in blm are important for radiosensitivity status but not for sce frequency." SIGNOR-88010 RDH5 protein Q92781 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "down-regulates quantity" "chemical modification" 9606 21621639 t lperfetto "Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10" SIGNOR-265113 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000776 20185585 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-163938 AMOTL2 protein Q9Y2J4 UNIPROT LATS2 protein Q9NRM7 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 34404733 t lperfetto "Ubiquitinated AMOTL2 then serves as a physical docking site for LATS2, which phosphorylates YAP to promote its cytoplasmic retention and degradation." SIGNOR-271875 HRH4 protein Q9H3N8 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256672 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL -1 20044479 t lperfetto "IGF-1R Directly Interacts with and Phosphorylates PDK1 in Vitro" SIGNOR-236548 TARS1 protein P26639 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI "up-regulates quantity" "chemical modification" 9606 25824639 t miannu "Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding." SIGNOR-270506 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 20185585 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-163941 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Thr189 LLLTTGGtLKISDLG 9606 BTO:0000781 11430832 t lperfetto "These data suggest that the phosphorylation of thr-189 negatively regulates lkb1 activity." SIGNOR-109028 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 7901013 t "The effect has been demonstrated using P07101-3" gcesareni "Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax" SIGNOR-34682 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr115 LTSQLHItPGTAYQS 9606 10617621 t lperfetto "Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis" SIGNOR-73638 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000176 14967450 t lperfetto "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121997 Ub:E2 complex SIGNOR-C497 SIGNOR NFX1 protein Q12986 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271015 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Ser325 VRRVPGSsGRLHKTE 9606 17190791 t gcesareni "Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)" SIGNOR-151659 "2-N,6-N-Bis(2,3-dihydroxy-N-benzoyl)-L-serine amide" chemical CHEBI:1219 ChEBI DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" -1 7576010 t miannu "D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole." SIGNOR-258436 EEF1A1P5 protein Q5VTE0 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269549 TUBE1 protein Q9UJT0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 f miannu "Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation" SIGNOR-267178 TTL protein Q8NG68 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates tyrosination 9606 22020298 t miannu "Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization" SIGNOR-266826 DUSP3 protein P51452 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0002552 21262974 t "We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR." SIGNOR-248532 (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI methionine smallmolecule CHEBI:16811 ChEBI "up-regulates quantity" "precursor of" 9606 10720211 t lperfetto "Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine." SIGNOR-253141 PRKAA1 protein Q13131 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates quantity" phosphorylation Ser30 EDLQEVLsSDENGGT 9606 27650555 t miannu "Here, we report that phosphorylation of CHOP at Ser30 by AMPK\u03b11 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo .|XREF_FIG showed the deletion of Ampkalpha1 but not Ampkalpha2 significantly increased CHOP protein levels in macrophages." SIGNOR-278381 FGF12 protein P61328 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253412 BRCC3 protein P46736 UNIPROT "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR "form complex" binding 9606 BTO:0000007 14636569 t lperfetto "These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer" SIGNOR-263205 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser16 PSANKPCsKQPPPQP 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198721 SH2B1 protein Q9NRF2 UNIPROT SYK protein P43405 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000776 32323266 t scontino "SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK." SIGNOR-268445 clozapine chemical CHEBI:3766 ChEBI HTR1E protein P28566 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258514 FZD5 protein Q13467 UNIPROT DVL3 protein Q92997 UNIPROT "up-regulates activity" binding 9606 23151663 t areggio "Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. " SIGNOR-258963 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT unknown phosphorylation Thr119 GAARVIGtLLGTVDK 9606 19245811 t lperfetto "Here, we identified a second eif3f phosphorylation site (thr119) by cdk11p46 during apoptosis.Thr119 is located in the mov34 domain of eif3f which is important for both the translational inhibitory function of eif3ffurther studies of how eif3f phosphorylation regulates its function will refine insights into the mechanism and regulation of translation initiation, apoptotic signaling, and tumorigenesis." SIGNOR-184185 CASP1 protein P29466 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto "Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis." SIGNOR-261755 SYVN1 protein Q86TM6 UNIPROT EIF2S1 protein P05198 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 29233968 t miannu "HRD1 overexpression also decreased the expression of eIF2alpha and p-eIF2alpha in HKC-8 cells.|HRD1 promoted eIF2alpha ubiquitylation and degradation, thereby providing a protective mechanism that suppressed tubular epithelial cell apoptosis." SIGNOR-278671 MZF1 protein P28698 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16297876 f irozzo "We demonstrated that both Elk-1 and MZF-1 were highly expressed in human poor differentiated HCC cells and involved in the up-regulation of PKCa, which was essential for cell migration and invasion. Over-expression assay confirmed that the PKCa expression may be modulated by these two factors at the transcriptional level." SIGNOR-256283 ATP6AP1 protein Q15904 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR "form complex" binding 9606 33065002 t miannu "Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes." SIGNOR-277752 GPR132 protein Q9UNW8 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256802 NEK8 protein Q86SG6 UNIPROT NEK8 protein Q86SG6 UNIPROT "up-regulates activity" phosphorylation Thr162 SSKSKAYtVVGTPCY -1 11864968 t miannu "Multimerization and autophosphorylation of Nek8 are important for its activation.Our data suggests that one site for Nek8 autophosphorylation may be Thr-210 within the activation loop." SIGNOR-250298 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 17063185 t flangone "Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively" SIGNOR-150197 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR2 protein P34972 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000142 29751001 t miannu "Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana." SIGNOR-264268 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273146 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CCT2 protein P78371 UNIPROT up-regulates phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 21440620 t lperfetto "Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process." SIGNOR-252780 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Thr169 FLPRHRDtGILDSIG -1 2413024 t miannu "Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-165" SIGNOR-250015 GNAO1 protein P09471 UNIPROT TRIM21 protein P19474 UNIPROT "up-regulates activity" binding 9606 BTO:0006001 39580518 t "Marta Tosoni" "These data demonstrate that GNAO1 recruits TRIM21 and mediates CREB ubiquitination and degradation to promote GSC differentiation." SIGNOR-278069 "ER stress" stimulus SIGNOR-ST9 SIGNOR ATF4 protein P18848 UNIPROT up-regulates 9606 23205607 f lperfetto "Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress" SIGNOR-253728 CASP8AP2 protein Q9UKL3 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates binding 9606 22075988 t lperfetto "In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex." SIGNOR-217385 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192617 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-235956 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000298 8974401 t lperfetto "A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively." SIGNOR-236110 TRHR protein P34981 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 9988720 t "Ga16 is phosphorylated in vivo by PMA and by TRH receptor stimulation" SIGNOR-278132 IRX1 protein P78414 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002392 20440264 f Luana "We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed." SIGNOR-261651 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12603837 t "Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation" gcesareni "Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2." SIGNOR-98724 WNT1 protein P04628 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 10116 11149923 f gcesareni "Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that wnt-1-mediated cell survival was dependent on the activation of beta-catenin/t cell factor (tcf) transcription" SIGNOR-85760 FAAP24 protein Q9BTP7 UNIPROT "Fanconi anemia core complex" complex SIGNOR-C300 SIGNOR "form complex" binding 9606 BTO:0000567 17396147 t lperfetto "This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo " SIGNOR-263239 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273049 PRKAA1 protein Q13131 UNIPROT GSR protein P00390 UNIPROT "up-regulates activity" phosphorylation Thr507 TKADFDNtVAIHPTS 9606 BTO:0001890 31530934 t miannu "Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. " SIGNOR-273734 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 11062067 t amattioni "Jnk full activation requires the phosphorylation of a threonine and a tyrosine residue in a thr-pro-tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (mkk)4 and mkk7. Mkk7 shows a striking preference for the threonine residue (thr-183)." SIGNOR-83736 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser705 LPEPAKKsEELVAEA 9606 10195894 t "Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response." SIGNOR-251283 Ub:E2 complex SIGNOR-C497 SIGNOR NSMCE1 protein Q8WV22 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270994 TWIST1 protein Q15672 UNIPROT SRPX protein P78539 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255534 CSNK2A1 protein P68400 UNIPROT RNF7 protein Q9UBF6 UNIPROT up-regulates phosphorylation Thr10 DVEDGEEtCALASHS 9606 BTO:0000567 12748192 t lperfetto "Ckbbp1 is phosphorylated in vivo and threonine to alanine mutation at residue 10 abrogates the phosphorylation of ckbbp1 observed in vivo, indicating that ckii is a major kinase that is responsible for in vivo phosphorylation of ckbbp1. As compared with the wild-type ckbbp1 or ckbbp1t10e (in which threonine 10 is replaced by glutamate), overexpression of nonphosphorylatable ckbbp1 (ckbbp1t10a) results in accumulation of ikappabalpha and p27kip1." SIGNOR-101187 IRF5 protein Q13568 UNIPROT IL10 protein P22301 UNIPROT down-regulates "transcriptional regulation" 9606 BTO:0000801 21240265 f "The role of IRF5 in inhibiting the transcription of the gene encoding IL-10 that we have identified here is important given its well- documented immunosuppressive activity." SIGNOR-254514 ATF4 protein P18848 UNIPROT "NLRP1 inflammasome" complex SIGNOR-C224 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 26086088 t miannu "Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression During Endoplasmic Reticulum Stress. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress." SIGNOR-260354 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNA13 protein Q14344 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t "inferred from 70% family members" milica "Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13." SIGNOR-269965 LATS1 protein O95835 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 21808241 t "Together,the YAP/TAZ-TEAD complex promotes proliferative and survival programs." gcesareni "Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators." SIGNOR-175783 CXCL1 protein P09341 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni "In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor." SIGNOR-152591 ACADM protein P11310 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR up-regulates 9606 BTO:0001370 28974683 f lperfetto "This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation" SIGNOR-261265 SRR protein Q9GZT4 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "chemical modification" 10090 BTO:0000142 12393813 t lperfetto "High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media." SIGNOR-268268 NR1H4 protein Q96RI1 UNIPROT ABCB4 protein P21439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000575 14527955 f miannu "Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor alpha heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (-1970 to -1958)." SIGNOR-254833 MAPK9 protein P45984 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni "Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress." SIGNOR-166698 (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI TET2 protein Q6N021 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001883 29090344 t miannu "Various studies have tried to investigate how the accumulation of R2-HG promotes leukemogenesis in cooperation with other frequently observed mutations in AML. An important role appears to be the ability of R2-HG to competitively inhibit multiple αKG-dependent dioxygenases. While TET2 normally catalyzes the conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), inhibition of TET2 by R2-HG has been found to result in a hypermethylated gene signature in HSPCs, which overlaps with the signatures of both IDH and TET2-mutated leukemic cells." SIGNOR-261829 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser497 EFDEDDWsD 9606 19012317 t gcesareni "Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo." SIGNOR-182362 AKT1 protein P31749 UNIPROT HTT protein P42858 UNIPROT unknown phosphorylation Ser419 GGRSRSGsIVELIAG 9606 BTO:0000938 12062094 t llicata "We demonstrate that huntingtin is a substrate of akt and that phosphorylation of huntingtin by akt is crucial to mediate the neuroprotective effects of igf-1." SIGNOR-252590 SMC4 protein Q9NTJ3 UNIPROT "Condensin II" complex SIGNOR-C342 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263909 ROCK1 protein Q13464 UNIPROT RND3 protein P61587 UNIPROT up-regulates phosphorylation Ser11 RRASQKLsSKSIMDP 9606 15775972 t lperfetto "We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability." SIGNOR-134703 PKNOX1 protein P55347 UNIPROT SYP protein P08247 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20864515 f miannu "Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content." SIGNOR-254923 CDK1 protein P06493 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 t gcesareni "Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1." SIGNOR-178202 BAZ1B protein Q9UIG0 UNIPROT WICH complex SIGNOR-C449 SIGNOR "form complex" binding 9606 16603771 t miannu "We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling." SIGNOR-268828 PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 29681515 f apalma "Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7, facilitating the recruitment of the ASH2L:MLL1/2:WDR5:RBBP5 histone H3 lysine 4 (H3K4) methyltransferase complex to the proximal promoter of Myf5 resulting in permissive H3K4 tri-methylation (H3K4me3) of the surrounding chromatin" SIGNOR-255899 FGFR2 protein P21802 UNIPROT GLO1 protein Q04760 UNIPROT "up-regulates activity" phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu "We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D)." SIGNOR-276184 FBXO15 protein Q8NCQ5 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0005816 24703837 t miannu "Fbxo15 Targets CLS1 Protein for Ubiquitination and Degradation to Disrupt Mitochondrial Function. S. aureus infection induces expression of a kinase, PINK1, that phosphorylates an indispensable protein CLS1, which in turn triggers CLS1 ubiquitination and degradation by the F box protein (SCFFbxo15)." SIGNOR-272171 HUWE1 protein Q7Z6Z7 UNIPROT POLL protein Q9UGP5 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys27 ASSKVLAkIPRREEG 9606 BTO:0000567 22203964 t miannu "We found that Pol λ can be ubiquitinated by the E3 ligase Mule in vitro and in vivo and that this interaction is functionally connected to the phosphorylation-dependent stabilization of Pol λ by Cdk2/cyclinA. " SIGNOR-272904 SETMAR protein Q53H47 UNIPROT CHEK1 protein O14757 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000007 25024738 f miannu "We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination.  Phosphorylated Chk1 phosphorylates S495 of Metnase. Phosphorylated Metnase decreases the interaction of DDB1 with Chk1, reducing Chk1 targeting to the Cul4a E3 ubiquitin ligase, increasing Chk1 stability." SIGNOR-273609 RAD51C protein O43502 UNIPROT RAD51B/RAD51C complex SIGNOR-C65 SIGNOR "form complex" binding 9606 11751636 t miannu "We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities." SIGNOR-113388 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Thr143 RCFTRKYtLPPGVDP 9606 19593530 t "11383510: to test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization" lperfetto "Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization" SIGNOR-186947 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPB protein P17676 UNIPROT "down-regulates activity" binding 9606 12524424 t lperfetto "C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs." SIGNOR-97117 GAK protein O14976 UNIPROT CLTC protein Q00610 UNIPROT "up-regulates activity" phosphorylation Thr606 ILGNQMFtHYDRAHI 10090 31272276 t miannu "Clathrin heavy chain (CHC) was phosphorylated at T606 by its association partner cyclin G-associated kinase (GAK). This phosphorylation was required for proper cell proliferation and tumor growth of cells implanted into nude mice. " SIGNOR-275448 gossypol chemical CHEBI:28584 ChEBI BCL2 protein P10415 UNIPROT down-regulates "chemical inhibition" 9606 23336025 t gcesareni "Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol." SIGNOR-200469 RAB7A protein P51149 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 10116 16040606 t Sara "Rab7-Rac1 interaction may mediate late endosomal transport between microtubules and microfilaments" SIGNOR-261304 SEMA3A protein Q14563 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates binding 9606 10679438 t gcesareni "Plexins form stable complexes with neuropilin-1 or -2." SIGNOR-75168 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 9606 21078818 t gcesareni "Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt Beta-catenin signaling." SIGNOR-253128 FNTA protein P49354 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242568 ST6GAL1 protein P15907 UNIPROT CD22 protein P20273 UNIPROT "down-regulates activity" glycosylation Asn101 FLGDKNKnCTLSIHP -1 8702538 t lperfetto "CD22-ligand interaction is regulated by the activity of a b-galactoside a2,6- sialyltransferase that can inactivate CD22-mediated binding by sialylating the CD22 receptor itself. These observations suggest that N-linked glycosylation sites on the CD22 molecule may play a role in the regulation of CD22-mediated adhesion." SIGNOR-261741 PPARGC1A protein Q9UBK2 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 23277535 f gcesareni "PGC1a is a positive regulator of mitochondrial biogenesis and respiration, adaptive thermogenesis, gluconeogenesis as well as many other metabolic proc" SIGNOR-228618 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr465 VPVPTNLyGDFFTGD -1 10210201 t llicata "Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624." SIGNOR-250784 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1080 IFYYFSNsPSKRLRE 9606 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104671 SERPINC1 protein P01008 UNIPROT F11 protein P03951 UNIPROT "down-regulates activity" cleavage 31030036 t lperfetto "Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1" SIGNOR-264137 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM2 protein P08172 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257469 CDK1 protein P06493 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 14697231 t gcesareni "Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase." SIGNOR-120368 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates phosphorylation Thr531 NTTGSDNtDTEGS 9606 17936701 t lperfetto "Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo" SIGNOR-158414 Ub:E2 complex SIGNOR-C497 SIGNOR BARD1 protein Q99728 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271102 HAP1 protein P54257 UNIPROT NEUROD1 protein Q13562 UNIPROT "up-regulates activity" binding -1 12881483 t lperfetto "We identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2" SIGNOR-234602 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-258999 NCK1 protein P16333 UNIPROT WASL protein O00401 UNIPROT up-regulates binding 9606 11340081 t gcesareni "Nck and cdc42 activate n-wasp by redundant mechanisms." SIGNOR-107634 NFE2L2 protein Q16236 UNIPROT TFB2M protein Q9H5Q4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15684387 f lperfetto "Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC" SIGNOR-268998 SOHLH1 protein Q5JUK2 UNIPROT LHX8 protein Q68G74 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 16690745 t Luana "Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters." SIGNOR-266076 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT "up-regulates activity" phosphorylation Ser514 SAPIRSAsQAEEEPS 10441130 t miannu "Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation" SIGNOR-249714 MAX protein P61244 UNIPROT MXD3 protein Q9BW11 UNIPROT "up-regulates activity" binding 9606 7954804 t 2 miannu "the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences." SIGNOR-240393 CHUK protein O15111 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates activity" phosphorylation Ser183 DGSPNAGsVEQTPKK 9606 23602409 t miannu "Reduced nuclear p27 was also found in MCF7 human breast cancer cells that were transiently transfected with an IKKalpha expression vector; increased IKKalpha expression resulted in a dose dependent decrease in nuclear p27 and increased cytoplasmic p27 (XREF_FIG).|We found that IKKalpha phosphorylates p27 at S183 to cause its nuclear export." SIGNOR-278438 SRR protein Q9GZT4 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI "up-regulates quantity" "chemical modification" 10090 BTO:0000142 12393813 t lperfetto "High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media." SIGNOR-268270 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 9712898 t lperfetto "Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2." SIGNOR-59689 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249684 ACTB protein P60709 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270599 NT5E protein P21589 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "down-regulates quantity" "chemical modification" -1 31461341 t Luana "Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine." SIGNOR-269743 RBBP8 protein Q99708 UNIPROT "BRCA1-C complex" complex SIGNOR-C299 SIGNOR "form complex" binding phosphorylation:Ser327 ELPTRVSsPVFGATS 25400280 t lperfetto "The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2|The interaction between BRCA1 and CtIP within this complex is mediated by CDK‐dependent phosphorylation of CtIP‐S327" SIGNOR-263220 GRB7 protein Q14451 UNIPROT RND1 protein Q92730 UNIPROT up-regulates binding 9606 BTO:0000150 10664463 t gcesareni "We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo." SIGNOR-74914 CHRM2 protein P08172 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates 9606 BTO:0000007 12665513 f lperfetto "Here we show that m2 muscarinic receptors and go require taos and mek3/6 as the primary intermediates activating p38 mapk in 293 cells" SIGNOR-235536 ARHGAP27 protein Q6ZUM4 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260482 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 26652733 f "These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK." SIGNOR-256107 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 t "CCR1 is also activated by MIP-1α, MCP-2, and MCP-3, although maximum responses are only obtained with RANTES and MIP-1α." SIGNOR-254366 WT1 protein P19544 UNIPROT SRY protein Q05066 UNIPROT up-regulates binding 9606 12970737 t miannu "Here we report that wt1 binds to and acts synergistically with sry to activate transcription from a promoter containing sry-binding sites" SIGNOR-100345 MFGE8 protein Q08431 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "down-regulates activity" 10116 19020771 f Giorgia "In our current study, we have shown that after LPS-stimulation, MFG-E8-mediated apoptotic cell phagocytosis suppresses various ERK1/2, p38, JNK, and NFκB activation, resulting in a lower TNF-α release. We also explored whether MFG-E8 helps to suppress the proinflammatory pathway within RPMs. We hence incubated the macrophages with apoptotic cells and stimulated them with LPS and examined the activation of MAP kinase and NFkB pathways after the exogenous addition of recombinant MFG-E8 (rMFG-E8). While apoptotic cells alone had no effect on these pathways, the addition of rMFG-E8 to apoptotic cells prior to phagocytosis and LPS stimulation had a marked suppressive effect on all of the investigated pathways, particularly on the p38 and NFκB pathways that play a key role in the cytokine response of macrophages" SIGNOR-260651 CSNK1D protein P48730 UNIPROT PPP5C protein P53041 UNIPROT "up-regulates activity" phosphorylation Thr362 LFSEDGVtLDDIRKI 9606 BTO:0000007 29141220 t miannu " Here, we show an ""on/off switch"" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90. " SIGNOR-277373 CALM2 protein P0DP24 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates binding 9606 11796223 t "inferred from 70% of family members" miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-269888 JUN protein P05412 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 23936544 t lperfetto "MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production" SIGNOR-251713 nefazodone chemical CHEBI:7494 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency" SIGNOR-259069 POU5F1 protein Q01860 UNIPROT GATA6 protein Q92908 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22795133 f lperfetto "Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)" SIGNOR-253159 KIF1A protein Q12756 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272522 hsa-miR-199a-5p mirna URS0000554A4F_9606 RNAcentral FZD6 protein O60353 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000391 25772759 t Parnian "Observations suggest that miR-199a-5p targeted the 3’-UTR of FZD6 mRNA directly, resulting in inhibition of its expression in CRC." SIGNOR-277971 ATP6V0B protein Q99437 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR "form complex" binding 9606 33065002 t miannu "Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes." SIGNOR-277758 Alamandine chemical CID:44192273 PUBCHEM MRGPRD protein Q8TDS7 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 23446738 t Luana "Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D." SIGNOR-262308 TG protein P01266 UNIPROT Thyroid_hormonogenesis phenotype SIGNOR-PH110 SIGNOR up-regulates 9606 BTO:0004710 30886364 f miannu "In humans, the thyroid hormones T3 and T4 are synthesized in the thyroid gland in a process that crucially involves the iodoglycoprotein thyroglobulin. The overall structure of thyroglobulin is conserved in all vertebrates. Upon thyroglobulin delivery from thyrocytes to the follicular lumen of the thyroid gland via the secretory pathway, multiple tyrosine residues can become iodinated to form mono-iodotyrosine (MIT) and/or di-iodotyrosine (DIT); however, selective tyrosine residues lead to preferential formation of T4 and T3 at distinct sites." SIGNOR-259915 GLI1/GLI2 complex SIGNOR-C450 SIGNOR MYCN protein P04198 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000304 32766732 t "GLI2 and GLI1 heterodimerize via the Zn-finger domain" SimoneGraziosi "GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells" SIGNOR-269212 SRC protein P12931 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates phosphorylation Tyr110 RGHAAIDyTQLGLRF 9606 20943948 t llicata "Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation." SIGNOR-168545 JAG2 protein Q9Y219 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 9315665 t gcesareni "Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1." SIGNOR-236922 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser26 GTASRPSsSRSYVTT -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248882 RPS6KA1 protein Q15418 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" phosphorylation 9606 14625384 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-265346 DOT1L protein Q8TEK3 UNIPROT MYCBP2 protein O75592 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 32814769 t miannu "Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly." SIGNOR-267151 ITGB1BP1 protein O14713 UNIPROT "AM/b2 integrin" complex SIGNOR-C170 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257651 PRKCA protein P17252 UNIPROT PPP1R14A protein Q96A00 UNIPROT "up-regulates activity" phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto "A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP." SIGNOR-249259 PCSK2 protein P16519 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0001073 11690596 t miannu "Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension." SIGNOR-270335 NODAL protein Q96S42 UNIPROT ACVR1B protein P36896 UNIPROT "up-regulates activity" binding 9606 19874624 t Regulation miannu "Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors." SIGNOR-251939 DIP2A protein Q14689 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI "up-regulates quantity" "chemical modification" -1 30672040 t miannu "In this paper, we summarized the conservation of gene sequences and protein domains of DIP2 family members and predicted that they may have a similar functional role in acetyl-coenzyme A (acetyl-CoA) synthesis. We then used the most characterized member, disconnected interacting protein 2 homolog A (DIP2A), for further study. DIP2A is a cytoplasmic protein that is preferentially localized to mitochondria, and its acetyl-CoA synthetase activity has been demonstrated in vitro. Furthermore, the level of acetyl-CoA in HEK293 cells overexpressing DIP2A was increased, which is consistent with its metabolically related function." SIGNOR-266590 serotonin smallmolecule CHEBI:28790 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264287 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto "THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones." SIGNOR-268655 TET2 protein Q6N021 UNIPROT OGT protein O15294 UNIPROT up-regulates binding 9606 23353889 t miannu "Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation" SIGNOR-200695 FBXO11 protein Q86XK2 UNIPROT TP53 protein P04637 UNIPROT down-regulates neddylation Lys321 SSPQPKKkPLDGEYF 9606 17098746 t miannu "Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321" SIGNOR-150673 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT "up-regulates quantity by stabilization" sumoylation Lys626 KKKSKALkEEKMEID 9606 BTO:0000007 23686912 t miannu "Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1." SIGNOR-263901 AKT3 protein Q9Y243 UNIPROT JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 38402584 f miannu "Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells. " SIGNOR-277224 TWIST2 protein Q8WVJ9 UNIPROT NR2F1 protein P10589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255506 IL31RA protein Q8NI17 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 18926762 t gcesareni "Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex." SIGNOR-161430 PRKAA1 protein Q13131 UNIPROT CCNY protein Q8ND76 UNIPROT "up-regulates activity" phosphorylation Ser326 SARKRSAsADNLTLP 32723157 t lperfetto "Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16" SIGNOR-273011 2'-deoxyadenosine smallmolecule CHEBI:17256 ChEBI "2'-deoxyadenosine 5'-monophosphate(2-)" smallmolecule CHEBI:58245 ChEBI "up-regulates quantity" "precursor of" 20637175 t lperfetto "Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis" SIGNOR-275811 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252881 WNT11 protein O96014 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131637 ADRB3 protein P13945 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256753 BCL2 protein P10415 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto "Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis" SIGNOR-249611 ETV6 protein P41212 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002883 16828711 f miannu "Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma." SIGNOR-254138 "L-cystathionine dizwitterion" smallmolecule CHEBI:58161 ChEBI "L-cysteine zwitterion" smallmolecule CHEBI:35235 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275813 PRPF19 protein Q9UMS4 UNIPROT PRPF3 protein O43395 UNIPROT "up-regulates activity" polyubiquitination 9606 20595234 t k63 miannu "Here, we report that the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains. The K63-linked chains increase the affinity of Prp3 for the U5 snRNP component Prp8, thereby allowing for the stabilization of the U4/U6.U5 snRNP. " SIGNOR-271966 TAF1 protein P21675 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263932 Naltriben chemical CID:5486827 PUBCHEM OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258426 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser454 YVPMNPNsPPRQHSS 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249460 PPM1B protein O75688 UNIPROT CDK2 protein P24941 UNIPROT "down-regulates activity" dephosphorylation 9606 20538721 t miannu "CDK2 can be dephosphorylated and inactivated by protein phosphatase type 2C beta isoform long (PP2Cbetal), a unique phosphatase that was originally cloned from human liver." SIGNOR-277153 SMARCC1 protein Q92922 UNIPROT "Neural progenitor-specific SWI/SNF" complex SIGNOR-C477 SIGNOR "form complex" binding 9606 25195934 t miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270617 "SCH 23390" chemical CHEBI:73297 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258732 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 21349850 t gcesareni "Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth." SIGNOR-172239 PTPRC protein P08575 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation 9606 11124968 t lperfetto "Taken together, these data indicate that CD45 inhibits PMA dependent PKCdelta activation by impeding PMA dependent PKCdelta tyrosine phosphorylation.|reduction in CD45 expression caused the duration of peak PMA-induced MEK and extracellular signal-regulated kinase (ERK) 1/2 activity to increase from 5 min to 30 min while leading to a 4-fold increase in PMA-dependent PKCdelta activation." SIGNOR-277028 FLT3 protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni "Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation." SIGNOR-245057 DAB2IP protein Q5VWQ8 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity" relocalization 10090 20080667 t miannu "DAB2IP prevents β-catenin nuclear translocation." SIGNOR-254755 SLC24A3 protein Q9HC58 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "down-regulates quantity" relocalization 9606 30173760 t miannu "K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+)" SIGNOR-264391 RYK protein P34925 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 17035295 t gcesareni "Interaction between ryk and fz has been reported, suggesting that the two proteins may form a multi-receptor complex signalling through the canonical pathway" SIGNOR-150010 ARHGEF15 protein O94989 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260541 glycogen smallmolecule CHEBI:28087 ChEBI "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI "up-regulates quantity" "precursor of" 9606 3346228 t "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267955 MAPK3 protein P27361 UNIPROT MAZ protein P56270 UNIPROT up-regulates phosphorylation Thr72 AAPAPPPtPQAPAAE 9606 11809795 t lperfetto "Together, these results show that activation of saf-1 in response to il-1 and -6 is mediated via map kinase-regulated phosphorylation." SIGNOR-114475 EP300 protein Q09472 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 SIGNOR-C6 11062529 t gcesareni "The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis." SIGNOR-83846 PRKACA protein P17612 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr90 NKQDRTLtIVDTGIG 9606 21919888 t lperfetto "Thr90 phosphorylation of hsp90_ by protein kinase a regulates its chaperone machinery" SIGNOR-176614 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT "down-regulates activity" phosphorylation Thr1116 AALGSTGtVAHLVAS 23871434 t "Phosphosite positions are derived from Figure S5" lperfetto "AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro" SIGNOR-275484 AMPK complex SIGNOR-C15 SIGNOR TBC1D1 protein Q86TI0 UNIPROT down-regulates phosphorylation Ser237 RPMRKSFsQPGLRSL 9606 17995453 t lperfetto "In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar" SIGNOR-216631 CSNK2A1 protein P68400 UNIPROT BMI1 protein P35226 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser110 SADAANGsNEDRGEV 9606 28270146 t miannu "Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function." SIGNOR-277345 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT "up-regulates activity" phosphorylation Ser151 VLPSSKRsPSTATLS 9606 BTO:0001061 31730483 t miannu "Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells." SIGNOR-276779 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109617 CSNK2A1 protein P68400 UNIPROT OTUB1 protein Q96FW1 UNIPROT "up-regulates activity" phosphorylation Ser16 QKQEPLGsDSEGVNC 34785775 t lperfetto "Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. |Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec" SIGNOR-276527 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11159537 f miannu "STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma." SIGNOR-253050 TLN1 protein Q9Y490 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257607 procainamide chemical CHEBI:8428 ChEBI ACHE protein P22303 UNIPROT "down-regulates activity" "chemical inhibition" -1 9301662 t miannu "With the aim of performing a rigorous test of the anti-AChE properties of our compounds, the kinetics of enzyme inhibition were studied in purified enzyme preparations. The inhibition data are shown in Table 1. Additionally, known competitive inhibitors of AChE (procainamide and edrophonium) were included in the study for comparative purposes." SIGNOR-258668 TNF protein P01375 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates activity" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253488 CREBBP protein Q92793 UNIPROT KLF1 protein Q13351 UNIPROT "up-regulates activity" acetylation Lys288 CAHPGCGkSYTKSSH 9606 11259590 t Regulation miannu "EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain." SIGNOR-251826 ASPA protein P45381 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI "down-regulates quantity" "chemical modification" 9606 17194761 t miannu "N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain." SIGNOR-267526 TP53 protein P04637 UNIPROT VCAN protein P13611 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12438652 t miannu "By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53." SIGNOR-255441 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269364 KLF6 protein Q99612 UNIPROT DLK1 protein P80370 UNIPROT down-regulates "transcriptional regulation" 9606 15917248 f "Repression of dlk1 requires hdac3 deacetylase activity" fspada "We have identified krappel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation." SIGNOR-210016 CSNK2A1 protein P68400 UNIPROT G6PD protein P11413 UNIPROT "up-regulates activity" phosphorylation Thr145 FYLALPPtVYEAVTK 9606 BTO:0002923 37478541 t miannu "CK2 phosphorylates G6PD T145 under ionizing radiation " SIGNOR-277890 "CAK complex" complex SIGNOR-C456 SIGNOR RARG protein P13631 UNIPROT "up-regulates activity" phosphorylation Ser77 SEEMVPSsPSPPPPP 9534 BTO:0000298 10748061 t miannu "Retinoic acid receptor gamma (RARgamma) is phosphorylated in COS-1 cells at two conserved serine residues located in the N-terminal region (serines 77 and 79 in RARgamma1 and serines 66 and 68 in RARgamma2) that contains the activation function AF-1. These serines are phosphorylated in vitro by cdk7, a cyclin-dependent kinase associated to cyclin H and MAT1 in the CAK complex (cdk7.cyclin H. MAT1), that is found either free or as a component of the transcription/DNA repair factor TFIIH. " SIGNOR-275969 EIF2B4 protein Q9UI10 UNIPROT EIF2S3 protein P41091 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269137 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1RN protein P18510 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000130;BTO:0000876 20032313 f miannu "The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils." SIGNOR-254794 TP53 protein P04637 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14985507 t gcesareni "Northern blot analysis with a specific probe demonstrates an increase in siah-1b transcription on activation of endogenous and inducible exogenous p53. To explore whether this effect is directly mediated by p53 we analyzed 20 kb of chromosome x dna, containing the siah-1b locus. A p53-binding site was identified in the siah-1b promoter, located at nucleotides -2155/-2103 relative to the translational start site." SIGNOR-122986 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR THBD protein P07204 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15677570 f miannu "We further show evidence suggesting that NF-κB inhibits TM expression indirectly by competition for the coactivator p300/CBP." SIGNOR-253909 belinostat chemical CHEBI:61076 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257955 HTR2C protein P28335 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257013 DDHD2 protein O94830 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "down-regulates quantity" "chemical modification" 9606 22922100 t miannu "Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain." SIGNOR-269649 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates "chemical activation" 9606 22944199 t lperfetto "Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell)." SIGNOR-252320 "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR RABGEF1 protein Q9UJ41 UNIPROT "up-regulates activity" relocalization 10090 27411398 t lperfetto "AP-1/sigma1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation." SIGNOR-260706 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser365 IVDQRPSsRASSRAS 9606 16474210 t lperfetto "We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity." SIGNOR-144461 "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI CAPZA1 protein P52907 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132 12788695 t lperfetto "We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations." SIGNOR-261842 MRPS11 protein P82912 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261458 erlotinib chemical CHEBI:114785 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258212 VKORC1 protein Q9BQB6 UNIPROT "Reduced Vitamin K" smallmolecule CHEBI:8784 ChEBI "up-regulates quantity" "chemical modification" 9606 31226734 t lperfetto "This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)" SIGNOR-265905 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269370 "Golimumab (Simponi)" antibody DB06674 DRUGBANK TNF protein P01375 UNIPROT "down-regulates activity" binding 9606 33369527 t "Golimumab is a transgenic anti-TNF monoclonal antibody that acts primarily by targeting and neutralizing TNF, thus preventing inflammation." SIGNOR-272491 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR POLR2A protein P24928 UNIPROT down-regulates phosphorylation 9606 14662762 t "inferred from 70% family members" lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-270156 BLVRB protein P30043 UNIPROT bilirubin(2-) smallmolecule CHEBI:57977 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000759 7929092 t lperfetto "This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions." SIGNOR-275523 MECP2 protein P51608 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0002881 19427855 f Luana "Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2" SIGNOR-264966 MARK2 protein Q7KZI7 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275437 HIC1 protein Q14526 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates quantity by repression" binding 9606 BTO:0000815 24067369 t miannu "HIC1 interacts with the DNA binding domain of STAT3 and suppresses the binding of STAT3 to its target gene promoters. HIC1 C-terminal domain binds to STAT3. HIC1 mutant defective in STAT3 interaction reduced its repressive effect on STAT3 DNA binding activity, the reporter activity and gene expression of the VEGF and c-Myc genes, and cell growth in MDA-MB 231 cells." SIGNOR-254246 CDK2 protein P24941 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 t gcesareni "In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2" SIGNOR-144000 "Succinate dehydrogenase-Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI "down-regulates quantity" "chemical modification" 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions." SIGNOR-266276 FGF5 protein P12034 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates binding 9606 8386828 t gcesareni "Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2." SIGNOR-38704 GSK3B protein P49841 UNIPROT EIF2B2 protein P49770 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175475 PRKCD protein Q05655 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251631 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT "down-regulates activity" phosphorylation Thr183 TLLMKKDtLTEEETQ 9606 BTO:0000567 26057687 t miannu "Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis. " SIGNOR-276913 FBXO7 protein Q9Y3I1 UNIPROT WDR62 protein O43379 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 phosphorylation:Thr1053 PSSSLPQtPEQEKFL 30566428 t lperfetto "WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053" SIGNOR-271711 Ub:E2 complex SIGNOR-C497 SIGNOR HERC3 protein Q15034 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271291 RPA2 protein P15927 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19586055 t esanto "The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. We observe a direct interaction between rpa with both nbs1 and mre11. By utilizing rpa bound to ssdna, we demonstrate that substituting rpa with phosphorylated rpa or a phosphomimetic weakens the interaction with the mrn complex." SIGNOR-186651 EEF1A2 protein Q05639 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 f lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269394 ADRA2B protein P18089 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257109 Ub:E2 complex SIGNOR-C497 SIGNOR RNF20 protein Q5VTR2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271111 SYK protein P43405 UNIPROT CGAS protein Q8N884 UNIPROT "up-regulates activity" phosphorylation Tyr215 LLNTGSYyEHVKISA 10090 BTO:0003292 36252040 t miannu "Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation." SIGNOR-277845 DLL1 protein O00548 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR "up-regulates activity" binding 9606 BTO:0000776 16140393 t lperfetto "Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate." SIGNOR-209741 CDK5 protein Q00535 UNIPROT SYN1 protein P17600 UNIPROT up-regulates phosphorylation Ser551 PAARPPAsPSPQRQA 9606 10880969 t lperfetto "Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin." SIGNOR-78883 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR FGFR4 protein P22455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 t miannu "Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA." SIGNOR-251569 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR GCH1 protein P30793 UNIPROT up-regulates 9606 9204951 f miannu "UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine." SIGNOR-252206 MAPK10 protein P53779 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 t gcesareni "Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells." SIGNOR-178926 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser18 RRLLFACsPPPASQP 9606 BTO:0002181 34363019 t miannu "Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. " SIGNOR-276736 DNMT3A protein Q9Y6K1 UNIPROT FGF21 protein Q9NSA1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29091029 f Gianni "Unbiased gene profiling studies revealed Fgf21 as a key negatively regulated Dnmt3a target gene in adipocytes with concordant changes in DNA methylation at the Fgf21 promoter region." SIGNOR-262200 CALM2 protein P0DP24 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266322 CDK1 protein P06493 UNIPROT SYN3 protein O14994 UNIPROT up-regulates phosphorylation Ser470 PQGQQPLsPQSGSPQ 9606 14732590 t lperfetto "A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action." SIGNOR-121398 PLK1 protein P53350 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by destabilization" phosphorylation 23972993 t "For phosphorylated residues see Figure 7" lperfetto "Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP" SIGNOR-274053 TGFB1 protein P01137 UNIPROT PPP2R2A protein P63151 UNIPROT "up-regulates activity" binding 9606 19114990 t lperfetto "The Balpha subunit interacts directly with activated T_RI. The Balpha interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity" SIGNOR-217894 isoprenaline chemical CHEBI:64317 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 8982677 t miannu "K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists." SIGNOR-258578 RITA1 protein Q96K30 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 21102556 t gcesareni "Thus, we propose that rita acts as a negative modulator of the notch signalling pathway, controlling the level of nuclear rbp-j/cbf-1, where its amounts are limiting." SIGNOR-170089 IDH1 protein O75874 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI "down-regulates quantity" 9606 26178471 t lperfetto "Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)" SIGNOR-253137 HTR4 protein Q13639 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257041 JAK2 protein O60674 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Tyr718 IPERDSRySQPLHEE 9606 19287004 t lperfetto "Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively." SIGNOR-184600 FFAR3 protein O14843 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256678 CSNK2A1 protein P68400 UNIPROT HDAC3 protein O15379 UNIPROT "up-regulates activity" phosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 t llicata "A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity." SIGNOR-250889 SRC protein P12931 UNIPROT WNK4 protein Q96J92 UNIPROT "down-regulates activity" phosphorylation Tyr1115 PVWMNYSySSLCLSS 9606 BTO:0002181 25805816 t miannu "Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. " SIGNOR-276895 PPM1A protein P35813 UNIPROT CDK2 protein P24941 UNIPROT "down-regulates activity" dephosphorylation -1 10934208 t miannu "Moreover, purified recombinant PP2C alpha and PP2C beta 2 proteins efficiently dephosphorylated monomeric Cdk2/Cdk6 in vitro." SIGNOR-277107 YY1 protein P25490 UNIPROT HSPA5 protein P11021 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15899857 f miannu "YY1, a constitutively expressed multifunctional transcription factor, activates the Grp78 promoter only under ER stress conditions." SIGNOR-255620 MAPK1 protein P28482 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t gcesareni "Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability." SIGNOR-77651 Ub:E2 complex SIGNOR-C497 SIGNOR HERC1 protein Q15751 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271306 ELANE protein P08246 UNIPROT SERPIND1 protein P05546 UNIPROT "down-regulates activity" cleavage Val458 QATTVTTvGFMPLST -1 2318847 t miannu "Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC." SIGNOR-256510 CDK2 protein P24941 UNIPROT ING5 protein Q8WYH8 UNIPROT "up-regulates quantity" phosphorylation Thr152 RRTSEEDtPKKKKHK 9606 25860957 t miannu "We report that ING5 is phosphorylated in a cell cycle dependent manner by CDK2 at T152 (Figs 1 and 3)." SIGNOR-279447 EEF1A1 protein P68104 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269506 MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000298 8974401 t lperfetto "A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively." SIGNOR-45366 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000150 10550055 t lperfetto "Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint." SIGNOR-72052 MAX protein P61244 UNIPROT MNT protein Q99583 UNIPROT "up-regulates activity" binding 9606 7954804 t 2 miannu "the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences." SIGNOR-240354 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr771 ADIESSNyMAPYDNY -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248415 DZIP3 protein Q86Y13 UNIPROT H2AW protein Q7L7L0 UNIPROT "up-regulates activity" monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu " 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation." SIGNOR-271757 SMURF1 protein Q9HCE7 UNIPROT TPM4 protein P67936 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272684 GART protein P22102 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI "up-regulates quantity" "chemical modification" 9606 11381136 t miannu "The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR." SIGNOR-267304 CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 15657060 t lperfetto "Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3." SIGNOR-133267 CHKA protein P35790 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" phosphorylation Tyr530 FTSTEPQyQPGENL 9606 28784162 t miannuccelli "Figure XREF_FIG shows that even though Chk phosphorylated Tyr 527 of Src to a level much lower than that of Csk, it was a much more efficient inhibitor of Src kinase activity.|These results suggest that Chk inhibited Src with a mechanism independent of Tyr-527 phosphorylation." SIGNOR-279731 "Neuromedin B" smallmolecule CHEBI:80139 ChEBI NMBR protein P28336 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257547 PRKCD protein Q05655 UNIPROT ADCY7 protein P51828 UNIPROT "up-regulates activity" phosphorylation 9606 12454008 t miannu "Immunoprecipitation data indicated that PKCdelta could bind and directly phosphorylate AC7." SIGNOR-279258 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT "up-regulates activity" phosphorylation Ser644 NLMFRKFsLERPFRP -1 24548923 t miannu "Akt phosphorylates S637 and S645 in the linker region of Carma1 " SIGNOR-276621 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT "up-regulates activity" cleavage Phe709 ENPTYKFfEQMQN -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261777 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser300 SMSDPGVsYRTREEI -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109555 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 14585074 f amattioni "Activation of the nf-kb pathway regulates a variety of ant-apoptotic factors" SIGNOR-96834 TFEB protein P19484 UNIPROT CD36 protein P16671 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 33176151 f lperfetto "Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)" SIGNOR-276785 SNRPD2 protein P62316 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270636 RHOH protein Q15669 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" relocalization 10090 BTO:0004850 18089848 t irozzo "Therefore, RhoH functions as a Rac1 antagonist by inhibiting Rac1 translocation to the cell plasma membrane in the regulation of cell migration and F-actin assembly of HPCs" SIGNOR-259085 DLAT protein P10515 UNIPROT PDH complex SIGNOR-C402 SIGNOR "form complex" binding 9606 20160912 t miannu "The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently." SIGNOR-266546 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical _-catenin pathway" SIGNOR-198843 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser13 GQDMSQVsGKESPPV 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo" SIGNOR-174824 NUP98 protein P52948 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262098 MAPK12 protein P53778 UNIPROT TP53BP1 protein Q12888 UNIPROT "down-regulates activity" phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto "Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK" SIGNOR-264448 MAP2K1 protein Q02750 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 11904294 t gcesareni "We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation." SIGNOR-116149 PIP3 smallmolecule CHEBI:16618 ChEBI "Macropinosomes formation" phenotype SIGNOR-PH227 SIGNOR up-regulates 9606 BTO:0001033 29572236 f miannu "PIP3 produced by type I PI3Ks is required for macropinosome closure; in some cell types, PIP3 is also required for membrane ruffling" SIGNOR-277769 AIMP1 protein Q12904 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates binding 9606 18448069 t lpetrilli "Here, we report that aimp1 negatively regulates tgf-? Signaling via stabilization of smurf2." SIGNOR-178498 NDUFA12 protein Q9UI09 UNIPROT "NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262152 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr794 LEMLVPStPTSTSGA 9606 15125835 t lperfetto "Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis." SIGNOR-124650 ELAVL3 protein Q14576 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 19221430 t miannu "Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure" SIGNOR-266864 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp546 ALQTDIVdLQRSPMG 9606 11741536 t gcesareni "Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis." SIGNOR-112796 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Thr325 TELEPLCtPVVTCTP phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto "Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos" SIGNOR-263010 SRC protein P12931 UNIPROT TNK2 protein Q07912 UNIPROT "up-regulates activity" phosphorylation Tyr860 KVSSTHYyLLPERPS -1 36178070 t miannu "We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity. " SIGNOR-276341 CCAR2 protein Q8N163 UNIPROT SIRT1 protein Q96EB6 UNIPROT "down-regulates activity" binding 9606 22735644 t lperfetto " Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death. " SIGNOR-267663 PRKCQ protein Q04759 UNIPROT ARHGEF6 protein Q15052 UNIPROT "up-regulates activity" phosphorylation Ser225 KSSERPLsPKAVKGF 25694429 t lperfetto "Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation.|More specifically, αPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway." SIGNOR-272169 CDK1 protein P06493 UNIPROT TOP1 protein P11387 UNIPROT "up-regulates activity" phosphorylation Ser112 EKENGFSsPPQIKDE -1 18408216 t miannu "In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells." SIGNOR-276156 EPHA5 protein P54756 UNIPROT GLO1 protein Q04760 UNIPROT "up-regulates activity" phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu "We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D)." SIGNOR-276183 FUS protein P35637 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR "up-regulates quantity" 9606 BTO:0000312 22051914 f lperfetto "Similarly, cytoplasmic inclu- sions containing mutant fused in sarcoma (FUS) protein have been observed in some patients with FUS-related FALS." SIGNOR-262277 CNR1 protein P21554 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257211 RABGGTA protein Q92696 UNIPROT RAB5A protein P20339 UNIPROT "up-regulates activity" lipidation 9606 BTO:0000007 18532927 t miannu "Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional" SIGNOR-265572 DAB2IP protein Q5VWQ8 UNIPROT PIK3CA protein P42336 UNIPROT "down-regulates activity" binding 9606 27858941 t miannu "DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit." SIGNOR-254750 HTR2A protein P28223 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256742 BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 20651737 t lperfetto "Engagement of cd40 with its ligand cd40l results in the recruitment of the TRAF3/TRAF2/cIAP Complex to the receptor. At the receptor, traf3 undergoes ciap-dependent k48-linked polyubiquitylation (ub) that targets it for proteasomal degradation. In the absence of traf3, nik protein levels accumulate as it can no longer be recruited to the TRAF2/cIAP Complex." SIGNOR-167057 NSD3 protein Q9BZ95 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" methylation Lys366 RLVMVLysVVPTC 9606 BTO:0002181 29101251 t irozzo "We found that lysine methyltransferase NSD3 interacts with and directly monomethylates IRF3 in the nucleus, leading to the enhanced IRF3 transcriptional activity and antiviral immune responses." SIGNOR-259198 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM FGFR2 protein P21802 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258080 Ub:E2 complex SIGNOR-C497 SIGNOR FANCL protein Q9NW38 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271099 RAD50 protein Q92878 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 10426999 t amattioni "Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex." SIGNOR-69701 NKX3-1 protein Q99801 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 16697957 t miannu "NKX3.1 negatively regulates AKT activity in an AR-dependent manner" SIGNOR-251552 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Ser20 KRPQRATsNVFAMFD 9606 8702756 t miannu "Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase." SIGNOR-261709 PIGBOS1 protein A0A0B4J2F0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0002181 31653868 f miannu "Here, we characterize a microprotein called PIGBOS and reveal a role for a mitochondrial protein in UPR signaling. Together, these results showed that loss of PIGBOS increases cellular sensitivity to ER stress, which in turn increases apoptosis and links PIGBOS levels to the ability of cells to survive stress." SIGNOR-261042 CP-91149 chemical CID:9843900 PUBCHEM PYGL protein P06737 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191112 TBK1 protein Q9UHD2 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 23023393 t miannuccelli "TBK1 induces NIK phosphorylation and degradation." SIGNOR-279767 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257985 rep protein P0C6X7 UNIPROT DDX5 protein P17844 UNIPROT "up-regulates activity" binding 9606 19224332 t lperfetto "To our knowledge, this is the first report to show that SARS-CoV helicase can interact directly with multifunctional protein Ddx5 in cell culture and that inhibition of Ddx5 results in the suppression of viral replication. We speculate that Ddx5 may act as a coactivator by direct binding to the SARS-CoV helicase, resulting in enhanced viral genome transcription and virus proliferation." SIGNOR-260250 SREBF2 protein Q12772 UNIPROT SND1 protein Q7KZF4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29296233 t irozzo "These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression." SIGNOR-259136 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257978 SCF-betaTRCP complex SIGNOR-C5 SIGNOR TIAM1 protein Q13009 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0002181 25124033 t miannu "Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site." SIGNOR-276675 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WEE1 protein P30291 UNIPROT down-regulates binding 9606 15340381 t lperfetto "Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1." SIGNOR-217184 TGFB1 protein P01137 UNIPROT ENPP1 protein P22413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000249 20930330 f miannu "TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line." SIGNOR-252200 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser670 SKVRGPVsGSPDSMN 9606 BTO:0000007 10195894 t "Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response." SIGNOR-251274 CTH protein P32929 UNIPROT "L-homocysteine zwitterion" smallmolecule CHEBI:58199 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275825 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT "up-regulates activity" phosphorylation Ser321 SKPSGNDsCELRNLK -1 26119734 t miannu "Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro" SIGNOR-276213 DMTF1 protein Q9Y222 UNIPROT ECT2 protein Q9H8V3 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004532 19816943 f Luana " Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. " SIGNOR-261589 CMC1 protein Q7Z7K0 UNIPROT "MITRAC complex" complex SIGNOR-C538 SIGNOR "form complex" binding 9606 BTO:0000007 23260140 t "By analyzing MITRAC12 interaction partners, we show that recently identified assembly factors, such as c12orf62, CMC1, and the novel assembly factor MITRAC15, are constituents of MITRAC complexes" SIGNOR-272481 "tacrolimus (anhydrous)" chemical CHEBI:61049 ChEBI PPP3CA protein Q08209 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127239 SMURF1 protein Q9HCE7 UNIPROT TOM1L2 protein Q6ZVM7 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272700 SPI1 protein P17947 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26622774 f miannu "In the present study, PU.1 siRNA was demonstrated to efficiently inhibit the transcription level of oncogene MEIS1 in the human acute myeloid non-MLL leukemia U937 cell line. In addition, PU.1, as a positive regulator of MEIS1, performed a crucial role in maintaining cell proliferation." SIGNOR-256002 "WRC complex" complex SIGNOR-C191 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 20332100 t miannu "The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex" SIGNOR-253573 STAT4 protein Q14765 UNIPROT LAMTOR5 protein O43504 UNIPROT "up-regulates activity" binding 9606 22740693 t miannu "It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. here we first report that the transcription factor STAT4 plays a role in regulating S100A4 mediated by HBXIP in breast cancer." SIGNOR-255247 SHANK1 protein Q9Y566 UNIPROT ACTN1 protein P12814 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264583 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser439 SIGHSPLsLSAQSVM 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204732 PAMPs stimulus SIGNOR-ST11 SIGNOR "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR up-regulates 9606 25720354 f scontino "APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis." SIGNOR-267855 WNT3 protein P56703 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131823 "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI acetyl-CoA smallmolecule CHEBI:15351 ChEBI "up-regulates quantity" "precursor of" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-268083 CDK1 protein P06493 UNIPROT UBE2A protein P49459 UNIPROT up-regulates phosphorylation Ser120 LDEPNPNsPANSQAA 9606 11953320 t llicata "Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity." SIGNOR-116504 PRKCE protein Q02156 UNIPROT RAB11A protein P62491 UNIPROT unknown phosphorylation Ser177 TEIYRIVsQKQMSDR -1 22188018 t miannu "This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε." SIGNOR-263170 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MTHFR protein P42898 UNIPROT "down-regulates activity" phosphorylation Thr34 KDSSRCStPGLDPER 9606 BTO:0000007;BTO:0000567 24769206 t miannu "We have demonstrated that MTHFR is phosphorylated on T34by CDK1/Cyclin B1 in vivo and this phosphorylation peaks duringmitosis and decreases its enzymatic activity." SIGNOR-263888 LYPLA2 protein O95372 UNIPROT GAP43 protein P17677 UNIPROT "down-regulates quantity by destabilization" deacetylation Cys3 cCMRRTKQ 9606 BTO:0000567 21152083 t miannu "Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43." SIGNOR-266767 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Ser93 YPGSYSRsPAGSQQQ 9606 17310276 t lperfetto "Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1" SIGNOR-153304 SAR1A protein Q9NR31 UNIPROT SEC24A protein O95486 UNIPROT "up-regulates quantity" binding SIGNOR-C370 30605680 t lperfetto "Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer." SIGNOR-265303 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates binding 9606 20006481 t lperfetto "Akt can phosphorylate pras40, a raptor binding protein that also acts as an inhibitor of torc1. Akt-mediated phosphorylation of pras40 again promotes 14-3-3 binding, in this case leading to relief from pras40-mediated inhibition." SIGNOR-217565 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 SIGNOR-C110 11955436 t gcesareni "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." SIGNOR-116528 verapamil chemical CHEBI:9948 ChEBI SCN2A protein Q99250 UNIPROT "down-regulates activity" "chemical inhibition" 10116 1658608 t miannu "This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner." SIGNOR-258355 IKBKE protein Q14164 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19940156 t lperfetto "Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna." SIGNOR-161834 INS protein P01308 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" binding 10029 16956584 t lperfetto "Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface." SIGNOR-236748 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr115 MPDDLLTtLDDTCDL 9606 BTO:0002181 25795775 t miannu "We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. " SIGNOR-276447 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser272 EEPSPLPsPTASPNH 9606 BTO:0000142 15262992 t lperfetto "Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd" SIGNOR-126843 AKT1 protein P31749 UNIPROT RARA protein P10276 UNIPROT down-regulates phosphorylation Ser96 FVCQDKSsGYHYGVS 9606 BTO:0000551 16417524 t miannu "We report that akt, which is constitutively activated in nsclc cells, phosphorylates raralpha and inhibits its transactivation. / mutation of ser96 to alanine abrogated the suppressive effect of akt." SIGNOR-252489 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr323 STVSFNPyEPELAPW 9606 BTO:0000776 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246605 SPI1 protein P17947 UNIPROT FLI1 protein Q01543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10523830 f irozzo "Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression." SIGNOR-256054 SMAD4 protein Q13485 UNIPROT SMAD4/JUN complex SIGNOR-C10 SIGNOR "form complex" binding 9606 9312063 t gcesareni "Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter." SIGNOR-50589 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" phosphorylation 6239 10517632 t gcesareni "In addition, CKI bound to and increased the phosphorylation of dishevelled, a known component of the Wnt pathway" SIGNOR-244097 RPL9 protein P32969 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262452 D-serine smallmolecule CHEBI:16523 ChEBI "NMDA receptor_2D" complex SIGNOR-C350 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0002609 12393813 t lperfetto "D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically" SIGNOR-268280 "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25901680 f lperfetto "Ribosomes are translational machineries that catalyse protein synthesis." SIGNOR-262413 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-219262 HCK protein P08631 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" phosphorylation Tyr354 SSNQELIyEGRRLVL 9606 BTO:0002181 28618271 t miannu "The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. " SIGNOR-276726 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 17035229 t "SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248792 MRPL27 protein Q9P0M9 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262368 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys784 HVKLERLkQVNGMFP 9606 BTO:0000938 17283082 t lperfetto "Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage." SIGNOR-249577 "perfluorooctane-1-sulfonic acid" chemical CHEBI:39421 ChEBI PPARA protein Q07869 UNIPROT "up-regulates activity" "chemical activation" 10090 BTO:0000759 34861291 t miannu "Perfluorooctane sulfonate (PFOS) is a stable environmental contaminant that can activate peroxisome proliferator-activated receptor alpha (PPARα). These results indicate that mouse PPARα can be activated in the liver by PFOS causing increased expression of Acox1, Cyp4a10 and histopathological changes in the liver." SIGNOR-268754 SF3B1 protein O75533 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270653 PPP3R1 protein P63098 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR "form complex" binding 9606 14623295 t miannu "Calcineurin is a heterodimer consisting of a catalytic subunit with a molecular mass of about 59 kDa (calcienurin A or CNA) and a regulatory subunit with a molecular mass of 19 kDa (calcineurin B or CNB)." SIGNOR-255289 GCHFR protein P30047 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates activity" binding 9606 11361142 t miannu "The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine" SIGNOR-252203 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259809 afatinib chemical CHEBI:61390 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000551 22452896 t "Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases." gcesareni "Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors." SIGNOR-259440 ALX4 protein Q9H161 UNIPROT NCAM1 protein P13591 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003952 11696550 f miannu "Alx4 Overexpression Represses Endogenous N-CAM Expression" SIGNOR-254548 AKT1 protein P31749 UNIPROT BECN1 protein Q14457 UNIPROT "down-regulates activity" phosphorylation Ser234 AQYQREYsEFKRQQL 9606 31852899 t miannu "In addition, pharmacological inhibition of AKT1 enhanced BECN1 stability in both assays, leaving about twice the amount of BECN1 at 90 min compared to control (Fig. 4i\u2013l).|The oncogenic kinase AKT1 phosphorylates BECN1 at positions S234, S295, which leads to sequestration of this peripheral membrane binding protein xref to the cytoskeleton with the result of inhibition of autophagy xref ." SIGNOR-279666 SATB1 protein Q01826 UNIPROT IL23A protein Q9NPF7 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255132 TFE3 protein P19532 UNIPROT ATP6V0D2 protein Q8N8Y2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 24448649 f lperfetto "Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A)." SIGNOR-276810 NHLRC1 protein Q6VVB1 UNIPROT AGL protein P35573 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 17908927 t miannu "The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL." SIGNOR-271669 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT "up-regulates activity" phosphorylation Thr12 DLSGRELtIDSIMNK -1 26119734 t miannu "Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro" SIGNOR-276202 SOD1 protein P00441 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 10090 BTO:0004488 29371591 t "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction)" "Incubating SOD1G93A or SOD1G85R, another well-established misfolded SOD1 mutant, in the absence of recombinant MIF resulted in an exponential increase in thioflavin T (ThT) fluorescence (which correlates with amyloid aggregate formation)" SIGNOR-262796 "Blood vessel damage" stimulus SIGNOR-ST26 SIGNOR F3 protein P13726 UNIPROT up-regulates 9606 BTO:0000131 32665005 f lperfetto "During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury." SIGNOR-263541 KIF7 protein Q2M1P5 UNIPROT GLI3 protein P10071 UNIPROT "up-regulates quantity by stabilization" binding 10090 19592253 t lperfetto "These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh." SIGNOR-209614 RET protein P07949 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 10829012 t gcesareni "Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways" SIGNOR-77587 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10195903 t "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis." SIGNOR-248695 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr426 NEEWYVSyITRPEAE -1 8702662 t "Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro" SIGNOR-251382 PP2B proteinfamily SIGNOR-PF18 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f "inferred from 70% family members" gcesareni "The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c." SIGNOR-269993 CLK3 protein P49761 UNIPROT SRSF1 protein Q07955 UNIPROT "up-regulates activity" phosphorylation -1 8617202 t miannu "In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors." SIGNOR-273859 KAT2B protein Q92831 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 t gcesareni "The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis." SIGNOR-84032 idelalisib chemical CHEBI:82701 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190813 VPS39 protein Q96JC1 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" relocalization 9534 12941698 t miannu "The data demonstrating binding of TLP to TGF-β and activin type II receptors and selective inhibition of Smad3/Smad4 complex formation by deregulated TLP suggest that TLP is involved in localizing these receptors and Smad4 to specific intracellular compartments, where it regulates formation of Smad3/Smad4 but not Smad2/Smad4 complexes." SIGNOR-261377 TNKS2 protein Q9H2K2 UNIPROT PSMF1 protein Q92530 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 23622245 t lperfetto "We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31." SIGNOR-263386 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser4 sGFESYGS 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation" SIGNOR-162160 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser124 PALKRSHsDSLDHDI 9606 20068082 t gcesareni "The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216)." SIGNOR-163134 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" 9606 15284455 t SimoneGraziosi "Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. " SIGNOR-269264 "Lipid peroxidation" phenotype SIGNOR-PH235 SIGNOR Ferroptosis phenotype SIGNOR-PH234 SIGNOR up-regulates 9606 BTO:0003081 37834426 t miannu " ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell’s antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC." SIGNOR-279880 STK39 protein Q9UEW8 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0000988 21317537 t lperfetto "WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression," SIGNOR-264644 FGF13 protein Q92913 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253435 PFKM protein P08237 UNIPROT "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266471 CAMK2A protein Q9UQM7 UNIPROT DLG1 protein Q12959 UNIPROT "down-regulates activity" phosphorylation Ser232 ITLERGNsGLGFSIA 9534 BTO:0000298 12933808 t llicata "Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. | We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII." SIGNOR-250618 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258196 CCL7 protein P80098 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 14991608 t "For example, 11 chemokines are reported to bind to CC chemokine receptor (CCR) 1, including macrophage inflammatory protein (MIP)‐1α , MIP‐1β, MIP‐1δ, regulated upon activation, normal T cell‐expressed and secreted (RANTES), monocyte chemotactic peptide (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, leukotactin‐1 (Lkn‐1), myeloid progenitor inhibitory factor (MPIF)‐1, and hemofiltrate CC chemokine (HCC)‐1" SIGNOR-254368 ITGB1BP1 protein O14713 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257640 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT "down-regulates activity" dephosphorylation Ser367 DTRSLEIsQSYTTTQ 9606 18265945 t lperfetto "More recently, Shreeram et al.  have also shown that Wip1 dephosphorylates human ATM at Ser367 as well as Ser1981.|Thus, overexpression of Wip1 in an oncogenic context could contribute to tumor promotion by inhibiting both p53 and ATM functions." SIGNOR-276955 PLK1 protein P53350 UNIPROT KIZ protein Q2M2Z5 UNIPROT up-regulates phosphorylation Thr379 WSTSSDLtISISEDD 9606 16980960 t lperfetto "Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz." SIGNOR-149630 CLTA protein P09496 UNIPROT "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260678 AKT3 protein Q9Y243 UNIPROT IWS1 protein Q96ST2 UNIPROT "up-regulates activity" phosphorylation Thr721 QRRRMNStGGQTPRR 9606 BTO:0003536 24462114 t miannu "The data presented in this report confirmed the differential phosphorylation of IWS1 at Ser720/Thr721 by Akt3 and Akt1 and showed that its phosphorylation at this site is required for the recruitment of SetD2 to the Spt6-IWS1-Aly/REF complex." SIGNOR-273495 GAB1 protein Q13480 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 11043767 t lperfetto "We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1." SIGNOR-252676 SYK protein P43405 UNIPROT MAP4K1 protein Q92918 UNIPROT "up-regulates activity" phosphorylation Tyr381 SESSDDDyDDVDIPT 9606 11514608 t lperfetto "BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation." SIGNOR-246567 ETS1 protein P14921 UNIPROT ITGA11 protein Q9UKX5 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001282 16300938 t lperfetto "We speculate that the ""mesenchymal signature"" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors." SIGNOR-253352 NLGN2 protein Q8NFZ4 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264146 miR-155 mirna URS000062749E_9606 RNAcentral INPP5D protein Q92835 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255764 SETD5 protein Q9C0A6 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "up-regulates activity" methylation -1 31515109 t miannu "SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription." SIGNOR-265350 proline smallmolecule CHEBI:26271 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264744 ASB3 protein Q9Y575 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 15899873 t miannu "While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-alpha by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation" SIGNOR-271544 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 20729857 f lperfetto "We found Irf4 to be one of the direct targets of Jmjd3-mediated demethylation. Finally, we found that Irf4 is a transcription factor crucial for the induction of M2 macrophage responses." SIGNOR-249543 RAP1GDS1 protein P52306 UNIPROT RAP1B protein P61224 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171552 SIRT1 protein Q96EB6 UNIPROT ADAMTS5 protein Q9UNA0 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21337390 f miannu "The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5." SIGNOR-255140 OPTN protein Q96CV9 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 10090 BTO:0005118 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259877 KLHL25 protein Q9H0H3 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22578813 t miannu "We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination." SIGNOR-272050 NAIP protein Q13075 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 BTO:0000938 15280366 t gcesareni "These results demonstrate that naip is distinct from the other iaps, both in demonstrating a ligand-dependent caspase-9 interaction and in demonstrating a distinct mechanism of inhibition." SIGNOR-127193 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "down-regulates activity" binding 9606 15829516 t irozzo "Two classes of models can describe how AML1-ETO could interfere with normal AML1 activity. First, because AML1-ETO has the potential to interact with AML1 co-factors (such as CBFβ) through its RD, it could act as a dominant-negative molecule by competing with AML1 for these co-factors. Although AML1-ETO has been shown to interact with CBFβ and repress the expression of AML1-regulated genes in vitro and in cell culture, the available data do not distinguish between these two models." SIGNOR-256100 PRKAA1 protein Q13131 UNIPROT CPT1C protein Q8TCG5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21892142 f gcesareni "In 2010, bungard et al., reported that ampk can target transcriptional regulation through phosphorylation of histone h2b on serine3681. Cells expressing a mutant h2b s36a blunted the induction of stress genes upregulated by ampk including p21 and cpt1c." SIGNOR-176422 UNII-XH2662798I chemical CID:16156006 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation, regulated by wee1- and myt1-mediated phosphorylation and cdc25c-mediated dephosphorylation. Cdc25a may also be involved in cdk1 dephosphorylation in the g2/m-phase checkpoint." SIGNOR-163127 EED protein O75530 UNIPROT "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR "form complex" binding 9606 23110252 t lperfetto "The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48)." SIGNOR-241897 PRKDC protein P78527 UNIPROT CASP2 protein P42575 UNIPROT up-regulates phosphorylation Ser139 LSCDYDLsLPFPVCE 9606 19203584 t lperfetto "Here we show that dna damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the s122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase dna-pkcs" SIGNOR-183895 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser645 LNEKARLsYSDKNLI 9606 9305920 t gcesareni "Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt." SIGNOR-51000 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT "down-regulates activity" phosphorylation Thr7 tPCSSMSN 9606 BTO:0000567 26057687 t miannu "Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis. " SIGNOR-276914 HBB protein P68871 UNIPROT CYP2E1 protein P05181 UNIPROT "up-regulates activity" 9606 BTO:0000575 19325051 f Regulation miannu "Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes." SIGNOR-251764 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR RUNX1 protein Q01196 UNIPROT "up-regulates activity" binding 9606 25287865 t miannu "The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2" SIGNOR-277669 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR MYH3 protein P11055 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136647 NUDCD2 protein Q8WVJ2 UNIPROT PAFAH1B1 protein P43034 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 20133715 t miannu "The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability." SIGNOR-252167 PTPRG protein P23470 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" dephosphorylation Tyr1248 PTAENPEyLGLDVPV -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254701 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser324 RDLELPLsPSLLGGP 10090 BTO:0000944 7889942 t lperfetto "We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235459 TLN1 protein Q9Y490 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257630 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7566157 t gcesareni "The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting g1/s entry." SIGNOR-29248 PRKACA protein P17612 UNIPROT RAP1B protein P61224 UNIPROT up-regulates phosphorylation Ser179 PGKARKKsSCQLL 9606 19651783 t llicata "These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation" SIGNOR-187410 MRPL4 protein Q9BYD3 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262357 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR IL22RA1 protein Q8N6P7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 26171402 t miannu "FBXW12 causes depletion of endogenous and plasmid-derived IL-22R in lung epithelia, binds the E3 ligase constituent Skp-1, and facilitates ubiquitination of IL-22R in vitro." SIGNOR-272428 MARK2 protein Q7KZI7 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT "down-regulates activity" phosphorylation Ser366 KTLPRSSsMAAGLER 9606 21282462 t miannu "Par1b directly phosphorylates IRSp53 on S366 in cell lysates and stimulates phosphorylation on S453/3/5 via an indirect mechanism.|These data are consistent with a scenario in which Par1b phosphorylation inhibits IRSp53 function." SIGNOR-278411 LCK protein P06239 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" phosphorylation Tyr394 RLIEDNEyTAREGAK 9606 2250907 t lperfetto "They also demonstrate that replacement of the major site of autophosphorylation of p56lck (tyrosine 394) by a phenylalanine residue abolishes the ability to activate p56lck by CD4 cross-linking, implying that this residue is critical for the positive regulation of the Lck tyrosine kinase activity by CD4." SIGNOR-81372 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys137 FSGFPFEkGSVQYKK 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E)." SIGNOR-272831 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 15618519 t gcesareni "We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins" SIGNOR-132669 regorafenib chemical CHEBI:68647 ChEBI BRAF protein P15056 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26254357 t miannu "A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF" SIGNOR-259176 cortisol smallmolecule CHEBI:17650 ChEBI NR3C1 protein P04150 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 8282004 t miannu "The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4)." SIGNOR-258708 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr209 TRKHYQPyAPPRDFA 9606 BTO:0000661 22936936 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals" SIGNOR-198751 PSMB1 protein P20618 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263356 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates activity" dephosphorylation Ser661 SSNDSRSsLIRKRST 9606 BTO:0000007 24333728 t "Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp" SIGNOR-272505 TFIIH complex SIGNOR-C457 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 21157430 t acerquone "Here, we show that the transcription factor tfiih, via its cdk7 kinase, phosphorylates the androgen receptor (ar) at position ar/s515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the mdm2 e3 ligase, the subsequent ubiquitination of ar at the promoter of target genes and its degradation by the proteasome machinery" SIGNOR-269331 APBA2 protein Q99767 UNIPROT STXBP1 protein P61764 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 9395480 t miannu "Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1." SIGNOR-264037 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Thr161 SDEEAEStKEAQNEL -1 12852856 t lperfetto "Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction" SIGNOR-103364 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT "up-regulates activity" phosphorylation Ser1219 KNLHSSHsSGLMDKS 9606 BTO:0000565 28630147 t miannu "Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C)." SIGNOR-266419 Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270902 PPARGC1A protein Q9UBK2 UNIPROT SOD2 protein P04179 UNIPROT up-regulates 10090 18074631 f lperfetto "In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat." SIGNOR-253395 TRIM21 protein P19474 UNIPROT GMPS protein P49915 UNIPROT down-regulates ubiquitination 9606 24462112 t miannu "Cytoplasmic sequestration of gmps requires ubiquitylation by trim21, a ubiquitin ligase associated with autoimmune disease." SIGNOR-204478 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 SIGNOR-C83 10428798 t gcesareni "Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity." SIGNOR-69718 SOX4 protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 BTO:0003104 24970928 t irozzo "The findings in this study raise the possibility that Sox4 may also antagonize Lef1 (Tcf1 is not expressed in pro-B lymphocytes) function by controlling the stability of β-catenin in pro-B lymphocytes." SIGNOR-256139 RAP1A protein P62834 UNIPROT PLCE1 protein Q9P212 UNIPROT "up-regulates quantity" binding 9606 BTO:0000783 21478675 t miannu " The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε." SIGNOR-278142 NXF1 protein Q9UBU9 UNIPROT mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 28831067 f lperfetto "SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1." SIGNOR-263298 SRC protein P12931 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Tyr289 MELQTYRyHGHSMSD 9606 BTO:0000007 26848621 t miannu "Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1). " SIGNOR-277204 MARK2 protein Q7KZI7 UNIPROT PINK1 protein Q9BXM7 UNIPROT "up-regulates activity" phosphorylation Thr313 EGLGHGRtLFLVMKN -1 22238344 t miannu " MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD. " SIGNOR-276401 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Thr218 TAANSRDtIFQKERF 9606 19366211 t llicata "This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop." SIGNOR-185303 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8892604 t lperfetto "Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function" SIGNOR-44669 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR FBXO30 protein Q8TB52 UNIPROT down-regulates 10090 BTO:0000887 24076600 f "BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1)" SIGNOR-256488 STUB1 protein Q9UNE7 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27007160 t miannu "Via this mechanism, CHIP ubiquitinates and degrades glucocorticoid receptor (GR), androgen receptor (AR), estrogen receptor (ER), ErbB2, and alpha-synuclein, only when bound to Hsp ." SIGNOR-278782 SRC protein P12931 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT "down-regulates activity" phosphorylation 9606 26280531 t miannu "Prior phosphorylation of Y395 dramatically increases the rate of EGFR phosphorylation of Mig6 on Y394 in vitro, and suppression of Src activity pharmacologically or by shRNA decreased phosphorylation of Mig6 on this site in cells, impairing EGFR binding and inhibition.|We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395." SIGNOR-279116 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation 10090 BTO:0003620 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling" SIGNOR-248347 PLEKHG1 protein Q9ULL1 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260563 SMURF1 protein Q9HCE7 UNIPROT FKBP3 protein Q00688 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272694 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser99 HFAIAADsEAEQDSW -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-250909 RPL26 protein P61254 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262497 PRKCA protein P17252 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 t lperfetto "A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis." SIGNOR-249236 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 17804415 t gcesareni "Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun." SIGNOR-157725 PPARGC1A protein Q9UBK2 UNIPROT COX5B protein P10606 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000443 23021218 f lperfetto "PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b)." SIGNOR-253099 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" deacetylation 10090 BTO:0001103 24003218 t lperfetto "SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation" SIGNOR-217963 CSNK2A1 protein P68400 UNIPROT ATXN3 protein P54252 UNIPROT "up-regulates activity" phosphorylation Ser236 LQRALALsRQEIDME 9606 BTO:0000007 19542537 t miannu "Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs." SIGNOR-276225 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT "up-regulates activity" phosphorylation Ser300 KKDQEGDsAAALSLY 9606 20643644 t Manara "We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase." SIGNOR-260793 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t gcesareni "...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation." SIGNOR-247902 YARS1 protein P54577 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI "up-regulates quantity" "chemical modification" 9606 14660560 t miannu "Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA." SIGNOR-270798 ATR protein Q13535 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser31 ALRLLDSsQIVIISA 10090 BTO:0001372 11459832 t lperfetto "These results thus suggest that this serine 31 residue is indeed an atm/atr phosphorylation site and in fact is the major site for atm/atr-mediated phosphorylation within e2f1. Thus, it is possible that the atm/atr-mediated phosphorylation inhibits the binding and function of skp2 and thus prevents the normal degradation of e2f1" SIGNOR-109420 ACTR2 protein P61160 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "form complex" binding 9606 12479800 t "The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc" SIGNOR-251512 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser332 STPKSKQsPISTPTS 9606 14741103 t llicata "In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35." SIGNOR-250667 ACTB protein P60709 UNIPROT "Muscle cell-specific SWI/SNF ARID1A variant" complex SIGNOR-C481 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270698 MAPK12 protein P53778 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" phosphorylation Ser201 SGDSDASsPRSNCSD 10090 BTO:0005930 20026657 t miannu " We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity. Phosphorylation of MyoD by p38-γ directs the assembly of a repressive transcriptional complex at the Myogenin promoter." SIGNOR-276273 EGFR protein P00533 UNIPROT TRIP13 protein Q15645 UNIPROT "up-regulates quantity" phosphorylation Tyr56 HNIVFGDyTWTEFDE 9606 BTO:0000007 32860853 t lperfetto "Reciprocally, TRIP13 was phosphorylated at tyrosine(Y) 56 by EGFRvIII and EGF-activated EGFR. Abrogating TRIP13 Y56 phosphorylation dramatically attenuated TRIP13 expression-enhanced EGFR signaling and GBM cell growth." SIGNOR-265083 POGZ protein Q7Z3K3 UNIPROT CBX5 protein P45973 UNIPROT "down-regulates activity" binding 9606 BTO:0000932 20562864 t miannu "POGZ was found to bind to HP1alpha through a zinc-finger-like motif. Binding by POGZ, mediated through its zinc-finger-like motif, competed with PxVxL proteins and destabilized the HP1alpha-chromatin interaction." SIGNOR-264487 TFIIH complex SIGNOR-C457 SIGNOR Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 9606 30860024 f lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair." SIGNOR-269322 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 24643073 t lperfetto "At the onset of mitosis, the protein phosphatase Cdc25C activates the Cdc2 and cyclin B1 complex by removing the inhibitory phosphate groups from Thr 14 and Tyr 15 on Cdc2.|Dephosphorylation of Tyr15 of Cdc2 is catalyzed by Cdc25C phosphatases, and this reaction is believed to be the rate limited step for the entrance into mitosis ." SIGNOR-276944 PCDHA13 protein Q9Y5I0 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-265672 H4C1 protein P62805 UNIPROT BRD4 protein O60885 UNIPROT "up-regulates activity" relocalization 9606 acetylation:Lys21;Lys17 GGAKRHRkVLRDNIQ;GLGKGGAkRHRKVLR 27991587 t lperfetto "BRD4 interacts with acetylated nucleosomes via both its BD1 and BD2 domains. Our results indicate that BRD4-BD1 binds to nucleosomes through the acetylated histone H4 tail and does not additionally interact with DNA." SIGNOR-262065 EID2 protein Q8N6I1 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "down-regulates activity" binding 9606 14612439 t lperfetto "Stable expression of eid-2 in the tgf-beta1-responsive cell line inhibits endogenous smad3-smad4 complex formation and tgf-beta1-induced expression of p21 and p15. These results suggest that eid-2 may function as an endogenous suppressor of tgf-beta signaling." SIGNOR-119174 AXIN1 protein O15169 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates binding 9606 SIGNOR-C110 12000790 t gcesareni "Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45)." SIGNOR-87401 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-143692 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RXRA protein P19793 UNIPROT "up-regulates activity" "chemical activation" 9606 18321241 t miannu "Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma)." SIGNOR-259237 NHS protein Q6T4R5 UNIPROT ABI2 protein Q9NYB9 UNIPROT "up-regulates activity" binding 9606 BTO:0000723 20332100 t miannu "NHS may preferentially bind one or more Abi's in vivo, and it is also likely that specificity is governed by spatiotemporal expression of both proteins. Abi2 is highly expressed in the lens and plays a pivotal role in the development of the anterior and posterior sutures. This suggests that an NHS–Abi2 interaction may be physiologically important for lens development and that null mutations in the NHS gene could cause congenital cataract by disruption of this interaction and the actin cytoskeleton." SIGNOR-253579 KCTD10 protein Q9H3F6 UNIPROT RHOA protein P61586 UNIPROT "down-regulates quantity" binding 9606 19782033 t miannu "BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex." SIGNOR-264237 CAMK4 protein Q16566 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates quantity by stabilization" phosphorylation 9606 23103515 t miannu "In summary, we have found that phosphorylation of Notch1-IC by CaMKIV inhibits the proteasomal degradation of Notch1-IC through Fbw7 ( Fig.\u00a07 )." SIGNOR-279596 CSNK2A2 protein P19784 UNIPROT NOL3 protein O60936 UNIPROT "up-regulates activity" phosphorylation Thr149 SEAVQSGtPEEPEPE 9606 12191471 t miannu "Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm." SIGNOR-262836 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 15952796 t "inferred from 70% family members" lperfetto "Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation" SIGNOR-270077 PRKCA protein P17252 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates phosphorylation Ser591 DKEKSKGsLKRK 9606 15269224 t llicata "Protein kinase calpha therefore critically and negatively regulates shp-1 function, forming part of a mechanism to retain shp-1 in a basal active state through interaction with its sh2 domains, and phosphorylating its c-terminal ser591 upon cellular activation" SIGNOR-126876 CDX2 protein Q99626 UNIPROT MUC2 protein Q02817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0004055 12559945 t "COS-7 cells were transiently transfected with a CDX1 or CDX2 expression construct and then used for the luciferase assay, reverse transcription-polymerase chain reaction, and electrophoretic mobility shift assay (EMSA). The CDX2 expression construct activated the MUC2 promoter and increased the endogenous MUC2 mRNA level, while the CDX1 one did not." SIGNOR-253966 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR G0/G1_transition phenotype SIGNOR-PH219 SIGNOR up-regulates 12640120 f lperfetto "Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0." SIGNOR-273193 PTPN1 protein P18031 UNIPROT MAPK15 protein Q8TD08 UNIPROT down-regulates dephosphorylation Tyr177 EDQAVTEyVATRWYR 9606 16336213 t lperfetto "Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%" SIGNOR-142981 BBS1 protein Q8NFJ9 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262558 MAPK7 protein Q13164 UNIPROT KLF2 protein Q9Y5W3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005787 BTO:0001103 23612709 f miannu "The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion" SIGNOR-255454 "vincaleukoblastine sulfate" chemical CHEBI:9984 ChEBI TUBB protein P07437 UNIPROT "down-regulates activity" "chemical inhibition" 9606 15579115 t miannu "Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs." SIGNOR-259256 USP10 protein Q14694 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0003704 21962518 t lperfetto "Since USP10 is known as a deubiquitinating protease of p53 (Yuan et al., 2010), inhibition of USP10 by spautin-1 may promote the degradation of p53. " SIGNOR-260297 JUN protein P05412 UNIPROT SMAD4 protein Q13485 UNIPROT "up-regulates activity" binding 9615 9312063 t lperfetto "Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter." SIGNOR-236139 MLLT1 protein Q03111 UNIPROT "AEP complex" complex SIGNOR-C117 SIGNOR "form complex" binding 9606 BTO:0000664 20153263 t 1 miannu "These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells." SIGNOR-239228 SGK3 protein Q96BR1 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 t lperfetto "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis." SIGNOR-252992 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Ser518 KGGTPAGsARGSPTR 9606 16611631 t lperfetto "Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-145975 YWHAQ protein P27348 UNIPROT GEM protein P55040 UNIPROT "up-regulates quantity by stabilization" binding 9534 14701738 t miannu "In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase" SIGNOR-261724 NFIX protein Q14938 UNIPROT EPHA4 protein P54764 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268908 THEM4 protein Q5T1C6 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates binding 9606 11598301 t lperfetto "Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308." SIGNOR-244455 CLOCK protein O15516 UNIPROT DPYD protein Q12882 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 17699798 f "Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors| The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women." SIGNOR-253986 BRCA1 protein P38398 UNIPROT CDC25C protein P30307 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23246971 t miannu "BRCA1 mediates cyclin B and Cdc25C ubiquitination.|Thus, BRCA1 dependent proteasomal degradation of cyclin B and Cdc25C precede the subsequent BRCA1 dependent cell cycle arrest." SIGNOR-278623 PINK1 protein Q9BXM7 UNIPROT CYCS protein P99999 UNIPROT "down-regulates quantity" 9606 BTO:0000938 20012177 t lperfetto "There is a strong cyto-protective role of PINK1 in maintaining mitochondrial homeostasis via different mechanisms. Overexpression of wild-type PINK1 in SH-SY5Y neuroblastoma cells stabilizes respiring mitochondrial networks through various mechanisms that include maintaining mitochondrial membrane potential, reducing basal and neurotoxin-induced ROS, suppression of cytochrome c release, reversal of toxin-induced fission, and suppression of autophagy" SIGNOR-249704 HDAC1 protein Q13547 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" deacetylation 10090 BTO:0000887 24463822 t "Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate that class I HDACs are key regulators of FoxO and the muscle-atrophy program during both nutrient deprivation and skeletal muscle disuse." SIGNOR-256485 Ub:E2 complex SIGNOR-C497 SIGNOR RNF168 protein Q8IYW5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271029 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser28 PHGSVTQsQGSSSQS 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to irser28 was also found to be phosphorylated in an atm-dependent manner" SIGNOR-81395 PPP2CA protein P67775 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 t "inferred from 70% of family members" gcesareni "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)." SIGNOR-269918 N protein P59595 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "down-regulates quantity" binding 9606 BTO:0000763 18055455 t miannu "In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis." SIGNOR-260427 HNF1A protein P20823 UNIPROT AKR1C4 protein P17516 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 2044952 f 2 miannu "Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C." SIGNOR-239964 TBK1 protein Q9UHD2 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser536 SGDEDFSsIADMDFS 9606 15489227 t lperfetto "Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter." SIGNOR-129951 GSK3B protein P49841 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" phosphorylation 7227 11955435 t lperfetto "We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog." SIGNOR-219231 TAF8 protein Q7Z7C8 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263927 MECP2 protein P51608 UNIPROT NEMF protein O60524 UNIPROT "up-regulates activity" binding 10090 BTO:0000142 21070191 t lperfetto "MeCP2 interacts directly with Prpf3 and Sdccag1|MeCP2’s association with Prpf3, a major component of the spliceosome, supports MeCP2 as having a role in modulating mRNA splicing|Notably, Mecp2308/Y mice, which produce a truncated form of MeCP2 and reproduce many of the classical features of RTT [43], have been shown to have multiple genes that are abnormally spliced in the brain [23]. This suggests the C-terminal portion of MeCP2, which we have identified as the putative Sdccag1 interaction domain, plays a critical role in regulating alternative splicing." SIGNOR-277692 UBTF protein P17480 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001412 7877691 t lperfetto "Rb specifically inhibits the activity of the RNA polymerase I transcription factor UBF (upstream binding factor) in vitro. |These results indicate that there is an additional mechanism by which Rb suppresses cell growth, namely that Rb directly represses transcription of the rRNA genes." SIGNOR-262590 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1101 GCRRRHSsETFSSTP 9606 BTO:0000975 17360977 t lperfetto "Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223" SIGNOR-236022 CSNK2A1 protein P68400 UNIPROT L1CAM protein P32004 UNIPROT unknown phosphorylation Ser1181 GEYRSLEsDNEEKAF 10116 BTO:0000142 8592152 t llicata "Serine to alanine substitutions in these peptides indicate that the CKII phosphorylation site is at Ser1,181. | Finally, in vivo radiolabeling indicates that Ser1,181 is phosphorylated in newborn rat brain. These data show that CKII is associated with and able to phosphorylate L1." SIGNOR-250913 PPP2CB protein P62714 UNIPROT CARD11 protein Q9BXL7 UNIPROT "down-regulates activity" dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 t "NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation." SIGNOR-248607 EIF2B1 protein Q14232 UNIPROT EIF2S2 protein P20042 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269129 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 14967450 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121984 NEK2 protein P51955 UNIPROT CD274 protein Q9NZQ7 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr194 EEKLFNVtSTLRINT 10090 BTO:0000584 34315872 t miannu "NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. " SIGNOR-277315 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT "up-regulates activity" phosphorylation Ser623 KGEKRASsPFRRVRE -1 12167624 t miannu "PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA." SIGNOR-250020 MAPK9 protein P45984 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 t lperfetto "However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity." SIGNOR-247062 FGFR1 protein P11362 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr446 GTEPEPVySMEAADY 9606 12601080 t lperfetto "Cortactin, which is an actin-binding protein that also plays a role in actin cytoskeleton dynamics (45), was phosphorylated on tyr-446 in our assay (by fgfr1).Phosphorylation of these residues attenuates the f-actin cross-linking activity" SIGNOR-98618 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SREBF1 protein P36956 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000599 10915800 t "inferred from 70% family members" lperfetto "Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo." SIGNOR-270081 MAPK11 protein Q15759 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 t lperfetto "Here we report that ews and ews-fli1 become phosphorylated at thr79 . but the p38_/p38_ mapks were the major kinases phosphorylating ews-fli1. It will be important to investigate how the p38_/p38_-stimulated phosphorylation of ews-fusion proteins affects their ability to transactivate and their oncogenic potential." SIGNOR-182774 EIF2B3 protein Q9NR50 UNIPROT EIF2S1 protein P05198 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269126 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR WNK4 protein Q96J92 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272123 4-fluoro-N-{2-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]ethyl}benzamide chemical CHEBI:64101 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258858 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 17713585 f lperfetto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB." SIGNOR-251503 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser181 NPLLRKEsAPPSLRR 9606 18339811 t "Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions." SIGNOR-248647 "Pyrin inflammasome" complex SIGNOR-C226 SIGNOR "Caspase 1 complex" complex SIGNOR-C220 SIGNOR "up-regulates activity" cleavage 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256383 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL -1 11171059 t miannu "EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499" SIGNOR-250354 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257984 CSNK2A1 protein P68400 UNIPROT XPC protein Q01831 UNIPROT "up-regulates activity" phosphorylation Ser94 VIKDEALsDGDDLRD 9606 BTO:0000552 29660033 t miannu "CK2 kinase mediates XPC phosphorylation at serine 94, and also promotes recruitment of ubiquitinated XPC to the chromatin after UVB irradiation." SIGNOR-277389 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 t gcesareni "The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation." SIGNOR-70563 SP1 protein P08047 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10644769 f miannu "these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation." SIGNOR-253872 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 9335504 t llicata "In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1" SIGNOR-52678 FBXW7 protein Q969H0 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by destabilization" ubiquitination Thr176 HLFGFPPtPPKEVSP 9606 BTO:0000007 25670854 t irozzo "Here, we demonstrate that F-box/WD repeat-containing protein 7 (Fbw7/Fbxw7), a component of Skp1, Cullin 1, F-box-containing complex (SCF)-type E3 ligase, is an E3 ligase for GATA2. GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation." SIGNOR-256005 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 9606 BTO:0001133 18977325 t irozzo "Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed." SIGNOR-255871 SRC protein P12931 UNIPROT WNK4 protein Q96J92 UNIPROT "down-regulates activity" phosphorylation Tyr1164 KKEIEDLySRLGKQP 9606 BTO:0002181 25805816 t miannu "Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. " SIGNOR-276896 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser636 SGDYMPMsPKSVSAP 10116 11287630 t lperfetto "Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten" SIGNOR-106586 SATB1 protein Q01826 UNIPROT TAF11 protein Q15544 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255130 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-201250 MECP2 protein P51608 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 15657354 f "Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT." SIGNOR-254035 GLDN protein Q6ZMI3 UNIPROT ANK3 protein Q12955 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000227 19840192 t miannu "Ankyrin-G is recruited to the nodes of Ranvier by gliomedin, which is produced by Schwann cells and accumulates in the perinodal extracellular matrix. As a ligand for neurofascin-186, gliomedin causes the nodal clustering of this cell adhesion molecule, which in turn recruits to the nodal plasma membrane an ankyrin-G protein network consisting of voltage-gated sodium or potassium channels (KCNQ2/3) and β4-spectrin." SIGNOR-266725 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Trp) smallmolecule CHEBI:29181 ChEBI "up-regulates quantity" "chemical modification" 9606 27911719 t lperfetto "RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)" SIGNOR-269498 E protein P59637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000661 16048439 f Luana "Overexpression of SARS-CoV E protein in T-cells promoted apoptosis" SIGNOR-260208 CUL2 protein Q13617 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR "form complex" binding 9606 11574546 t miannu "The von Hippel-Lindau tumor-suppressor protein (pVHL) forms a protein complex (VCB-Cul2) with elongin C, elongin B, Cul-2, and Rbx1, which functions as a ubiquitin-protein ligase (E3). The alpha-subunits of the hypoxia-inducible factors have been identified as targets for the VCB-Cul2 ubiquitin ligase. " SIGNOR-271519 MAPK12 protein P53778 UNIPROT PFKFB3 protein Q16875 UNIPROT "up-regulates quantity" phosphorylation Ser467 NSVTPLAsPEPTKKP 9606 32580961 t miannu "KRAS transformation and overexpression of p38gamma increased expression of PFKFB3 and glucose transporter GLUT2" SIGNOR-279539 NLK protein Q9UBE8 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates activity" phosphorylation Ser128 QHVRAHSsPASLQLG 9606 BTO:0000007 27979971 t done miannu "Here, we report that osmotic stress stimulates transient YAP nuclear localization and increases YAP activity even when YAP Ser127 is phosphorylated. Osmotic stress acts via the NLK kinase to induce YAP Ser128 phosphorylation. Phosphorylation of YAP at Ser128 interferes with its ability to bind to 14-3-3, resulting in YAP nuclear accumulation and induction of downstream target gene expression. " SIGNOR-273909 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248510 CHEK1 protein O14757 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation 9606 26658951 t miannu "Chk1 inhibition with small interfering RNA (siRNA) reduces Rad9A stabilization and accumulation.|In the case of DNA damage, an activated Chk1 phosphorylates Rad9A or other proteins (TLK1) as a feedback mechanism to prevent Rad9A (poly) ubiquitination and degradation." SIGNOR-279503 UBE3A protein Q05086 UNIPROT NELFCD protein Q8IXH7 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 17131388 t miannu "In this paper, we identify here trihydrophobin 1 (TH1), an integral subunit of the human negative transcription elongation factor (NELF) complex, as a novel E6-AP interaction protein and a target of E6-AP-mediated degradation. Overexpression of E6-AP results in degradation of TH1 in a dose-dependent manner, whereas knock-down of endogenous E6-AP elevates the TH1 protein level. " SIGNOR-271404 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT "down-regulates activity" phosphorylation Ser66 MLTKQNNsFQRSKRR 9534 15228384 t lperfetto "The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain." SIGNOR-249265 SREBF1 protein P36956 UNIPROT ACACA protein Q13085 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11994399 f Luana "SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16:0])." SIGNOR-267957 CSNK1A1 protein P48729 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser316 FKSIMKKsPFSGPTD -1 26082493 t miannu "These data strongly suggested that CKI phosphorylated Ser-316 of p65. Our data suggested that phosphorylation of p65 on Ser-316 controls the activity and function of NF-κB. Importantly, we found that phosphorylation at the novel Ser-316 site and other two known phosphorylation sites, Ser-529 and Ser-536, either individually or cooperatively, regulated distinct groups of NF-κB-dependent genes, suggesting the unique role of each individual phosphorylation site on NF-κB-dependent gene regulation. " SIGNOR-276916 BORA protein Q6PGQ7 UNIPROT AURKA protein O14965 UNIPROT up-regulates binding 9606 16890155 t gcesareni "Both drosophila and human bora can bind to aurora-a and activate the kinase in vitro." SIGNOR-148661 8a protein Q7TFA0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001950 17597455 f Luana "Open Reading Frame 8a of the Human Severe Acute Respiratory Syndrome Coronavirus Not Only Promotes Viral Replication but Also Induces Apoptosis" SIGNOR-260206 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp546 ALQTDIVdLQRSPMG 9606 11741536 t gcesareni "Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis." SIGNOR-256435 PRKCG protein P05129 UNIPROT CYTH2 protein Q99418 UNIPROT "down-regulates activity" phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 BTO:0000567 10531036 t lperfetto "ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'." SIGNOR-249025 CHEK2 protein O96017 UNIPROT MPEG1 protein Q2M385 UNIPROT "up-regulates activity" phosphorylation Thr288 VPFYPGItLQAWQQG 9606 24798733 t miannu "Chk2 phosphorylates Mps1-T288 after DNA damage.|In the present study, we show that Chk2 stabilizes Mps1 protein and phosphorylates Aurora B-B-serine 331 to prevent mitotic exit in vertebrate cells when the majority of kinetochores are unattached." SIGNOR-279160 CPT1A protein P50416 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR "up-regulates activity" 9606 31900483 f "As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and in disease, including cancer. The CPT1 family of proteins contains 3 isoforms: CPT1A, CPT1B, and CPT1C. This review focuses on CPT1A, the liver isoform that catalyzes the rate-limiting step of converting acyl-coenzyme As into acyl-carnitines, which can then cross membranes to get into the mitochondria" SIGNOR-267757 KDM3A protein Q9Y4C1 UNIPROT H3-5 protein Q6NXT2 UNIPROT "up-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu "Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. " SIGNOR-276847 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT "up-regulates activity" phosphorylation His118 QVGRNIIhGSDSVKS -1 8132589 t miannu "Using site-directed mutagenesis of the cDNA encoding NM23-H2, we have created a mutant substituting for the amino acid histidine 118, the presumed site of phosphorylation in the formation of the phosphoenzyme intermediate, the nonphosphorylatable amino acid phenylalanine. The H118F mutant protein is shown to be catalytically inactive" SIGNOR-250304 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates phosphorylation Ser328 VLPSISLsPGPQPPK 9606 18940270 t llicata "Tlk1b phosphorylates hrad9 at s328 after the induction of dsb, occupancy of rad9 adjacent to the break increased during repair while that of asf1 decreased, and the effect was more pronounced in tlk1b-overexpressing cells. We propose that following genotoxic stress, tlk1/1b is first recruited to the dsb in a complex with rad9. It then exchanges with asf1 to promote nucleosomes eviction at the dsb and access of the repair machinery to unencumbered dna." SIGNOR-181748 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates 9606 23994464 t apalma "Activation of those receptors triggers the dissociation of the GPCR-specific GŒ± subunit from the shared GŒ≤Œ≥ dimer and concomitant activation of various signal transduction pathways by both G-protein fragments" SIGNOR-255009 SLBP protein Q14493 UNIPROT H2BC18 protein Q5QNW6 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265394 AURKA protein O14965 UNIPROT KIF4A protein O95239 UNIPROT "up-regulates activity" phosphorylation Thr799 PPKLRRRtFSLTEVR -1 31881080 t miannu "We show that Aurora A phosphorylates the condensin I-dependent pool of KIF4A and thus actively promotes chromosome congression from the spindle poles to the metaphase plate. In vitro kinase assays showed that recombinant KIF4A can be phosphorylated by Aurora A and that this activity is inhibited by the specific Aurora A inhibitor MLN8537 (Fig. 7 C)." SIGNOR-265993 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser45 GATTTAPsLSGKGNP -1 17208333 t llicata "We showed that CCND1-CDK6 phosphorylates beta-catenin on serine 45 (S45). This phosphorylation creates a priming site for glycogen synthase kinase 3beta (GSK3beta) and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade." SIGNOR-250647 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser608 TAADMYLsPVRSPKK BTO:0001968 10207050 t llicata "In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule." SIGNOR-250747 NPR1 protein P16066 UNIPROT ORM2 protein P19652 UNIPROT "up-regulates activity" phosphorylation 9606 23363605 t miannuccelli "On TORC1 inhibition by rapamycin treatment or nutrient limitation, Npr1 phosphorylates and activates Orm1 and Orm2, which in turn promotes synthesis of complex sphingolipids downstream of SPT.|Thus Npr1 directly phosphorylates Orm1 and Orm2 downstream of TORC1." SIGNOR-279747 IL23A protein Q9NPF7 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 12671732 t gcesareni "Based on these analyses, we propose an integrated model of il-12rbeta1 structure and function. This significantly enhances our molecular understanding of the human il-12 and il-23 systems." SIGNOR-99716 MAVS protein Q7Z434 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" binding 9606 25636800 t miannu "Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. " SIGNOR-260143 CCT6A protein P40227 UNIPROT TRiC complex SIGNOR-C539 SIGNOR "form complex" binding 9606 36185250 t miannu "Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC)." SIGNOR-272865 NARS2 protein Q96I59 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI "up-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270464 GABARAP protein O95166 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR "up-regulates activity" binding 9606 BTO:0000938 25882190 t miannu "GABARAP was originally isolated as a binding partner of the GABAA receptor γ2-subunit in a yeast two-hybrid screen, and was suggested to have a role in the targeting and clustering of GABAA receptors." SIGNOR-264972 glucose chemical CHEBI:17234 ChEBI Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity by stabilization" 9606 BTO:0004424 26323688 t "inferred from family member" "Consistently, treatment of cells with 2-deoxy-d-glucose (2DG), which completely inhibits glucose metabolism, leads to HK2 degradation and cell death in combination with C43" SIGNOR-270265 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1693 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248821 "PAR-1 (Protease-Activated Receptor) Selective Activating Peptide" smallmolecule CID:71312048 PUBCHEM F2R protein P25116 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257484 CDH24 protein Q86UP0 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265862 BIRC3 protein Q13489 UNIPROT PACS2 protein Q86VP3 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 24633224 t miannu "Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay." SIGNOR-272852 miR-155 mirna URS000062749E_9606 RNAcentral JARID2 protein Q92833 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 31390932 t miannu " Mechanically, LINC01133 functioning as a ceRNA targeted miR-4784 to augment AHDC1 expression. Finally, LINCO1133/miR-4784 aggravated the malignant growth and aggressiveness and EMT of cervical cancer in an AHDC1-dependant way. In conclusion, we unveiled that LINC01133 may function as a ceRNA for miR-4784 to advance AHDC1 expression, intensifying CC cell malignant phenotypes and EMT process, which may demonstrate the implied value of LINC01133 as a therapeutic target for CC patients." SIGNOR-269188 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 9275162 t gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-50614 BDKRB1 protein P46663 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257304 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser1893 PANLDSEsEHFFRCC 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." SIGNOR-170465 MAPK3 protein P27361 UNIPROT MYL1 protein P05976 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni "Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein." SIGNOR-148002 STK11 protein Q15831 UNIPROT ETV4 protein P43268 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 16912160 t miannu "LKB1 phosphorylated PEA3 and promoted its degradation through a proteasome-mediated mechanism." SIGNOR-279293 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr119 LLTTLDDtCDLFAPL 9606 BTO:0002181 25795775 t miannu "We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. " SIGNOR-276450 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates 9606 31226023 f miannu "PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses." SIGNOR-260167 CDK2 protein P24941 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser991 PALPPPEsPPKVQPE 9606 20807815 t llicata "We identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we conclude that pelp1 is a novel substrate of interphase cdks and that its phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function." SIGNOR-167766 RNF11 protein Q9Y3C5 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 14755250 t miannu "RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome." SIGNOR-272952 "diisononyl phthalate" chemical CHEBI:35459 ChEBI NR1I2 protein O75469 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 27551952 t miannu "We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR)." SIGNOR-268775 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5D protein Q9BY66 UNIPROT "up-regulates activity" "chemical activation" 29981745 t lperfetto "Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3." SIGNOR-273473 CDK1 protein P06493 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates phosphorylation 9606 8114697 t lperfetto "P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well" SIGNOR-244847 MSTN protein O14793 UNIPROT ACVR2B protein Q13705 UNIPROT "up-regulates activity" binding 10090 11459935 t gcesareni "The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA" SIGNOR-235153 TYRO3 protein Q06418 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation 9606 21291561 t miannu "However, the present study in tPA and NMDA treated neurons establishes the link between PS mediated activation of Tyro3 and FKHRL1 phosphorylation which inactivates pro apoptotic FKHRL1 and mediates PS 's beneficial effects.|We also show that inhibition of the extrinsic apoptotic cascade by PS requires Tyro3 mediated phosphorylation of FKHRL1 which in turn inhibits FasL production and FasL dependent caspase-8 activation in the extrinsic pathway." SIGNOR-279669 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser343 TVSKTETsQVAPA -1 9099669 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-248968 SGK2 protein Q9HBY8 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 11154281 t lperfetto "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis." SIGNOR-249132 ADORA2A protein P29274 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257038 SOSTDC1 protein Q6X4U4 UNIPROT WNT4 protein P56705 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242707 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE8A protein O60658 UNIPROT "up-regulates activity" phosphorylation Ser359 HKDRRKGsLDVKAVA -1 22673573 t miannu "We show that under elevated cAMP conditions, PKA acts to phosphorylate PDE8A on serine 359 and this action serves to enhance the activity of the enzyme. " SIGNOR-276416 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT "down-regulates activity" phosphorylation Ser83 PRRSPRIsFFLEKEN -1 23901111 t miannu "Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. " SIGNOR-276118 PRKCA protein P17252 UNIPROT NRGN protein Q92686 UNIPROT "up-regulates activity" phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto "Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM." SIGNOR-248913 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120260 HLA-DRB1 protein P01911 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000776 21178476 f scontino "Fusion with a B cell requires a ternary complex of gHgLgp42. Fusion is triggered by an interaction between gp42 and HLA class II." SIGNOR-266631 RXRA protein P19793 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 1310351 t "inferred from 70% of family members" gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-269850 meloxicam chemical CHEBI:6741 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" -1 9083488 t miannu "Meloxicam (5),an NSAID in the enol−carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. This favorable therapeutic index has been confirmed in clinical trials. In subsequent studies we and others discovered that it possessed a selectivity profile for COX-2 superior to several other marketed NSAIDs.1 A comparison of 5 with piroxicam (6) revealed different inhibitory profiles for the two enzymes" SIGNOR-258609 NMUR2 protein Q9GZQ4 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257218 GTF2I protein P78347 UNIPROT GSC protein P56915 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 16611241 f lperfetto "For example, TFII-I binds to the Inr element of the T cell receptor Vbeta gene and activates its transcription in reporter gene assays (Cheriyath et al. 1998). TFII-I also activates transcription of c-fos and Goosecoid through binding to the serum response element and the distal element, respectively (Grueneberg et al. 1997; Ku et al. 2005)." SIGNOR-268536 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding -1 10713164 t llicata "SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function." SIGNOR-237617 PRKCD protein Q05655 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Ser12 KSKPKDAsQRRRSLE 9606 BTO:0001938 18069897 t gcesareni "We conclude that treatment with either UV or PMA induces the phosphorylation of the PKC site Ser12 on c-SRC and that this specific phosphorylation event is significantly diminished in cells overexpressing PR55" SIGNOR-247974 CAPN2 protein P17655 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251608 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89288 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu56 KKGHLEReCMEETCS -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263667 PDGFRB protein P09619 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7935391 t fspada "A pathway leading to activation of the gtp-binding protein ras involves the adaptor molecule grb2. Here we show that tyr-716, a novel autophosphorylation site in the pdgf beta-receptor kinase insert, mediates direct binding of grb2 in vitro and in vivo." SIGNOR-34765 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding 9606 25875593 t irozzo "C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site." SIGNOR-256368 3b protein P59633 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 21561061 f Luana "3b Augments c-Fos Levels by Activating the ERK Pathway. | An increase of∼2.0-fold inphospho ERK (Thr-202/Tyr-204) levels in 3b-expressing Huh7cells as compared to GFP-transfected control cells (Figure 4a)was observed. This increase in phospho ERK levels was also" SIGNOR-260763 FYN protein P06241 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation 9606 24586768 t miannu "Taken together, these results suggest that p130Cas is directly phosphorylated by Fyn kinase in the cytoplasm of oligodendrocytes." SIGNOR-279372 C25H27N5O4S chemical CID:66577011 PUBCHEM KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189711 FBXW7 protein Q969H0 UNIPROT PSEN1 protein P49768 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 12354302 t miannu "SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. These observations suggest that SEL-10 mediated ubiquitination of PS1-CTF and PS1-NTF leads to their degradation." SIGNOR-272600 ROCK1 protein Q13464 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" phosphorylation Ser637 VPVARKLsAREQRDC 10090 31063459 t lperfetto "We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes" SIGNOR-262549 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI α-D-glucose smallmolecule CHEBI:17925 ChEBI "up-regulates quantity" "precursor of" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266577 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr211 EYLDDRNtFRHSVVV 9606 22611192 t gcesareni "We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma)." SIGNOR-197606 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 9792724 f miannu "AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP." SIGNOR-254447 PITX1 protein P78337 UNIPROT GNRH1 protein P01148 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19106114 f miannu "Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter." SIGNOR-254921 IGF1 protein P05019 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 2689937 f fspada "Preadipocytes converted to adipocytes when insulin-like growth factor-1 or insulin was added to a medium depleted of those compounds" SIGNOR-23166 HCK protein P08631 UNIPROT GLI1 protein P08151 UNIPROT "up-regulates activity" phosphorylation 9606 26619401 t miannu "These results suggest that the interaction between Gli1 and Hck or the phosphorylation of Gli1 by Hck disrupts Sufu-Gli1 interaction.|We showed that tyrosine kinase Hck activates Gli1 and the kinase activity is required for its maximum effect." SIGNOR-279374 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition." SIGNOR-252907 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 12024016 t gcesareni "Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner." SIGNOR-87845 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-252806 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 17178712 t gcesareni "Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna" SIGNOR-151261 procaterol chemical CHEBI:135209 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257863 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150 23632474 t "Neratinib (HKI-272) is a tyrosine kinase inhibitor, under investigation for the treatment breast cancer and other solid tumours." gcesareni "Ineratinib is a potent irreversible pan-erbb tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (her)-2-positive breast cancer and other solid tumours." SIGNOR-202015 PELI3 protein Q8N2H9 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates ubiquitination 9606 17997719 t gcesareni "These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4." SIGNOR-159061 AKT proteinfamily SIGNOR-PF24 SIGNOR PIKFYVE protein Q9Y2I7 UNIPROT up-regulates phosphorylation Ser307 PARNRSAsITNLSLD 9606 BTO:0000887 15546921 t gcesareni "Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme." SIGNOR-130920 Ub:E2 complex SIGNOR-C497 SIGNOR "HECT E3 ligase" proteinfamily SIGNOR-PF104 SIGNOR "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270943 MTMR3 protein Q13615 UNIPROT MTOR protein P42345 UNIPROT "down-regulates activity" 9606 BTO:0000007 SIGNOR-C3 26787466 t lperfetto "The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity." SIGNOR-245105 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI INSR protein P06213 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192871 PIK3R3 protein Q92569 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9415396 t gcesareni "The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha" SIGNOR-53597 KAT2B protein Q92831 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR "form complex" binding 9606 21131905 t lperfetto "Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators." SIGNOR-170276 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT "up-regulates activity" phosphorylation Ser108 DKYGQNEsFARIQVR -1 26119734 t miannu "Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro" SIGNOR-276220 LMP1 protein P03230 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" 9606 26428373 f scontino "AP1 is a dimeric transcription factor composed of members of the Jun and Fos protooncoprotein families. AP1 was found induced by LMP1 through the JNK signaling cascade, involving JNK1-mediated phosphorylation and activation of c-Jun. JNK1 activation critically relies on CTAR2 and its P379VQLSYY motif. It has long been unclear which signaling mediators at CTAR2 are involved in JNK activation." SIGNOR-267617 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4F protein A0A1W2PPD8 UNIPROT "up-regulates activity" "chemical activation" 29981745 t lperfetto "Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3." SIGNOR-273480 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CAPN2 protein P17655 UNIPROT up-regulates phosphorylation 9606 14993287 t "inferred from 70% family members" lperfetto "Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo." SIGNOR-270078 HES5 protein Q5TA89 UNIPROT ASCL1 protein P50553 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 30030829 f lperfetto "The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production" SIGNOR-265147 NatA complex SIGNOR-C415 SIGNOR CHEK2 protein O96017 UNIPROT "down-regulates activity" acetylation 9606 BTO:0001109 21351257 t miannu "The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer.  lack of acetylation by hNatA activated H2A.X and Chk2 in both HCT116 cell lines independent of TP53 status (Fig. 6)." SIGNOR-267228 N protein P59595 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" 9534 15294014 f Luana "Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways." SIGNOR-261131 3b protein P59633 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" 9606 21561061 f Luana "An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP" SIGNOR-260760 "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI acyl-CoA(4-) chemical CHEBI:58342 ChEBI "up-regulates quantity" "precursor of" 9606 21498505 t miannu "Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. " SIGNOR-272769 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation Ser543 SLLSTLSsPGPKLDN 9606 BTO:0000093 15383283 t miannu "P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators." SIGNOR-250104 PRKD1 protein Q15139 UNIPROT KCNH2 protein Q12809 UNIPROT "down-regulates activity" phosphorylation Ser284 ASVRRASsADDIEAM 9606 BTO:0000007 29949809 t miannu "Based on LC-MS results from in vivo and HEK293 cell experiments we chose four KV11.1 mutant candidates for further functional analysis. Ablation of the putative PKD phosphorylation site in the mutant S284A increased the maximal current indicating S284 as a main PKD target in KV11.1." SIGNOR-277612 PRKCA protein P17252 UNIPROT APLP2 protein Q06481 UNIPROT unknown phosphorylation Thr723 LRKRQYGtISHGIVE -1 9109675 t lperfetto "We report here that a cytoplasmic domain peptide from APLP1 is phosphorylated in vitro by protein kinase C and that a cytoplasmic domain peptide from APLP2 is phosphorylated in vitro by protein kinase C and cdc2 kinase." SIGNOR-248970 N protein P59595 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9534 BTO:0000298 15294014 f Luana "Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways." SIGNOR-261132 3a protein P59632 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9606 BTO:0001950 18632968 f Luana "Severe Acute Respiratory Syndrome Coronavirus 3a Protein Activates the Mitochondrial Death Pathway Through p38 MAP Kinase Activation" SIGNOR-260193 7a protein P59635 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9606 BTO:0000007 16378980 f Luana "While there is a low level of activated p38 normally found in 293T cells, expression of 7a-protein stimulated larger amounts of activated p38 during the 24-h time course. " SIGNOR-260754 E protein P59637 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 10090 BTO:0000763 25122212 f Luana "Interestingly, an increase in p38 MAPK activation was observed during infection with viruses containing E protein PBM, similarly to what was observed in the lungs of SARS-CoV-infected mice. These results indicated that the E protein PBM is involved in p38 MAPK activation in response to SARS-CoV infection." SIGNOR-260751 IL15RA protein Q13261 UNIPROT IL2RB protein P14784 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 t milica "The il-15 receptor comprises a heterotrimeric complex consisting of the common ?cytokine Receptor (?c), the il-2 ? Receptor subunit (il-2r?), And an il-15-specific ? Receptor (il-15r?)" SIGNOR-157418 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Thr110 PRSGVRGtPVRQRPD 9606 BTO:0000567 SIGNOR-C83 12714602 t lperfetto "We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a." SIGNOR-100889 mTORC1 complex SIGNOR-C3 SIGNOR ATP6V1A protein P38606 UNIPROT "up-regulates quantity by expression" 10090 21804531 f Giorgia "These data suggested that V-ATPase mRNA levels were upregulated by mTORC1 through a transcriptional mechanism. Tfeb is required for mTORC1-induced V-ATPase expression." SIGNOR-260636 CDK5 protein Q00535 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-197945 CDK5 protein Q00535 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 t gcesareni "Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins" SIGNOR-175696 CARD10 protein Q9BWT7 UNIPROT PRKCQ protein Q04759 UNIPROT "up-regulates activity" relocalization 9606 31792381 t "TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation" SIGNOR-272471 PDPK1 protein O15530 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates phosphorylation Thr566 LNGVTTTtFCGTPDY 9606 11964154 t llicata "In the present study, we analysed the contribution of the phosphoinositide-dependent kinase 1 (pdk-1) and pkcepsilon kinase activity in controlling the phosphorylation of thr(566) and ser(729). pdk-1 phosphorylation of the activation loop triggers autophosphorylation of the hydrophobic motif" SIGNOR-117320 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR BCL2L11 protein O43521 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17960585 f miannu "Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells." SIGNOR-260425 ATM protein Q13315 UNIPROT MRE11 protein P49959 UNIPROT up-regulates phosphorylation Ser264 EQQLFYIsQPGSSVV 9606 10608806 t lperfetto "In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage." SIGNOR-73366 retinol smallmolecule CHEBI:50211 ChEBI "all-trans-retinyl ester" smallmolecule CHEBI:63410 ChEBI "up-regulates quantity" "precursor of" 10090 18093970 t lperfetto "We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis" SIGNOR-265109 AMER1 protein Q5JTC6 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" relocalization 9606 SIGNOR-C110 21304492 t gcesareni "Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6." SIGNOR-171886 MAPK1 protein P28482 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto "Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action." SIGNOR-249428 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000007 19881549 t lperfetto "Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis" SIGNOR-236302 PTGES2 protein Q9H7Z7 UNIPROT "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI "up-regulates quantity" "chemical modification" -1 10922363 t Luana "Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently." SIGNOR-269766 F9 protein P00740 UNIPROT "Factor VIIIa-IXa" complex SIGNOR-C320 SIGNOR "form complex" binding 10090 BTO:0000131 25769543 t lperfetto "The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin." SIGNOR-263552 DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" binding 9606 15494734 t miannu "Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling." SIGNOR-268371 SPOP protein O43791 UNIPROT TRIM24 protein O15164 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations." SIGNOR-272825 IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" binding 9606 21798082 t lperfetto "Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor." SIGNOR-175662 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation 10090 11730323 t "Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs" SIGNOR-258990 WNT5A protein P41221 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 22773843 t areggio "Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells." SIGNOR-258970 GCC2 protein Q8IWJ2 UNIPROT M6PR protein P20645 UNIPROT "up-regulates activity" relocalization 18195106 t lperfetto "Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector" SIGNOR-253086 AKT1 protein P31749 UNIPROT SOX2 protein P48431 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr116 KYRPRRKtKTLMKKD 9606 BTO:0002428 30894683 t miannu "Phosphorylation of SOX2 at threonine 116 by AKT inhibits the interaction of UBR5 with SOX2 and thus stabilizes SOX2. " SIGNOR-277445 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 22710723 t lperfetto "Furthermore, we demonstrate that src phosphorylates p130cas y128. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation" SIGNOR-197927 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK -1 10734133 t miannu "Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant." SIGNOR-75894 MIB1 protein Q86YT6 UNIPROT MIB1 protein Q86YT6 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 12351649 t miannu "The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system. " SIGNOR-272603 ADORA2A protein P29274 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257364 Guanfacine chemical CHEBI:5558 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258919 STAT1 protein P42224 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 19029990 f lperfetto "STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others." SIGNOR-249496 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Ser374 GLYSRSGsLSGRSSL -1 10467162 t lperfetto "Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect." SIGNOR-249021 SMAD1 protein Q15797 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 22298955 t gcesareni "Smad1 interacts with runx2 on the promoter of target genes and controls osteoblast gene expression and differentiation" SIGNOR-195642 AKT1 protein P31749 UNIPROT UBE2S protein Q16763 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr152 AARARLLtEIHGGAG 9606 BTO:0000007 27593939 t lperfetto "Mechanistically, Akt1 physically interacted with and phosphorylated UBE2S at Thr 152, enhancing its stability by inhibiting proteasomal degradation." SIGNOR-265078 CSNK2A1 protein P68400 UNIPROT VDR protein P11473 UNIPROT up-regulates phosphorylation Ser208 SFSNLDLsEEDSDDP 9606 17368182 t lperfetto "Casein kinase ii (ckii) phosphorylates vdr both in vitro and in vivo at serine 208 within the hinge domain. This phosphorylation does not affect the ability of vdr to bind dna, but increases its ability to transactivate target promoters" SIGNOR-153711 AURKB protein Q96GD4 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser67 S-->K 9606 32049046 t miannu "AURKB directly phosphorylates MYC at serine 67, counteracting GSK3\u03b2-directed threonine 58 phosphorylation and subsequent FBXW7- mediated proteasomal degradation." SIGNOR-279439 SCN1A protein P35498 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu "The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons." SIGNOR-253448 ASXL1 protein Q8IXJ9 UNIPROT "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR "up-regulates activity" binding 9606 BTO:0001271 22897849 t irozzo "These data led us to hypothesize that ASXL1 interacts with the PRC2 complex; co-immunoprecipitation studies revealed that ASXL1 associates with members of the PRC2 complex including EZH2 and SUZ12 but not with the PRC1 repressive complex. Importantly, ASXL1 downregulation resulted in loss of EZH2 recruitment to the HOXA locus indicating a role of ASXL1 in recruiting the PRC2 complex to known leukemogenic loci." SIGNOR-255923 M protein P59596 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0005029 25271362 f Luana "Consistent with our previous result, we detected a reduced phosphorylated PKB/Akt level and diminished PKB/Akt activity in mammalian cells expressing M-protein." SIGNOR-260200 POMT1 protein Q9Y6A1 UNIPROT POMT complex SIGNOR-C372 SIGNOR "form complex" binding 9606 BTO:0000007 16698797 t miannu " Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex." SIGNOR-265428 RIPK1 protein Q13546 UNIPROT MPRIP protein Q6WCQ1 UNIPROT "up-regulates activity" phosphorylation 9606 24653026 t miannuccelli "Under such conditions, RIP1 phosphorylates and activates RIP3, which in turn phosphorylates its downstream substrate MLKL, leading to plasma membrane rupture and necrosis( xref )." SIGNOR-279755 MRGPRX1 protein Q96LB2 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257171 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000938 26136660 t miannu "The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current." SIGNOR-264929 MAPK1 protein P28482 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser333 KGLVSPQsPQKSDCQ 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni "Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway." SIGNOR-58481 TWIST2 protein Q8WVJ9 UNIPROT AKR1C2 protein P52895 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255498 MAPK8IP1 protein Q9UQF2 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 20508646 t "Interferes with binding to RBP-J" gcesareni "Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them." SIGNOR-165710 AKT1 protein P31749 UNIPROT ZRANB1 protein Q9UGI0 UNIPROT "up-regulates activity" phosphorylation Ser78 SARPRVKsSYSMENA 9606 BTO:0000007 29748601 t miannu "Our findings also identify an essential role for activation of Trabid by AKT-mediated phosphorylation at Ser78/Thr117 in negatively regulating Twist1 signaling, which further provides insights into the mechanisms by which Trabid regulates Twist1 ubiquitination." SIGNOR-273483 PPP1R8 protein Q12972 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "down-regulates activity" binding -1 1322907 t lperfetto "We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity." SIGNOR-264673 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT "up-regulates activity" phosphorylation Tyr387 SEEPEPDyEAIQTLN 9534 16920712 t miannu "Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn." SIGNOR-262893 ETF complex SIGNOR-C463 SIGNOR FAD smallmolecule CHEBI:16238 ChEBI "down-regulates quantity" "chemical modification" 9606 33450351 t miannu "ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a)." SIGNOR-269454 POLH protein Q9Y253 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 21242293 f miannu "In this study we show that, in human cells, polη becomes phosphorylated by ATR at Ser601 after UV irradiation. Phosphorylation requires physical interaction of polη with Rad18 but is independent of PCNA monoubiquitination. We show that UV-induced phosphorylation of polη is required for normal survival and postreplication repair and is involved in checkpoint control." SIGNOR-259061 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248399 KAT2A protein Q92830 UNIPROT H3-4 protein Q16695 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269596 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Thr1141 NRKSLRRtLKSGLGD 9606 18239683 t lperfetto "Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres." SIGNOR-160552 RIPK1 protein Q13546 UNIPROT RIPK3 protein Q9Y572 UNIPROT "up-regulates activity" phosphorylation 9606 26694384 t miannu "In the current scenario, RIPK1 phosphorylates and activates RIPK3, and activated RIPK3 then phosphorylates MLKL." SIGNOR-278429 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral VIM protein P08670 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003792 26675258 t Parnian "The overexpression of miR-30a restored E-cadherin levels, and inhibited the expression of both vimentin and Snail." SIGNOR-277999 MFGE8 protein Q08431 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 SIGNOR "up-regulates activity" binding 10116 BTO:0000452 31958465 t miannu "Milk fat globule-EGF factor 8 (MFGE8), a protein known as lactadherin in humans, contains C domains interacting with extracellular matrices and epidermal growth factor–like domains with an RGD motif binding to integrins αvβ3 and αvβ5." SIGNOR-260645 hsa-miR-21-5p mirna URS000039ED8D_9606 RNAcentral CCL20 protein P78556 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002210 22001440 t Parnian "MiR-21 may suppress gene expression through miR-21-binding sequences at the 3′-UTR of CCL20 gene . This suggests that miR-21 represses CCL20 expression by targeting the 3′UTR." SIGNOR-278006 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269245 PRMT6 protein Q96LA8 UNIPROT SIRT7 protein Q9NRC8 UNIPROT "down-regulates activity" methylation Arg388 ILGGWFGrGCTKRTK 30420520 t lperfetto "Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization." SIGNOR-275888 EEF1A2 protein Q05639 UNIPROT Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269534 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 ChEBI ADRA1A protein P35348 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258472 Verdinexor chemical CID:71492799 PUBCHEM XPO1 protein O14980 UNIPROT down-regulates "chemical inhibition" 9606 30541831 t "Simone Vumbaca" "We show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and a reduction inRSV titers." SIGNOR-261129 IRF8 protein Q02556 UNIPROT CD68 protein P34810 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000801 12676954 f "However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element." SIGNOR-254285 CDK1 protein P06493 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Thr537 LGQNKAHtPFRESKL 9606 20368358 t llicata "We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation." SIGNOR-164761 CSNK2A2 protein P19784 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250978 ROR1 protein Q01973 UNIPROT ERBB3 protein P21860 UNIPROT "up-regulates activity" phosphorylation 9606 22439932 t miannu "Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation.|ROR1 knockdown decreased phosphorylations of ERBB3, c-Src, and AKT in NKX2-1 + / ROR1 + NCI-H1975, SK-LC-5, and NCI-H358 cells." SIGNOR-279279 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr201 DIPEKPKtPQQLWYT 9606 11741541 t lperfetto "Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna" SIGNOR-112817 PEX5 protein P50542 UNIPROT SQSTM1 protein Q13501 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 ubiquitination:Lys209 VAKVDDPkLANSEFL 26344566 t "Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy. " SIGNOR-262793 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" binding 9606 17259966 t miannu "The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells" SIGNOR-254946 JAK2 protein O60674 UNIPROT ATOH1 protein Q92858 UNIPROT "up-regulates quantity" phosphorylation Tyr80 CTARAAQyLLHSPEL 9606 BTO:0004328 29168692 t Gianni "We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling." SIGNOR-262201 HACE1 protein Q8IYU2 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 22036506 t "The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation" SIGNOR-255538 MYD88 protein Q99836 UNIPROT DHX36 protein Q9H2U1 UNIPROT "up-regulates activity" binding 9606 BTO:0002042 20696886 t miannu "We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing." SIGNOR-260956 Ub:E2 complex SIGNOR-C497 SIGNOR RNF181 protein Q9P0P0 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271230 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val58 KGVTVETvFSVDEFS -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263591 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT "down-regulates activity" phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 t done miannu "Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A)." SIGNOR-273789 BCL2L1 protein Q07817 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003328 9393856 f fcortellessa "Bcl-xL Expression Prevents Cytochrome c Redistribution and Subsequent Mitochondrial Depolarization during Apoptosis. Bcl-xL expression prevented both cytochrome c redistribution and mitochondrial membrane depolarization. In contrast, zVAD treatment could not prevent either cytochrome c redistribution or mitochondrial membrane depolarization in control transfectants withdrawn from IL-3. Thus, cytochrome c redistribution from mitochondria is an early apoptotic event that precedes mitochondrial membrane depolarization. Bcl-xL expression functions to inhibit both of these events. In at least some forms of cell death, the ability of Bcl-xL to regulate these mitochondrial events cannot be mimicked by caspase inhibition" SIGNOR-261683 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT "up-regulates activity" phosphorylation Ser230 PKYSRQFsLEHVHGS -1 35080342 t miannu "Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9." SIGNOR-277580 MAP3K3 protein Q99759 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" binding 9606 BTO:0000298 9162092 t lperfetto "These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3." SIGNOR-48628 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258169 RNF123 protein Q5XPI4 UNIPROT CBX1 protein P83916 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 23077635 t miannu "In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation." SIGNOR-272034 TWIST2 protein Q8WVJ9 UNIPROT ILK protein Q13418 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255504 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2D2 protein P62837 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271323 hsa-miR-582-3p mirna URS00002573C3_9606 RNAcentral DKK3 protein Q9UBP4 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003009 26468775 t Parnian "MiR-582-3p directly targets multiple negative regulators of the Wnt pathway. | Overall, our results demonstrate that miR-582-3p activates Wnt signalling by targeting AXIN2, DKK3 and SFRP1 enhances stem cell-like traits; and leads to tumour recurrence and poor prognosis in NSCLC patients." SIGNOR-278018 GTF2H2 protein Q13888 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t Manara "TFIIH Phosphorylates Human Estrogen Receptor α at Serine 118 | We report here that Cdk7 overexpression stimulates transcription activation by ERα by stimulating phosphorylation of S118 in a ligand-dependent manner." SIGNOR-260817 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR MSX2 protein P35548 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 31548378 t miannu " Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase.  Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation." SIGNOR-272261 KLKB1 protein P03952 UNIPROT HGF protein P14210 UNIPROT "up-regulates activity" cleavage Arg494 CAKTKQLrVVNGIPT -1 12372819 t miannu "the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain." SIGNOR-256512 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 9534 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252752 NMUR1 protein Q9HB89 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256894 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr222 TSHNSLTtPCYTPYY 9606 8846784 t fstefani "Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk." SIGNOR-44343 DUSP5 protein Q16690 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni "The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues." SIGNOR-166574 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 17015473 t "The effect has been demonstrated using Q01196-8" lperfetto "Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a." SIGNOR-217340 hsa-miR-320c mirna URS0000010D30_9606 RNAcentral GNAI1 protein P63096 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003227 23691483 t Parnian "GNAI1 was a target of miR-320a/c/d in HCC cells.| Western blot assays revealed that miR-320a/c/d dramatically down-regulated the endogenous GNAI1 protein level, which indicates that these miRNAs may directly target GNAI1 in HCC cells.| Taken together, these observations indicate that miR-320a/c/d facilitate the migration and invasion of HCC cells." SIGNOR-278027 ATR protein Q13535 UNIPROT FANCA protein O15360 UNIPROT up-regulates phosphorylation Ser1449 AAPDADLsQEPHLF 9606 19109555 t lperfetto "The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site" SIGNOR-182953 CHEK1 protein O14757 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" phosphorylation Thr210 YDGERKKtLCGTPNY 9606 34197606 t miannu "These results suggest that both PLK1 S137 and T210 sites can be phosphorylated in vitro by CHK1, but that S137 is the major site.|We reason that PARG and CHK1 inhibitors should also cause synthetic lethality : PARG inhibition sustains PLK1 inhibition at the PAR forest , while CHK1 inhibition blocks PLK1 reactivation and RAD51 phosphorylation at S14 and T309 ." SIGNOR-279501 SMO protein Q99835 UNIPROT STK36 protein Q9NRP7 UNIPROT up-regulates binding 9606 17089004 t gcesareni "Smo then activates stk36 serine/threonine kinase to stabilize gli family members and to phosphorylate sufu for nuclear accumulation of gli.| sufu binds to the kinesin cos2 to transduce the hh signal downstream of smo" SIGNOR-150540 MAPK1 protein P28482 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto "Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK." SIGNOR-209876 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT "up-regulates activity" cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263426 ERBB2 protein P04626 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 8816440 t gcesareni "Most breast, skin, lung, ovary, and gastrointestinal tract tumors express erbb-4, and heterodimerization of this receptor with erbb-2, may be involved in some cancer" SIGNOR-43844 PRKACA protein P17612 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1364 PSGSQRPsVSDDTGC 9606 17615294 t lperfetto "Additionally, we show that s1360 and s1364 of beta4 are the only residues phosphorylated by pkc and pka in cells, respectivelywe have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (s1356, s1360, and s1364), previously implicated in hd regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated" SIGNOR-156873 hsa-miR-320d mirna URS0000010C72_9606 RNAcentral GNAI1 protein P63096 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003227 23691483 t Parnian "GNAI1 was a target of miR-320a/c/d in HCC cells.| Western blot assays revealed that miR-320a/c/d dramatically down-regulated the endogenous GNAI1 protein level, which indicates that these miRNAs may directly target GNAI1 in HCC cells.| Taken together, these observations indicate that miR-320a/c/d facilitate the migration and invasion of HCC cells." SIGNOR-278028 WYE-687 chemical CID:25229450 PUBCHEM MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor mTOR" gcesareni SIGNOR-207818 CDH1 protein P12830 UNIPROT CTNNA1 protein P35221 UNIPROT up-regulates binding 9606 24336504 t milica "Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm." SIGNOR-203468 EID1 protein Q9Y6B2 UNIPROT EP300 protein Q09472 UNIPROT "down-regulates activity" binding 11073989 t lperfetto "Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity." SIGNOR-253379 CDK5 protein Q00535 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser191 SRHAIMRsPQMVSAI 9606 26509276 t miannu "By combining multiple network relations with PTM proteoform specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity.|CDK5 phosphorylates beta-catenin on Ser-191 and Ser-246 (PR:000037229)" SIGNOR-279515 ACTL6A protein O96019 UNIPROT "INO80 complex" complex SIGNOR-C498 SIGNOR "form complex" binding 9606 25016522 t miannu "Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication." SIGNOR-270847 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 25624485 t "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity." gcesareni "Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts" SIGNOR-175256 CDK1 protein P06493 UNIPROT IREB2 protein P48200 UNIPROT down-regulates phosphorylation Ser157 LQKAGKLsPVKVQPK 9606 SIGNOR-C17 18574241 t lperfetto "Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity" SIGNOR-179171 "NLRC4 inflammasome" complex SIGNOR-C223 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu "Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma." SIGNOR-263122 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 15644327 t lperfetto "Baff interacts with baff receptor (baffr)." SIGNOR-133210 CDK2 protein P24941 UNIPROT TP73 protein O15350 UNIPROT "down-regulates activity" phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C16 12676926 t gcesareni "Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86." SIGNOR-99746 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190708 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248310 DPH5 protein Q9H2P9 UNIPROT EEF2 protein P13639 UNIPROT "down-regulates activity" methylation His715 TLHADAIhRGGGQII 9606 23486472 t "Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5." SIGNOR-261146 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI ALK protein Q9UM73 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258219 MAP3K3 protein Q99759 UNIPROT SQSTM1 protein Q13501 UNIPROT "up-regulates activity" phosphorylation Ser272 RSRLTPVsPESSSTE 9606 26279575 t miannu "MEKK3 overexpression, but not that of a kinase dead mutant, was able to induce the phosphorylation of p62 at T269 and S272 (XREF_FIG), which correlated with mTORC1 activation (XREF_FIG), suggesting that MEKK3 could be a bona fide regulator of p62 phosphorylation and mTORC1 activity." SIGNOR-279533 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "AX/b2 integrin" complex SIGNOR-C171 SIGNOR "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259026 IFNG protein P01579 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu "High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity." SIGNOR-261024 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000551 15329413 t gcesareni "Egfr is a tk of the erbb family that is the presumptive target of the tk inhibitor (tki) gefitinib." SIGNOR-126976 NAT8L protein Q8N9F0 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI "down-regulates quantity" "chemical modification" 9606 19524112 t miannu "The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA." SIGNOR-267522 AMPK complex SIGNOR-C15 SIGNOR CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation Ser768 LQARRRQsVLNLMTH 9606 19095655 t Luana "AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as ""inhibitory"" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions" SIGNOR-72708 PHPT1 protein Q9NRX4 UNIPROT KCNN4 protein O15554 UNIPROT "down-regulates activity" dephosphorylation His358 FRQVRLKhRKLREQV 9606 18796614 t miannu "We now show that the mammalian protein histidine phosphatase (PHPT-1) directly binds and inhibits KCa3.1 by dephosphorylating histidine 358 on KCa3.1.|Overexpression of wild-type, but not a phosphatase dead, PHPT-1 inhibited KCa3.1 channel activity." SIGNOR-277071 RPS6KB1 protein P23443 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 t gcesareni "Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b." SIGNOR-49371 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257953 MAPKAPK2 protein P49137 UNIPROT HSF1 protein Q00613 UNIPROT "down-regulates activity" phosphorylation Ser121 NIKRKVTsVSTLKSE 9606 16278218 t miannu "A potential mechanism for MK2-induced HSF1 inactivation is suggested by the findings that phosphorylation of serine 121 enhances HSF1 binding to HSP90, a major repressor of HSF1.|Phosphorylation of HSF1 by MAPK activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding." SIGNOR-279541 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Thr405 VGGSGIGtPPSVLKR BTO:0000007 10593981 t llicata "Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity." SIGNOR-250737 IGF1R protein P08069 UNIPROT SIRPA protein P78324 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001260 11779860 f gcesareni "These studies indicate that igf-ir stimulates phosphorylation of shps-1 which is critical for shp-2 recruitment to the plasma membrane and for its recruitment to the igf-ir" SIGNOR-113640 PARP1 protein P09874 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni "Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process" SIGNOR-111680 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 9445476 t gcesareni "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-55306 EEF1A2 protein Q05639 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269540 SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR DLX5 protein P56178 UNIPROT up-regulates "transcriptional regulation" 10090 BTO:0000165 12815054 f ggiuliani "Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining" SIGNOR-255790 NMBR protein P28336 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 8026589 t fspada "G-proteins of the q family have been implicated as mediators of bombesin receptors action. This suggests that nmb-r couples to g?q, and that grp-r and nmb-r show distinct g-protein coupling preferences in the xenopus oocyte." SIGNOR-35864 DGC complex SIGNOR-C217 SIGNOR NRXN2 protein Q9P2S2 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 11470830 t miannu "In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan." SIGNOR-265448 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates activity" phosphorylation Ser72 PPRKRLKsKGSDKDF 9606 20663873 t miannu "We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27." SIGNOR-259819 GSTA1 protein P08263 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000018 29928434 f irozzo "In addition, the downregulation of GSTA1 in A549 cells significantly induced cell apoptosis in vitro. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line." SIGNOR-256297 CDK1 protein P06493 UNIPROT CDC16 protein Q13042 UNIPROT up-regulates phosphorylation Ser560 KTLKNIIsPPWDFRE 9606 14657031 t lperfetto "Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation" SIGNOR-119762 MDGA2 protein Q7Z553 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 26206665 f miannu "MDGA2 acts as a novel tumour suppressor in gastric cancer through inhibiting cell proliferation, suppressing G1–S cell cycle transition and inducing cell apoptosis." SIGNOR-264239 N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI "up-regulates quantity" "precursor of" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-268091 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr341 GQRDSSYyWEIEASE 9606 12551923 t gcesareni "We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain." SIGNOR-97639 SRPK1 protein Q96SB4 UNIPROT RBM8A protein Q9Y5S9 UNIPROT down-regulates phosphorylation Ser168 GGRRRSRsPDRRRR 9606 16100109 t gcesareni "We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc." SIGNOR-139555 IFNA10 protein P01566 UNIPROT LPL protein P06858 UNIPROT "down-regulates activity" 10090 BTO:0000944 1632769 f Regulation miannu "Interleukin-1 and interferon-alpha and gamma induce lipolysis and decrease LPL activity but do not stimulate much PG production. These results demonstrate that cytokines enhance lipolysis and decrease LPL activity in 3T3 adipocytes by a PG independent mechanism." SIGNOR-251859 PRKCA protein P17252 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata "The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl." SIGNOR-17905 "A6/b1 integrin" complex SIGNOR-C164 SIGNOR TERT protein O14746 UNIPROT "up-regulates quantity by expression" 10090 18757303 f lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253280 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser62 IDLKRGGsSDDRQIV 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262712 NTSR1 protein P30989 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 10030 BTO:0000457 28341345 t "Marta Tosoni" "Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways" SIGNOR-278061 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JUN protein P05412 UNIPROT up-regulates phosphorylation 9606 12169099 t "inferred from 70% family members" gcesareni "Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein." SIGNOR-270033 SRC protein P12931 UNIPROT UGT2B7 protein P16662 UNIPROT up-regulates phosphorylation Tyr438 RVINDPSyKENVMKL 9606 19289110 t gcesareni "Overexpression of regular or active src, but not dominant-negative src, in 2b7-transfected cos-1 cells increased 2b7 activity and phospho-y438-2b7 by 50%" SIGNOR-184613 EHMT2 protein Q96KQ7 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19822740 f "Regulation of transcription" miannu "G9a activation of the βmaj globin gene was shown to be independent of G9a MT activity." SIGNOR-251788 PRKCD protein Q05655 UNIPROT G6PD protein P11413 UNIPROT up-regulates phosphorylation Ser180 FGRDLQSsDRLSNHI 9606 BTO:0001260 20649491 t lperfetto "A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity." SIGNOR-167049 CPT1C protein Q8TCG5 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI "down-regulates quantity" "chemical modification" 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267128 BCKDK protein O14874 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation 9606 35070754 t miannu "BCKDK can activate ACLY and promote the cleavage of citric acid into acetyl-CoA, and oxaloacetate.|BCKDK can phosphorylate BCKDHA and ATP citrate lyase (ACLY), exerting opposing effects on both." SIGNOR-280194 LRRC45 protein Q96CN5 UNIPROT CROCC protein Q5TZA2 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 24035387 t miannu "Here, we show that LRRC45 is a centrosome linker that localizes at the proximal ends of the centrioles and forms fiber-like structures between them. Depletion of LRRC45 results in centrosome splitting during interphase. LRRC45 interacts with C-Nap1 and rootletin" SIGNOR-273704 calcium(2+) smallmolecule CHEBI:29108 ChEBI "Calprotectin complex" complex SIGNOR-C293 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0001044 16690079 t miannu "S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization." SIGNOR-262826 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys84 PFTIAQGkGQKLCEI 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E)." SIGNOR-272829 MMP2 protein P08253 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256327 RALY protein Q9UKM9 UNIPROT PRMT1 protein Q99873 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 BTO:0000567 30354839 t lperfetto "RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression.|We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels" SIGNOR-262273 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9534 7839144 t lperfetto "Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase." SIGNOR-232156 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser122 DQHLMKCsPAQLLCS 9606 SIGNOR-C17 10864927 t gcesareni "Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b." SIGNOR-78416 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR IFNAR complex SIGNOR-C243 SIGNOR "up-regulates activity" binding 9606 11278538 t miannu "Interferons have antiviral, antigrowth and immunomodulatory effects. The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex." SIGNOR-260331 GHSR protein Q92847 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256782 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr492 ALGADDSyYTARSAG 9606 8756661 t lperfetto "The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492" SIGNOR-226624 BIRC2 protein Q13490 UNIPROT RIPK4 protein P57078 UNIPROT "up-regulates activity" polyubiquitination lys145 9606 BTO:0000007 21931591 t miannu "CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation." SIGNOR-272708 "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "up-regulates quantity" "precursor of" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266465 CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0001009 10753867 f lperfetto "Creb activity by akt signaling leads to increased bcl-2 promoter activity and cell survival." SIGNOR-76558 PTPRG protein P23470 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000876 25624455 t miannu "Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG." SIGNOR-254689 calcium(2+) smallmolecule CHEBI:29108 ChEBI FLNA protein P21333 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132 27871158 t lperfetto "Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. The actin cross-linking complex, GP1b/IX-filamin, translocates from the plasma membrane to the cytoskeleton during this step." SIGNOR-261845 EXOSC10 protein Q01780 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR "form complex" binding -1 24189234 t miannu "The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40)." SIGNOR-261390 ADCY3 protein O60266 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR "up-regulates activity" binding 9606 BTO:0000552 33802009 t "Marta Tosoni" "Although the generated cAMP is primarily involved in transmitting odor information to the olfactory bulbs in the brain, it has been demonstrated that an increase in cellular cAMP by ADCY3 could stimulate protein kinase A (PKA) signaling, which is well-known to regulate diverse physiological and pathological processes" SIGNOR-278073 CAMKK2 protein Q96RR4 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 t gcesareni "Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli." SIGNOR-176602 MRGPRX2 protein Q96LB1 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257059 CDH1 protein P12830 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 SIGNOR up-regulates binding 9606 BTO:0000782 7969453 t gcesareni "Here we show that heterotypic adhesive interactions between epithelial cells and intraepithelial lymphocytes in vitro are mediated by e-cadherin and the alpha e beta 7 integrin." SIGNOR-35210 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 BTO:0000567 19836242 t "We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173" SIGNOR-248697 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI "up-regulates quantity" "precursor of" 9606 8755651 t scontino "Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3" SIGNOR-266950 fentanyl chemical CHEBI:119915 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258938 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Thr185 EGSRQALtLQDWAAQ -1 18184589 t Manara "Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition." SIGNOR-260803 FGF2 protein P09038 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 20974802 f "inferred from 70% of family members" gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription." SIGNOR-269929 GNAQ protein P50148 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" binding 7108 BTO:0001240 9305846 t "Marta Tosoni" "AlF− 4-activated Gaq-GDP increased Btk activity as expected, whereas AlF− 4 alone had no stimulatory effect (Table 1), so we conclude that Gaq directly stimulates Btk kinase activity" SIGNOR-278083 tetrafluoroaluminate(1-) chemical CHEBI:30111 ChEBI GNAQ protein P50148 UNIPROT "up-regulates activity" "chemical activation" 7108 BTO:0001240 9305846 t "Marta Tosoni" "Aluminium tetrafluoride (AlF−4) interacts with Gα-bound GDP to mimic GTP and to activate G proteins13. AlF−4-activated Gαq-GDP increased Btk activity as expected" SIGNOR-278084 BMP2 protein P12643 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates 9606 22298955 f lperfetto "Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation." SIGNOR-195561 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni "We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch)." SIGNOR-93313 "Nucleolar ribonuclease P complex" complex SIGNOR-C571 SIGNOR tRNA(Lys) smallmolecule CHEBI:29185 ChEBI "up-regulates quantity" "chemical modification" 9606 30454648 t miannu "Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA." SIGNOR-280712 PI3K complex SIGNOR-C156 SIGNOR BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000899 10201980 t lperfetto "Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation" SIGNOR-252709 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica "Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ" SIGNOR-201154 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 24117889 t lperfetto "Camkii represses transcriptionally active beta-catenin to mediate acute ethanol neurodegeneration and can phosphorylate beta-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human beta-catenin at t332, t472, and s552" SIGNOR-202825 APC-c complex SIGNOR-C150 SIGNOR KIF2C protein Q99661 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 25504441 t miannu "Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis." SIGNOR-276864 WNT1 protein P04628 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21078818 t gcesareni "Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling." SIGNOR-169648 PRKACA protein P17612 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD -1 9016641 t miannu "PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1." SIGNOR-250336 hsa-miR-326 mirna URS00000A939F_9606 RNAcentral CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002035 25173582 f Parnian "The upregulation of miR-326 not only inhibited the activity of the Hh pathway but also reduced the expression of additional Hh signaling components, including GLI1, N-myc, and CyclinD1." SIGNOR-277981 GSK3B protein P49841 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 17726008 t gcesareni "Here we show that similar to the interaction with traf4 and axin, the kinase domain of mekk4 interacts with the multifunctional serine/threonine kinase gsk3beta. Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways" SIGNOR-157544 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Thr575 SNSCRSStTTCPEQD 9606 16862148 t lperfetto "ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2)." SIGNOR-249299 CSNK2A2 protein P19784 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT "down-regulates activity" phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 t llicata "We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified" SIGNOR-250986 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 t milica "The protease-activated receptors (PAR)2 are a class of G protein-coupled receptors (GPCR) that are activated by the proteolysis of the N-terminal exodomain. Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13)." SIGNOR-196006 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK9 protein P50750 UNIPROT "down-regulates activity" "chemical inhibition" -1 29901072 t miannu "AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9." SIGNOR-262217 FZD7 protein O75084 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR "form complex" binding 9606 BTO:0002314 BTO:0001103 23290138 t apalma "We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells." SIGNOR-255848 "OST-A complex" complex SIGNOR-C535 SIGNOR Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272055 GATA2 protein P23769 UNIPROT TRH protein P20396 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0000318 33201916 t scontino "The rat prepro-TRH gene is activated by GATA2." SIGNOR-267259 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." SIGNOR-244247 bevacizumab antibody DB00112 DRUGBANK VEGFB protein P49765 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 15961063 t miannu "Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy." SIGNOR-259885 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates quantity by stabilization" binding 9606 23438602 t miannu "XRCC3 activation is essential for the recruitment of RAD51 to the sites of DNA lesions. It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation." SIGNOR-262667 RNF216 protein Q9NWF9 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 16968706 t miannu "Triad3A promotes proteolytic degradation of adapter proteins. Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins." SIGNOR-271608 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR1 protein P03372 UNIPROT up-regulates "chemical activation" 9606 BTO:0000150 17478088 t gcesareni "Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters." SIGNOR-154660 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 t lperfetto "These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2" SIGNOR-112483 4-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]aniline chemical CHEBI:92250 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258852 LAMTOR3 protein Q9UHA4 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates binding 9606 15547943 t lperfetto "We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations." SIGNOR-244874 1038915-60-4 chemical CID:24958200 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194399 VKORC1L1 protein Q8N0U8 UNIPROT "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI "down-regulates quantity" "chemical modification" 9606 31226734 t lperfetto "The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form" SIGNOR-265902 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Thr509 PVFDLTTtPKGGTPA 9606 16611631 t lperfetto "Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-145979 HMGA1 protein P17096 UNIPROT SLC2A3 protein P11169 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22706202 f miannu "CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization." SIGNOR-254427 C1R protein P00736 UNIPROT "Complement C1 complex" complex SIGNOR-C309 SIGNOR "form complex" binding -1 29449492 t lperfetto "The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases" SIGNOR-263395 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Ser54 ELQPMPTsPGVDLQS 9606 BTO:0000567 12714602 t lperfetto "We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a." SIGNOR-217348 ADRA2A protein P08913 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256698 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t lperfetto "Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2." SIGNOR-59631 TAL1 protein P17542 UNIPROT UBE2H protein P62256 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 20028976 t lperfetto "Tal1 expression activated UBE2H expression, whereas Tal1 knock-down reduced UBE2H expression and ubiquitin transfer activity.|Binding of Tal1 to UBE2H was confirmed by chromatin immunoprecipitation." SIGNOR-269000 GPR119 protein Q8TDV5 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257153 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr417 SLPQATVtPPRKEER 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 t lperfetto "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex" SIGNOR-216953 AURKC protein Q9UQB9 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 12588998 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-265357 CDK5 protein Q00535 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Ser114 RKLQGRPsPGPPAPE 9606 BTO:0000938 20213743 t llicata "Together, our data suggest that cdk5 can phosphorylate enos at the ser-113 site and down-regulate enos-derived no levels." SIGNOR-164080 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates activity" phosphorylation Ser367 GTQNPVSsPGMSQEL -1 29967145 t miannu "CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro." SIGNOR-277651 BRCA1 protein P38398 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates ubiquitination 9606 16818604 t gcesareni "In conclusion, our data show that ctip is a physiological substrate of the brca1 e3 ligase. Brca1 recruits ctip through its c-terminal brct domains and promotes ctip ubiquitination through its n-terminal ring domain. The ubiquitinated ctip is not targeted for degradation. Instead, ubiquitinated ctip binds to chromatin following dna damage and is likely to be involved in dna damage checkpoint control." SIGNOR-147711 creatine smallmolecule CHEBI:16919 ChEBI CKB protein P12277 UNIPROT "up-regulates activity" "chemical activation" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265783 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR -1 15486195 t miannu "Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination." SIGNOR-250080 HSPA1A protein P0DMV8 UNIPROT NOD2 protein Q9HC29 UNIPROT "up-regulates quantity by stabilization" binding 9606 24790089 t miannu "The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease." SIGNOR-252416 PLAUR protein Q03405 UNIPROT KRT1 protein P04264 UNIPROT "up-regulates activity" binding 9606 14691569 t "Regulation of binding" miannu "Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored." SIGNOR-251880 CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 t lperfetto "Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome" SIGNOR-165022 SCN11A protein Q9UI33 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253407 "Phenylalanyl-tRNA synthetase" complex SIGNOR-C473 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 20223217 t miannu "Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers." SIGNOR-270437 succinate(2-) smallmolecule CHEBI:30031 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI "up-regulates quantity" "precursor of" 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions." SIGNOR-266275 AKT2 protein P31751 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." SIGNOR-109732 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t "The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction." SIGNOR-175817 RELA protein Q04206 UNIPROT IL1B protein P01584 UNIPROT "down-regulates activity" "transcriptional regulation" 10090 BTO:0000801 23667107 t lperfetto "Early Inhibition of IL-1 beta Expression by IFN-gamma Is Mediated by Impaired Binding of NF-kappa B to the IL-1 beta Promoter but Is Independent of Nitric Oxide|We report that IFN-γ suppressed bacterial RNA and LPS induced IL-1β transcription in primary murine macrophages" SIGNOR-251736 INPPL1 protein O15357 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates 9606 18486448 f gcesareni "Ship2 positively modulated the mlk3/jip1-mediated jnk1 activation" SIGNOR-178652 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR TRIM71 protein Q2Q1W2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269239 AMPK complex SIGNOR-C15 SIGNOR CTH protein P32929 UNIPROT "up-regulates activity" phosphorylation Ser346 ESLGGFEsLAELPAI 9606 BTO:0000007 37922764 t miannu " Here we define an important mechanism of increased persulfide and polysulfide production involving cystathionine gamma lyase (CSE) phosphorylation at serine 346 and threonine 355 in a substrate specific manner, under acute hypoxic conditions. Hypoxic phosphorylation of CSE occurs in an AMP kinase dependent manner increasing enzyme activity involving unique inter- and intramolecular interactions within the tetramer. " SIGNOR-277794 lisinopril chemical CHEBI:43755 ChEBI ACE protein P12821 UNIPROT "down-regulates activity" "chemical inhibition" -1 9187274 t miannu "We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range." SIGNOR-258611 SLBP protein Q14493 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265413 PRKAA1 protein Q13131 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser635 DTHFRSPsSSVGSPP 9606 SIGNOR-C15 19815529 t llicata "We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635)." SIGNOR-188403 N protein P59595 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling." SIGNOR-260342 3b protein P59633 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling." SIGNOR-260343 6 protein P59634 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling." SIGNOR-260344 RBPJ protein Q06330 UNIPROT MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 21873209 t gcesareni "When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects" SIGNOR-176197 Ub:E2 complex SIGNOR-C497 SIGNOR RNF138 protein Q8WVD3 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271027 GOLPH3 protein Q9H4A6 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 19553991 f "Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo." SIGNOR-253555 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT "up-regulates activity" phosphorylation Tyr666 GQEVYHAyAEPLPIT -1 23770091 t done miannu "Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding." SIGNOR-273946 azelastine chemical CHEBI:2950 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 21381763 t Luana "Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively. " SIGNOR-257894 FGF11 protein Q92914 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253442 EGFR protein P00533 UNIPROT EPS15 protein P42566 UNIPROT up-regulates phosphorylation Tyr849 NFANFSAyPSEEDMI 9606 24269888 t lperfetto "Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly;" SIGNOR-203311 NCOR2 protein Q9Y618 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 12897056 t gcesareni "The spen protein, sharp (smrt/hdac1-associated repressor protein), was identified as a component of transcriptional repression complexes in both nuclear receptor and notch/rbp-jkappa signaling pathways." SIGNOR-104489 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192601 FYN protein P06241 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Tyr15 EKIGEGTyGTVFKAK 9606 14757045 t "Constitutively active Fyn phosphorylated Tyr15 of Cdk5. Fyn Facilitates Kinase Activity of Cdk5 Via Tyr15 Phosphorylation" SIGNOR-251156 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-156848 BDKRB1 protein P46663 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257036 GAD1 protein Q99259 UNIPROT "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "up-regulates quantity" "chemical modification" 9606 32041144 t miannu "Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions." SIGNOR-267552 PYHIN1 protein Q6K0P9 UNIPROT HDAC1 protein Q13547 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 18247378 f miannu "We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1." SIGNOR-268495 CCP110 protein O43303 UNIPROT CETN1 protein Q12798 UNIPROT "up-regulates activity" binding 9606 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-265966 EEF1A1 protein P68104 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269503 MCL1 protein Q07820 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17289999 t gcesareni "Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w" SIGNOR-151787 TP53 protein P04637 UNIPROT FGF2 protein P09038 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10029407 f miannu "p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1." SIGNOR-255431 "GABA-A (a5-b1-g2) receptor" complex SIGNOR-C335 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268595 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto "P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-124847 MAPKAPK2 protein P49137 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates activity" phosphorylation 9606 35554104 t miannu "MK2 Phosphorylates Caspase-3, Facilitates Nuclear Translocation of Caspase 3, and Regulates Apoptosis.|Over-expression of MK2 led to an increase in nuclear caspase-3 activity." SIGNOR-278960 AKT proteinfamily SIGNOR-PF24 SIGNOR USP14 protein P54578 UNIPROT "up-regulates activity" phosphorylation Ser432 THQGRSSsSGHYVSW 9606 BTO:0000007 26523394 t lperfetto "Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt." SIGNOR-265055 CDK1 protein P06493 UNIPROT CGAS protein Q8N884 UNIPROT "down-regulates activity" phosphorylation Ser305 MKRKRGGsPAVTLLI 32351706 t lperfetto "The major mitotic kinase CDK1-cyclin B complex phosphorylates human cGAS at S305 or mouse cGAS at S291, which inhibits its ability to synthesize cGAMP upon mitotic entry." SIGNOR-276526 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 t lperfetto "Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells." SIGNOR-264443 ZC3HAV1 protein Q7Z2W4 UNIPROT PARN protein O95453 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21876179 t "We provide evidence indicating that ZAP selectively recruits cellular poly(A)-specific ribonuclease (PARN) to shorten the poly(A) tail of target viral mRNA and recruits the RNA exosome to degrade the RNA body from the 3′ end." SIGNOR-261296 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT "up-regulates activity" phosphorylation Ser136 ATNNLSRsNSDESNF 9606 BTO:0000007 16818229 t miannu "Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling." SIGNOR-276290 FOXO4 protein P98177 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260102 EEF1A1P5 protein Q5VTE0 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 f lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269395 TBK1 protein Q9UHD2 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation 9606 33310066 t miannuccelli "It was found that TBK1 phosphorylates both Cdc20 as well as Cdh1 (Figure 2F)." SIGNOR-279766 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:RING_E3 complex SIGNOR-C519 SIGNOR "form complex" binding 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag." SIGNOR-271380 (RS)-Ppcc chemical CID:16726095 PUBCHEM SIGMAR1 protein Q99720 UNIPROT "up-regulates activity" "chemical activation" 9606 17328523 t Federica "We suggest that 4b may act as a ơ1/ơ2 agonist and that the ơ ligands may modulate TG-2 differently." SIGNOR-261107 PPARG protein P37231 UNIPROT ARNTL protein O00327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19041764 t miannu " Rosiglitazone treatment induced aortic expression of Bmal1 mRNA, and ChIP and promoter assays revealed that Bmal1 is a direct PPARgamma target gene. These studies have uncovered a role for vascular PPARgamma as a peripheral factor participating in regulation of cardiovascular rhythms." SIGNOR-268026 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT "up-regulates activity" phosphorylation Thr182 KSGEPLStWCGSPPY 9606 18946175 t miannu "Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182." SIGNOR-262844 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Ror1 and ror2 bind wnt5a." SIGNOR-199644 KAT2A protein Q92830 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269602 RARB protein P10826 UNIPROT RXRB protein P28702 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16581 CAMK2A protein Q9UQM7 UNIPROT RIMS1 protein Q86UR5 UNIPROT up-regulates phosphorylation Ser242 PSAPPDRsKGAEPSQ 9606 BTO:0000938 BTO:0000142 12871946 t gcesareni "Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3," SIGNOR-103886 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR "Macropinosomes formation" phenotype SIGNOR-PH227 SIGNOR up-regulates 9606 39000072 f miannu "The signaling for the regulation of macropinocytosis normally starts with the activation of RAS protein by macropinocytic stimulators, which in turn initiate signaling cascades involving RAC1 and phosphatidylinositol kinases and their downstream effectors or product that lead to actin cytoskeleton remodeling for plasma membrane ruffle and macropinocytic cup formation. Macropinosomes are further matured by regulation of the small GTPases RAC1 and CDC42 as well as phosphatidylinositol lipids, and matured macropinosomes undergo recycling or degradation processes." SIGNOR-277767 POU3F2 protein P20265 UNIPROT GNRH1 protein P01148 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11875100 f miannu "Functional studies demonstrated that Brn-2 increased promoter activity of the human and mouse GnRH genes." SIGNOR-254928 AKT1 protein P31749 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Ser985 THLSRVRsLDLDDWP 9606 BTO:0001130 19176382 t llicata "In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2." SIGNOR-183543 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr536 QKGQESEyGNITYPP 9606 8692915 t Manara "The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites." SIGNOR-260820 SKP2 protein Q13309 UNIPROT CDT1 protein Q9H211 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 10790373 t miannu " Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3." SIGNOR-272565 BCL9 protein O00512 UNIPROT PYGO1 protein Q9Y3Y4 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 t miannu "Here we report the identification of two segment polarity genes in drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human bcl9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking pygo to beta-catenin." SIGNOR-116577 COPS7B protein Q9H9Q2 UNIPROT "COP9 signalosome variant 2" complex SIGNOR-C487 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270760 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 12058066 t lperfetto "Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association." SIGNOR-216662 ENO1 protein P06733 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "chemical modification" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266524 SSTR2 protein P30874 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256963 XPOT protein O43592 UNIPROT NPC complex SIGNOR-C263 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 9660920 t miannu "Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus." SIGNOR-261393 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-252484 bosutinib chemical CHEBI:39112 ChEBI ABL1 protein P00519 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258088 RPS6KB1 protein P23443 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation 9606 33353667 t miannu "D1R-PKA appears intact and elevated DARPP-32(pT34) in Rheb(S16H) mice is reduced by S6K1 inhibition (Figure 3).|S6K1 directly phosphorylates DARPP-32." SIGNOR-279654 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT "up-regulates activity" phosphorylation Ser321 SKPSGNDsCELRNLK -1 26119734 t miannu "Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro" SIGNOR-276212 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." SIGNOR-106436 AMPK complex SIGNOR-C15 SIGNOR SIRT7 protein Q9NRC8 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr153 TLTHMSItRLHEQKL 27511885 t lperfetto "Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ." SIGNOR-275865 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219308 TBX5 protein Q99593 UNIPROT SNCG protein O76070 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20802524 f miannu "TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2." SIGNOR-255255 PRKCZ protein Q05513 UNIPROT VIM protein P08670 UNIPROT "up-regulates activity" phosphorylation Ser34 SRSYVTTsTRTYSLG 9606 BTO:0001033 33525953 t miannu "Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells." SIGNOR-277622 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269383 RBM10 protein P98175 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001938 30403180 f irozzo "Cell apoptosis is an important event in cancer progression. Overexpression of RBM10 dramatically induced U2OS cell apoptosis compared with negative control cells." SIGNOR-259150 "abiraterone acetate" chemical CHEBI:68639 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205573 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0002552 23479728 t lperfetto "Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists|" SIGNOR-267668 SEC16A protein O15027 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265293 amitriptyline chemical CHEBI:2666 ChEBI CHRM4 protein P08173 UNIPROT "down-regulates activity" "chemical inhibition" 10029 8100134 t miannu "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine." SIGNOR-258704 CDK4 protein P11802 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser477 ADALKLRsPRGSPDG 9606 BTO:0000150 20807815 t llicata "Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function." SIGNOR-167770 "Melanotan II" chemical CID:92432 PUBCHEM MC3R protein P41968 UNIPROT "up-regulates activity" binding BTO:0000614 17702843 t lperfetto "Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases." SIGNOR-253065 CDC34 protein P49427 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "up-regulates activity" binding 9606 25425648 t miannu "The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases." SIGNOR-277331 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1114 HGHVSNAsIRVGENV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262902 PARK7 protein Q99497 UNIPROT "MTA1/DJ1 complex" complex SIGNOR-C123 SIGNOR "form complex" binding 9606 BTO:0000567 21368136 t 1 miannu "we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3." SIGNOR-239448 hsa-miR-101-3p mirna URS00001230A0_9606 RNAcentral PTX3 protein P26022 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 9606 BTO:0002181 39559327 t miannu "MiR-101-3p suppresses proliferation of orbital fibroblasts by targeting pentraxin-3 in thyroid eye disease" SIGNOR-279939 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT unknown phosphorylation Tyr564 SKHKEDVyENLHTKN -1 12468540 t gcesareni "Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect" SIGNOR-246240 NCOA2 protein Q15596 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 24239470 t miannu "The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis" SIGNOR-251530 CDK1 protein P06493 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 SIGNOR-C17 20937773 t lperfetto "In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387" SIGNOR-168446 HLTF protein Q14527 UNIPROT PCNA protein P12004 UNIPROT "up-regulates activity" ubiquitination 9606 21845734 t miannu "HLTF promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen (PCNA) that is required for maintaining genomic stability." SIGNOR-278608 SRC protein P12931 UNIPROT CEACAM1 protein P13688 UNIPROT "up-regulates activity" phosphorylation Tyr493 NKMNEVTySTLNFEA 9606 BTO:0000007 9867848 t lperfetto "Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515" SIGNOR-246471 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL6 protein P05231 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 20086235 f "Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2)" SIGNOR-254511 "CoREST-HDAC complex" complex SIGNOR-C105 SIGNOR SCN2A protein Q99250 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 16140033 f lperfetto "This suggests that the HDACs in the LSD1 complex are likely to function upstream of CoREST/LSD1, generating a hypoacetylated histone substrate, which can then be better recognized by CoREST/LSD1. Further supporting this model, we found that inhibition of HDAC activity by TSA resulted in derepression of two LSD1 target genes, the human neuronal-specific sodium channel (SCN) genes, SCNA2 and SCNA3 (Figure 1H)." SIGNOR-268541 ERG protein P11308 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25277175 f miannu "Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3." SIGNOR-251554 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207938 AKT proteinfamily SIGNOR-PF24 SIGNOR SRPK2 protein P78362 UNIPROT up-regulates phosphorylation Thr492 PSHDRSRtVSASSTG 9606 BTO:0000938 BTO:0000142 19592491 t lperfetto "Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis." SIGNOR-244341 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Thr5794 REFSGPStPTGTLEF 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262767 hsa-miR-100-3p mirna URS00001A405B_9606 RNAcentral FZD8 protein Q9H461 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000093 26537584 t Parnian "These findings suggest that miR-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/β-catenin signaling pathway and manipulation of miR-100 may provide a promoting therapeutic strategy for cancer breast treatment" SIGNOR-277972 PPP2CB protein P62714 UNIPROT ELF1 protein P32519 UNIPROT "down-regulates activity" dephosphorylation Thr231 CPKYIKWtQREKGIF 9606 18714041 t "Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response" SIGNOR-248591 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 f lperfetto "IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization." SIGNOR-249559 MAPK3 protein P27361 UNIPROT GABBR1 protein Q9UBS5 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 t miannu "We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1." SIGNOR-277854 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 20185585 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-163956 NBEAL2 protein Q6ZNJ1 UNIPROT VWF protein P04275 UNIPROT up-regulates 9606 BTO:0000132 28082341 f lperfetto "Recent in vitro megakaryopoiesis studies using HSCs from GPS patients with NBEAL2 mutations showed normal MK differentiation with defective proplatelet formation and reduced α-granule proteins such as von Willebrand factor (VWF), thrombospondin and P-selectin." SIGNOR-261884 lovastatin chemical CHEBI:40303 ChEBI NR1I2 protein O75469 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000318 9727070 t miannu "The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C)." SIGNOR-258828 PLCE1 protein Q9P212 UNIPROT PRKCA protein P17252 UNIPROT up-regulates 9606 12645577 f miannu "TNF-alpha Binds to tnfr1 and activates pc-plc to induce pkc? And c-src activation" SIGNOR-99307 GH1 protein P01241 UNIPROT GHR protein P10912 UNIPROT up-regulates binding 9606 7862673 t gcesareni "The hghr only binds primate gh. Arg43 in hghr interacts with asp171 of hgh." SIGNOR-34129 Tiospirone chemical CID:55752 PUBCHEM HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258863 FZD5 protein Q13467 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 18077588 t areggio "Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction." SIGNOR-258966 PTK2 protein Q05397 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates activity" phosphorylation 9606 33498611 t miannu "Then, FAK phosphorylates and activates YAP, leading to the activation and nuclear translocation of YAP/TAZ transcription factor, which is known to be involved in such cellular mechanoresponses [ xref , xref ]." SIGNOR-280099 "AEP complex" complex SIGNOR-C117 SIGNOR HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" 9606 20854876 f irozzo "Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented." SIGNOR-255879 GABPB1 protein Q06547 UNIPROT HCFC1 protein P51610 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 10675337 t miannu "The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation" SIGNOR-221377 AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 t "We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo" SIGNOR-256135 PDPK1 protein O15530 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 16207722 t miannu "We found that PDK1 directly phosphorylates IKKbeta at the Ser(181) residue in the activation loop, leading to NF-kappaB nuclear translocation and NF-kappaB-dependent anti-apoptotic gene expression." SIGNOR-279088 PRKAA1 protein Q13131 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 17900900 t gcesareni "The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation" SIGNOR-157947 CD3D protein P04234 UNIPROT CD3 complex SIGNOR-C432 SIGNOR "form complex" binding 9606 12507424 t miannu "The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules." SIGNOR-255295 PDPK1 protein O15530 UNIPROT PGK1 protein P00558 UNIPROT "up-regulates activity" phosphorylation Thr243 IGGGMAFtFLKVLNN 9606 BTO:0002036 30029001 t miannu "PDPK1 Phosphorylates PGK1 T243. Macrophages increase PGK1 pT243 to reduce the 3-PG affinity of PGK1, which alters the equilibrium of the PGK1-catalyzed reaction toward glycolysis, promoting tumor cell proliferation." SIGNOR-277402 CHEK2 protein O96017 UNIPROT PPP2R5C protein Q13362 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 15380617 t gcesareni "Found that chk2 associated with the b' regulatory subunit of protein phosphatase pp2a. In vitro kinase assays showed that b'gamma3 was a potent chk2 substrate. This phosphorylation increased the catalytic phosphatase activity of pp2a." SIGNOR-129255 TFEB protein P19484 UNIPROT HEXA protein P06865 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 19556463 f "Figure 1" lperfetto "Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells." SIGNOR-276541 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24505269 t miannu "Recurrent gene fusion between the androgen-regulated gene TMPRSS2 and members of the ETS transcription factor family, most commonly ERG, are present in about 50% of prostate cancer cases. Presence of this fusion gene is a critical event in the development of prostate cancer. the more aggressive phenotype that arises with the presence of TMPRSS2-ERG at least in part is caused by changes in the tumor stroma." SIGNOR-251545 MECP2 protein P51608 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 10090 BTO:0000614 18511691 t Luana "Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) | In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1" SIGNOR-264682 UBE3A protein Q05086 UNIPROT PSMD7 protein P51665 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 28559284 t lperfetto "Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits." SIGNOR-265134 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 t lperfetto "Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182." SIGNOR-236103 CECR2 protein Q9BXF3 UNIPROT CERF complex SIGNOR-C340 SIGNOR "form complex" binding 9606 BTO:0000227 15640247 t miannu "Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation." SIGNOR-263891 AUTS2 protein Q8WXX7 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 28505103 f miannu "Cytoplasmic AUTS2 regulates actin cytoskeleton to control neuronal migration and neurite extension, while nuclear AUTS2 controls transcription of various genes as a component of the polycomb complex 1 (PRC1)." SIGNOR-266816 POU5F1 protein Q01860 UNIPROT EOMES protein O95936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254930 MAPK3 protein P27361 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Ser284 RRDYDDMsPRRGPPP 9606 16564677 t gcesareni "Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353." SIGNOR-145375 ADORA2B protein P29275 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257307 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t "inferred from 70% family members" gcesareni "Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus" SIGNOR-270005 BCL6 protein P41182 UNIPROT FCER2 protein P06734 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 11342629 f "In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability" SIGNOR-253928 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT "up-regulates activity" phosphorylation Ser825 GGGQAKTsPKPAVVE 9606 BTO:0000567 25097229 t miannu "Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins. " SIGNOR-276670 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR TNNC2 protein P02585 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136755 Tomivosertib chemical CID:118598754 PUBCHEM MKNK2 protein Q9HBH9 UNIPROT "down-regulates activity" "chemical inhibition" 9606 29526098 t "Simone Vumbaca" "Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation." SIGNOR-261117 ECM stimulus SIGNOR-ST20 SIGNOR "A4/b7 integrin" complex SIGNOR-C187 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259041 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr382 DHYRYSDtTDSDPEN 9606 21779440 t gcesareni "The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity" SIGNOR-89826 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 16537444 t gcesareni "Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion." SIGNOR-145141 GPER1 protein Q99527 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 10696571 t "GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; the activated receptor induces a conformational change in the associated G protein α-subunit leading to release of GDP followed by binding of GTP and α-subunit dissociation from the receptor." SIGNOR-251102 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Ser328 ERALTEDsTQTSDTA -1 7836371 t gcesareni "Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation." SIGNOR-247763 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR miR-495 mirna URS000075C517_9606 RNAcentral "down-regulates quantity by repression" "transcriptional regulation" 10090 21730352 f miannu "We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation." SIGNOR-256242 CHD8 protein Q9HCK8 UNIPROT NEFM protein P07197 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 32839322 t Gianni "Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells" SIGNOR-268917 HNF1A protein P20823 UNIPROT ALDOB protein P05062 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8383844 f miannu "Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators" SIGNOR-253834 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Gln) smallmolecule CHEBI:29168 ChEBI "up-regulates quantity" "chemical modification" 9606 27911719 t lperfetto "RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)" SIGNOR-269485 CDK3 protein Q00526 UNIPROT LIN9 protein Q5TKA1 UNIPROT up-regulates phosphorylation Thr96 KFTATMStPDKKASQ 9606 BTO:0002181 24475316 t lperfetto "In this report, we demonstrate that cyclin e1/cdk3 phosphorylates lin-9 on thr-96. Mutating thr-96 to alanine inhibits activation of cyclins a2 and b1 promoters, whereas a phosphomimetic asp mutant strongly activates their promoters and triggers accelerated entry into g2/m phase in 293t cells." SIGNOR-204529 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 9606 9973379 t "CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.  Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4." SIGNOR-251160 FAM13A protein O94988 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260502 SETD2 protein Q9BYW2 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" methylation Lys525 QLNMLGEkLLGPNAS 9606 BTO:0000007 28753426 t Gianni "SETD2 enhances antiviral immunity by directly methylating STAT1 on K525. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response." SIGNOR-269091 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-18253 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates "chemical activation" 9606 10884684 t miannu "Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations" SIGNOR-266333 hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral MET protein P08581 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000599 25965999 t Parnian "These results show that miR-122 directly inhibits c-Met translation by targeting the 3’UTR region." SIGNOR-279816 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT "up-regulates activity" phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 t lperfetto "The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130." SIGNOR-238621 SH2B1 protein Q9NRF2 UNIPROT CD79B protein P40259 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000776 "SIGNOR-C433; SIGNOR-C434; SIGNOR-C435; SIGNOR-C436" 32323266 t scontino "SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK." SIGNOR-268458 CSNK2A1 protein P68400 UNIPROT HSF1 protein Q00613 UNIPROT "up-regulates activity" phosphorylation Thr142 DSVTKLLtDVQLMKG -1 12659875 t llicata "Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2." SIGNOR-250898 ACADM protein P11310 UNIPROT decanoyl-CoA smallmolecule CHEBI:28493 ChEBI "down-regulates quantity" "chemical modification" 9606 3035565 t miannu "Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation. " SIGNOR-280356 PRKCD protein Q05655 UNIPROT KCNE3 protein Q9Y6H6 UNIPROT "up-regulates activity" phosphorylation Ser82 LILGYTRsRKVDKRS 21911611 t lperfetto "Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit (mutation of the site for PKCdelta-promoted phosphorylation and modulation of the activity of KCNE3) showed rapid run-down and insensitivity to E2. " SIGNOR-275964 tRNA(Gln) smallmolecule CHEBI:29168 ChEBI Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270393 7a protein P59635 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 16303160 f Luana "Expression of SARS-CoV ORF7a block cell cycle arrest in G0/G1" SIGNOR-260207 cysteine smallmolecule CHEBI:15356 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264759 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites." SIGNOR-252869 VPS4A protein Q9UN37 UNIPROT CHMP3 protein Q9Y3E7 UNIPROT "up-regulates activity" cleavage -1 30989108 t Giorgia "Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission." SIGNOR-260847 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000298 9305639 t lperfetto "These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1." SIGNOR-50894 KMT5C protein Q86Y97 UNIPROT H4C1 protein P62805 UNIPROT "down-regulates activity" methylation Lys21 GGAKRHRkVLRDNIQ -1 24396869 t miannu "SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation." SIGNOR-266650 FOXP1 protein Q9H334 UNIPROT PITX3 protein O75364 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000596 20175877 t Gianni "We identified FoxP1 as a novel marker for midbrain dopamine neurons. Enforced expression of FoxP1 in embryonic stem cells actuates the expression of Pitx3, a homeobox protein that is exclusively expressed in midbrain dopaminergic neurons and is required for their differentiation and survival during development and from embryonic stem cells in vitro. We show that FoxP1 can be recruited to the Pitx3 locus in embryonic stem cells and regulate Pitx3 promoter activity in a dual-luciferase assay." SIGNOR-269049 SLC5A5 protein Q92911 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI "up-regulates activity" "chemical activation" 9606 14623893 t miannu "Iodide is an essential element in thyroid physiology as a critical component of thyroxine and triiodothyronine molecules and a key regulator of thyroid gland function. The first step in iodide metabolism is represented by thyroid trapping, which is achieved by an active, energy-dependent transport process across the basolateral plasma membrane of the thyrocytes. The protein responsible for this process, the sodium/iodide symporter (NIS),1 is an intrinsic plasma membrane protein that mediates active transport of I- in the thyroid, lactating mammary gland, stomach, and salivary glands" SIGNOR-251996 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT "up-regulates activity" phosphorylation Tyr171 NNANYTEyVATRWYR -1 16935860 t miannu "Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif." SIGNOR-245876 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys70 GKAVRGAkGHHHPHP 9606 12408818 t gcesareni "Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300" SIGNOR-95169 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2J2 protein Q8N2K1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271373 bethanechol chemical CHEBI:3084 ChEBI CHRM3 protein P20309 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258623 domperidone chemical CHEBI:31515 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258720 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258187 BBIP1 protein A8MTZ0 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262561 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI "up-regulates quantity" "chemical modification" 9606 33179964 t miannu "The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS)." SIGNOR-267318 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Thr478 CNENFKKtFKRILHI 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" fspada "The peptide p10-t478a (thr478 to alanine) was not phosphorylated by pkc, indicating that thr478 can be phosphorylated by pkc." SIGNOR-124356 EZH2 protein Q15910 UNIPROT "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR "form complex" binding 9606 23110252 t lperfetto "The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48)." SIGNOR-241894 SRC protein P12931 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr104 RSPSTGLyDNLEKYH 9606 BTO:0000007 24996174 t miannu "In this study, we investigated the potential regulation of SIRT2 function by c-Src. We found that the protein levels of SIRT2 were decreased by c-Src, and subsequently rescued by the addition of a Src specific inhibitor, SU6656, or by siRNA-mediated knockdown of c-Src. The c-Src interacts with and phosphorylates SIRT2 at Tyr104." SIGNOR-263104 nilotinib chemical CHEBI:52172 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258257 SIRT1 protein Q96EB6 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 t gcesareni "We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation." SIGNOR-252445 ALG1 protein Q9BT22 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI "up-regulates quantity" "chemical modification" 9606 28575298 t lperfetto "The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum." SIGNOR-260418 ATF4 protein P18848 UNIPROT ASNS protein P08243 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002182 18940792 f miannu "C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene." SIGNOR-253838 SOX17 protein Q9H6I2 UNIPROT SOX17/POU5F1 complex SIGNOR-C451 SIGNOR "form complex" binding 23474895 t SimoneGraziosi "Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm|We show that Sox17 partners with Oct4 and binds to a unique ‘compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical' binding sites." SIGNOR-269220 COPS3 protein Q9UNS2 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates quantity by stabilization" binding 9606 30631038 t miannu "Our observations characterizing the interaction between CSN3 and the Sos1 HD suggest that this domain not only functions regulating Sos-GEF autoinhibition but is also involved in other functional roles, such as the control of Sos protein stability and homeostasis by modulating the degradation and intracellular levels of Sos1." SIGNOR-256217 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT down-regulates phosphorylation Ser1565 LSPFRRHsWGPGKNA 9606 15229649 t llicata "Elevation of the cellular concentration of camp activates the pka holoenzyme anchored to akap-lbc, which phosphorylates the anchoring protein on the serine 1565. This phosphorylation event induces the recruitment of 14-3-3, which inhibits the rho-gef activity of akap-lbc." SIGNOR-126723 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248655 F2RL3 protein Q96RI0 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257157 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 SIGNOR-C2 21157483 t lperfetto "Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism" SIGNOR-170604 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates activity" phosphorylation Ser378 RICMRNFsRSDHLTT 10090 BTO:0000944 8662759 t llicata "Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10." SIGNOR-250856 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 9657565 t "allergic rhinitis" gcesareni SIGNOR-251689 MYT1L protein Q9UL68 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0002572 28379941 t miannu "ChIP–seq experiments showed that 80% of Myt1l targets, including the transcription factor Hes1, were co-bound by the repressive Sin3b–HDAC1 complex early during reprogramming" SIGNOR-266775 POU4F3 protein Q15319 UNIPROT LHX3 protein Q9UBR4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000630 17331196 t lperfetto "Using oligonucleotide microarrays to generate expression profiles of inner ears of Pou4f3(ddl/ddl) mutant and wild-type mice, we have identified and validated Lhx3, a LIM domain transcription factor, as an in vivo target gene regulated by Pou4f3. Lhx3 is a hair cell-specific gene expressed in all hair cells of the auditory and vestibular system as early as embryonic day 16. The level of Lhx3 mRNA is greatly reduced in the inner ears of embryonic Pou4f3 mutant mice. Our data also show that the expression of Lhx3 is regulated differently in auditory and vestibular hair cells." SIGNOR-262586 PAK1 protein Q13153 UNIPROT FXR1 protein P51114 UNIPROT "up-regulates activity" phosphorylation Ser420 SERKDELsDWSLAGE 9534 BTO:0000298 20417602 t done miannu "Identification of Ser420 in FXR1 as a PAK1 Kinase Target. During zebrafish muscle development, FXR1 Ser420 phosphorylation is needed for protein function." SIGNOR-273713 GFs stimulus SIGNOR-ST12 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 9606 23300340 f lperfetto "Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation" SIGNOR-245411 MRPS12 protein O15235 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261457 CSNK2A1 protein P68400 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation -1 8954982 t llicata "Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149." SIGNOR-250951 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR CBFB protein Q13951 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f irozzo "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins." SIGNOR-255854 CHEK2 protein O96017 UNIPROT ELAVL1 protein Q15717 UNIPROT "up-regulates activity" phosphorylation Ser100 VSYARPSsEVIKDAN 9606 21745814 t miannu "Taken together, these findings indicate that phosphorylation at residue S100 by Chk2 enhances HuR-binding to the occludin mRNA, while phosphorylation at S88 and T118 reduces this interaction; these modifications in turn regulate occludin translation." SIGNOR-278161 WWP2 protein O00308 UNIPROT SOX2 protein P48431 UNIPROT "down-regulates quantity" ubiquitination 9606 34732716 t miannu "Among the four E3 ligases, only WWP2 knockdown was found to increase SOX2 protein levels in GSCs (Fig.\u00a04A).|We first verified that WWP2 ubiquitinates SOX2 in vitro." SIGNOR-278798 SMARCB1 protein Q12824 UNIPROT "Neural progenitor-specific SWI/SNF" complex SIGNOR-C477 SIGNOR "form complex" binding 9606 25195934 t miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270618 TWIST1 protein Q15672 UNIPROT SNAI2 protein O43623 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255524 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 12213813 t lperfetto "In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E" SIGNOR-262993 VX-745 chemical CHEBI:90528 ChEBI MAPK14 protein Q16539 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258310 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Thr141 DLSSRSKtDLDCIFG 9606 20573420 t lperfetto "Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation." SIGNOR-166329 glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" 10090 BTO:0000222 18477450 f "Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK)." SIGNOR-256137 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206124 CATSPER2 protein Q96P56 UNIPROT "CatSpermasome complex" complex SIGNOR-C574 SIGNOR "form complex" binding 9606 34225353 t miannu "The cation channel of sperm (CatSper) is essential for sperm motility and fertility1,2. CatSper comprises the pore-forming proteins CATSPER1-4 and multiple auxiliary subunits, including CATSPERβ, γ, δ, ε, ζ, and EFCAB91,3-9. " SIGNOR-280742 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 t lperfetto "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition." SIGNOR-252906 "Spike protein-ACE2" complex SIGNOR-C240 SIGNOR "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 18554741 f miannu "Endocytosis of the Receptor-Binding Domain of SARS-CoV Spike Protein Together With Virus Receptor ACE2. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells." SIGNOR-260289 "CoV2 Spike protein-ACE2" complex SIGNOR-C254 SIGNOR "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 32221306 f miannu "We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease." SIGNOR-260743 "CoV2 spike protein-NRP1" complex SIGNOR-C267 SIGNOR "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 10090 BTO:0000108 33082293 t Luana "NRP mediates entry of nanoparticles coated with SARS-CoV-2 (SARS-2) S–derived CendR peptides into cultured cells, olfactory epithelium, and the central nervous system of mice." SIGNOR-262316 "CoV2 Spike protein-ACE2" complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32231345 f doi.org/10.1101/2020.03.09.983247 miannu "Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell-cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity." SIGNOR-260741 "CoV2 Spike protein-ACE2" complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32221306 f miannu "We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease." SIGNOR-260744 glycine smallmolecule CHEBI:15428 ChEBI GLRA2 protein P23416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu "The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina." SIGNOR-264981 BAG3 protein O95817 UNIPROT SIRT5 protein Q9NXA8 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30910998 f Monia "Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. we demonstrated that BAG3 overexpression decreased SIRT5 expression in HepG2 cells (Fig. 5d)." SIGNOR-261205 CSF1R protein P07333 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr904 TKSLDNNySTPNERG 9606 21049007 t miannu "In our study, CSF-1R induced the tyrosine phosphorylation of p120 Y904 and Y228 in a SRC-dependent manner ( xref )." SIGNOR-278929 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Tyr354 LKAYGNGySSNGNTG 10029 BTO:0000246 8557631 t "Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors." SIGNOR-251302 "BRCA1-C complex" complex SIGNOR-C299 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 25400280 f lperfetto "The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2" SIGNOR-263228 RAR proteinfamily SIGNOR-PF45 SIGNOR THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t "inferred from 70% family members" gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-269955 SGI-1776 chemical CID:24795070 PUBCHEM PIM2 protein Q9P1W9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206862 FOXP2 protein O15409 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 25232744 t miannu "By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets." SIGNOR-266834 midostaurin chemical CHEBI:63452 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258248 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT "down-regulates activity" phosphorylation Ser316 EKKGKDQsGEVLSSV 9615 11742978 t llicata "We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII." SIGNOR-250976 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 t lperfetto "Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4." SIGNOR-244739 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t gcesareni "Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a." SIGNOR-252971 TGFBR2 protein P37173 UNIPROT USP2 protein O75604 UNIPROT "up-regulates activity" phosphorylation Ser225 SRVPEIIsPTYRPIG -1 29490279 t miannu "Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1." SIGNOR-273603 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 12510059 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-96936 CDH7 protein Q9ULB5 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265869 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-251477 IL21R protein Q9HBE5 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000876 BTO:0000763;BTO:0001253 15667561 f gcesareni "Interleukin 24 (il-24) is a new member of the il-10 family of cytokines and it signals through two heterodimeric receptors: il-20r1/il-20r2 and il-22r1/il-20r2. Upon binding to its receptors, il-24 induces rapid activation of stat-1 and stat-3 transcription factors," SIGNOR-133379 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" -1 31995776 t miannu "This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. ." SIGNOR-268730 APOE protein P02649 UNIPROT SORL1 protein Q92673 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11557679 t gcesareni "Lr11 binds the apolipoprotein e (apoe)-rich lipoproteins, beta-very low density lipoproteins (vldls), with a high affinity similar to that of other members, such as the ldlr and vldl receptor.Incubation For 48 hours with beta-vldl of lr11-overexpressing cells, but not of control cells, promotes the appearance of numerous intracellular lipid droplets." SIGNOR-110555 MAPK14 protein Q16539 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 t gcesareni "Moreover, this region (wac domain) was also phosphorylated by recombinant proteins of p38_? And jnk2_? But not by akt1" SIGNOR-188160 ROCK1 protein Q13464 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 19386264 t lperfetto "Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. We performed an in vitro kinase assay with 80 selected kinases on an ezrin peptide containing the t567 phosphorylation site (figure 3a). In this screen, we identified the mst and rock kinases as the most potent kinases for the ezrin peptide" SIGNOR-185567 STK4 protein Q13043 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 t lperfetto "The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells" SIGNOR-171009 EIF5 protein P55010 UNIPROT EIF5B protein O60841 UNIPROT "up-regulates activity" relocalization 9606 30211544 t lperfetto "eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC." SIGNOR-269122 AKT proteinfamily SIGNOR-PF24 SIGNOR SH2B2 protein O14492 UNIPROT "up-regulates activity" phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 t gcesareni "This study identifies APS as a novel physiological substrate for PKB and the first serine phosphorylation site on APS" SIGNOR-248042 RUSC1 protein Q9BVN2 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates binding 9606 15024033 f miannu "Overexpression studies in PC12 cells indicate that Nesca facilitates neurotrophin-dependent neurite outgrowth at nonsaturating doses of nerve growth factor (NGF)." SIGNOR-272776 PTPN6 protein P29350 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation 9534 8943354 t "Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1" SIGNOR-248466 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr95 DKTQLNPtSLQKLFR 9606 15319445 t gcesareni "Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1." SIGNOR-128268 E2F2 protein Q14209 UNIPROT CCNE1 protein P24864 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8649818 f gcesareni "We have found that cell cycle regulation of cyclin e transcription is mediated by e2f binding sites present in the promoter" SIGNOR-42020 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10230394 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-67379 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT "up-regulates activity" binding 9606 14607242 t "It turned out that RGS domain of p115RhoGEF is specific for Gα12 and Gα13, and does not bind Gαi, Gαs and Gαq (Kozasa et al., 1998). The binding of Gα13 but not Gα12 stimulated GEF activity for Rho" SIGNOR-256521 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto "Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions." SIGNOR-251525 LYN protein P07948 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 9606 17146444 t miannu "An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3." SIGNOR-279062 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT down-regulates dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000149 10993888 t gcesareni "A cytosolic protein-tyrosine phosphatase ptp1b specifically dephosphorylates and deactivates prolactin-activated stat5a and stat5b." SIGNOR-82042 SMURF1 protein Q9HCE7 UNIPROT OTUD6B protein Q8N6M0 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272687 CSNK1D protein P48730 UNIPROT UHRF1 protein Q96T88 UNIPROT up-regulates phosphorylation Ser95 SELSDTDsGCCLGQS 9606 23297342 t llicata "We further show that uhrf1 physically interacts with _-trcp1 in a manner dependent on phosphorylation of serine 108 (s108(uhrf1)) within the dsg degron. Furthermore, we demonstrate that s108(uhrf1) phosphorylation is catalyzed by casein kinase 1 delta (ck1_) and is important for the recognition of uhrf1 by scf(_-trcp)." SIGNOR-200349 TLR9 protein Q9NR96 UNIPROT TICAM2 protein Q86XR7 UNIPROT "up-regulates activity" binding 10090 22664090 t scontino "To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group" SIGNOR-266750 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "precursor of" 9606 31422819 t miannu "This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-267516 ethanol chemical CHEBI:16236 ChEBI GLRA2 protein P23416 UNIPROT "up-regulates activity" "chemical activation" 8355 BTO:0000964 8700149 t miannu "Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations." SIGNOR-258496 CRYAA protein P02489 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 22982024 f miannu "Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin." SIGNOR-252156 IL2 protein P60568 UNIPROT TNFSF10 protein P50591 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782 22128144 f miannu "We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression." SIGNOR-253895 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." SIGNOR-106432 PTGER2 protein P43116 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256899 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Ser668 DVEFCVMsGTDSQPK 9606 15194694 t lperfetto "Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability." SIGNOR-125869 FOXM1 protein Q08050 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 26912724 t miannu "Nuclear FoxM1 then directly interacted with nuclear β‐catenin, which released β‐catenin from ICAT and enhanced recruitment of β‐catenin to the promoter of Wnt target gene, hence increasing the expression of Wnt target gene." SIGNOR-277211 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000567 BTO:0000887;BTO:0001103 8454633 t gcesareni "Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190." SIGNOR-39151 LPAR1 protein Q92633 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256696 GALR3 protein O60755 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257114 ALK protein Q9UM73 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates phosphorylation 9606 BTO:0000785 12185581 t gcesareni "Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc." SIGNOR-91537 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Asp62 VETVFSVdEFSASVL -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263593 MAPK1 protein P28482 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Thr614 AFRLEPLtPRGVLTV 9606 17311928 t llicata "Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1" SIGNOR-153383 ABL1 protein P00519 UNIPROT PAX7 protein P23759 UNIPROT "up-regulates activity" phosphorylation 9606 33777928 t miannuccelli "Furthermore, we show that c-Abl interacts with and phosphorylates Pax7 protein.|Indeed, reporter gene assays indicate that c-Abl inhibition decreases Pax7 dependent activation of the 6xPRS9-luc reporter." SIGNOR-279773 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Thr276 GFRKRWFtMDDRRLM -1 12893243 t lperfetto "The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time." SIGNOR-249226 CSNK2A2 protein P19784 UNIPROT SUZ12 protein Q15022 UNIPROT "up-regulates activity" phosphorylation Ser583 PQEMEVDsEDEKDPE 9606 BTO:0002181 36351927 t miannu "CK2 is the kinase for the phosphorylation of S583 of SUZ12." SIGNOR-277811 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 19135894 t gcesareni "Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4." SIGNOR-183285 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser2996 QECKRNLsDIDQSFN 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." SIGNOR-170473 TWIST2 protein Q8WVJ9 UNIPROT ERBB3 protein P21860 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255501 IL12A protein P29459 UNIPROT IL12B protein P29460 UNIPROT up-regulates binding 9606 7527811 t fspada "However, a proper conformation required for high affinity binding is achieved only when p40 is associated with a p35 subunit or another p40 subunit. When p40 is associated with a p35 subunit, the heterodimer acts as an agonist mediating biologic activity. However, when p40 associates with another p40, the homodimer behaves as an antagonist in vitro" SIGNOR-27619 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR MDM2 protein Q00987 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000356 31138683 t lperfetto "SCFFBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis|we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCFFBXO22) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation." SIGNOR-273441 panobinostat chemical CHEBI:85990 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257751 DOK1 protein Q99704 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257670 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275753 MAOA protein P21397 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI "down-regulates quantity" "chemical modification" 9606 31024440 t brain lperfetto "Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA)." SIGNOR-264014 L-thyroxine(1-) chemical CHEBI:60302 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258051 CSNK2A1 protein P68400 UNIPROT IP6K2 protein Q9UHH9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser356 AEDLEDLsEESADES 9606 BTO:0000007 21262846 t miannu "CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation." SIGNOR-273625 PDRG1 protein Q9NUG6 UNIPROT "URI1 prefoldin co-chaperone" complex SIGNOR-C514 SIGNOR "form complex" binding 9606 30484151 t miannu "In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR92" SIGNOR-270915 HIPK2 protein Q9H2X6 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser422 AHPPHAPsPGQTVKP 9606 BTO:0002552 15708980 t lperfetto "Homeodomain-interacting protein kinase-2 mediates ctbp phosphorylation and degradation in uv-triggered apoptosishipk2 phosphorylates ctbp at ser-422" SIGNOR-134040 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "AD/b2 integrin" complex SIGNOR-C172 SIGNOR "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259028 "(4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester" chemical CHEBI:103931 ChEBI ADRA1B protein P35368 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258465 MGLL protein Q99685 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 26997225 f irozzo "Overexpression of MGLL inhibits proliferation and delays cell cycle progression in QGY-7703 cells. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression [.]" SIGNOR-259139 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates phosphorylation Tyr970 GEGYKKKyQQVDEEF 9606 BTO:0000150;BTO:0000527 19275932 t gcesareni "These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis." SIGNOR-184556 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000586 16293724 f lperfetto "We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt" SIGNOR-252711 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109613 PPP1CA protein P62136 UNIPROT SP1 protein P08047 UNIPROT "down-regulates activity" dephosphorylation 9606 12684058 t miannu "Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression." SIGNOR-251952 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC9 protein Q93079 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271991 RCOR1 protein Q9UKL0 UNIPROT REST protein Q13127 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10449787 t miannu "We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity." SIGNOR-220618 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 t "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-248496 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CC2D1A protein Q6P1N0 UNIPROT "up-regulates activity" phosphorylation Ser208 PASTPTYsPAPTQPA 20171170 t nucleus lperfetto "We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation." SIGNOR-268296 GRM5 protein P41594 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 20055706 t miannu "MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits." SIGNOR-264078 PRKCA protein P17252 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 16963226 t gcesareni "Pkcalfa, but not pkcbeta, is the predominant cpkc isoenzyme required for cpla2 protein phosphorylation and maximal induction of cpla2 enzymatic activity." SIGNOR-149406 SRC protein P12931 UNIPROT NDUFV2 protein P19404 UNIPROT "up-regulates activity" phosphorylation Tyr193 VQINDNYyEDLTAKD 9606 BTO:0001583 22823520 t miannu "Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants. " SIGNOR-276419 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser342 LAHDRAPsRKDSLES 9606 21317289 t gcesareni "We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation." SIGNOR-171999 CACNA1C protein Q13936 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 30849329 t miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795])." SIGNOR-264325 CASP3 protein P42574 UNIPROT GAS2 protein O43903 UNIPROT up-regulates cleavage Asp278 MLQISRVdGKTSPIQ 9606 10564664 t gcesareni "We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279." SIGNOR-72347 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257977 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser274 TSPSPISsPTFSPIE 9606 23442801 t lperfetto "It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation" SIGNOR-201515 CDK2 protein P24941 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 SIGNOR-C16 18332217 t llicata "We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2." SIGNOR-177972 PKLR protein P30613 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "chemical modification" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266537 KDM6A protein O15550 UNIPROT HOXC11 protein O43248 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260026 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser74 VEIRSRHsSYPAGTE 9606 22096607 t lperfetto "Bad is a pro-apoptotic member of the bcl-2 family of proteins, which can be phosphorylated on numerous sites to modulate binding to bcl-2 and 14-3-3 proteins and inhibit its pro-apoptotic activities. Together, these findings demonstrate that pak1 phosphorylates bad directly at s111, but phosphorylated s112 through raf-1. These two sites of bad serve as redundant regulatory sites for bcl-2 binding" SIGNOR-177271 NR3C1 protein P04150 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR "form complex" binding 9606 8878484 t fspada "We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter." SIGNOR-44373 KMT2E protein Q8IZD2 UNIPROT RARA protein P10276 UNIPROT "up-regulates activity" binding 9606 21205756 t miannu "MLL5 binds to retinoic acid receptor α (RARα) and induces transcriptional activation of RARα target genes by methylation of lysine residues of histone H3." SIGNOR-260041 FBXL5 protein Q9UKA1 UNIPROT DCTN1 protein Q14203 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 17532294 t miannu "FBXL5 binds to p150(Glued)in vitro and in vivo. FBXL5 and p150(Glued) co-localize primarily in the cytoplasm with peri-nuclear enrichment in HeLa cells. Overexpression of FBXL5 promotes poly-ubiquitination of p150(Glued) and protein turnover of p150(Glued). Our findings provide a potential mechanism by which p150(Glued) protein function is regulated by SCFs." SIGNOR-271652 GDNF protein P39905 UNIPROT RET protein P07949 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni "A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling" SIGNOR-49094 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89252 "orotidine 5'-phosphate(3-)" smallmolecule CHEBI:57538 ChEBI UMP smallmolecule CHEBI:16695 ChEBI "up-regulates quantity" "precursor of" 9606 2912371 t miannu "Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase)." SIGNOR-267439 ACLY protein P53396 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI "up-regulates quantity" "chemical modification" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-268080 RUNX3 protein Q13761 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255098 "Fanconi anemia ID complex" complex SIGNOR-C302 SIGNOR BRCA2 protein P51587 UNIPROT up-regulates 18985065 f lperfetto "Once monoubiquitinated, the ID complex becomes associated with chromatin and is redistributed to DNA-damage sites, forming foci that are visible by immunofluorescence and colocalizing with other DNA-repair molecules, notably BRCA1, BRCA2 and γH2AX." SIGNOR-263270 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 9271428 t gcesareni "Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation." SIGNOR-50594 SMARCC1 protein Q92922 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t miannu "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-132933 CDK9 protein P50750 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Thr217 PSEYQNMtVDILCND 9606 23603988 t lperfetto "We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr." SIGNOR-201927 "sedoheptulose 7-phosphate" smallmolecule CHEBI:15721 ChEBI "D-erythrose 4-phosphate(2-)" smallmolecule CHEBI:16897 ChEBI "up-regulates quantity" "precursor of" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-268135 MYLK3 protein Q32MK0 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" phosphorylation Thr80 NEPHESRtNSDIVET 9606 BTO:0000007 21556048 t lperfetto "Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis.|Here, we show that skMLCK directly phosphorylates MEF2C, leading to p300/PCAF recruitment, increased acetylation of skeletal muscle-specific genes, and enhanced skeletal myogenesis" SIGNOR-264565 PTPN11 protein Q06124 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 18482983 t "we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin" SIGNOR-248670 ATXN1 protein P54253 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21315774 t Luana "Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner " SIGNOR-261577 CSNK2B protein P67870 UNIPROT CACNA1S protein Q13698 UNIPROT "up-regulates activity" phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 t miannu "To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2." SIGNOR-263115 SLBP protein Q14493 UNIPROT H2BC15 protein Q99877 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265392 TOP2B protein Q02880 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24463367 f lperfetto "While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development" SIGNOR-242210 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 16140393 t lperfetto "Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate." SIGNOR-209735 MOS protein P00540 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 10090 7731726 t Manara "Our data indicate that Mos activated MEK1 in vitro as well as in vivo by phosphorylating Ser 222." SIGNOR-260920 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7535768 t "We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively" SIGNOR-248464 TAF8 protein Q7Z7C8 UNIPROT "SAGA complex" complex SIGNOR-C465 SIGNOR "form complex" binding 9606 34811519 t lperfetto "Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module" SIGNOR-269573 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates activity" phosphorylation Ser289 PPPLAPQsPQGGVMG 9606 24101154 t miannu "Specifically, we found that YAP is phosphorylated in vitro and in vivo by the cell cycle kinase CDK1 at T119, S289, and S367 during G2/M phase of the cell cycle." SIGNOR-279362 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one chemical CHEBI:91348 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258294 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Ser368 NTSPRAIsRVDRERK 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250808 CSNK1A1 protein P48729 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser82 GSSESTDsGFCLDSP 9606 20348946 t lperfetto "Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a" SIGNOR-164738 PLK1 protein P53350 UNIPROT TOPORS protein Q9NS56 UNIPROT "up-regulates activity" phosphorylation Ser718 KDRDGYEsSYRRRTL 9606 19473992 t lperfetto "Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation." SIGNOR-185838 ATM protein Q13315 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser498 QIVMAPSsQSQPSGS 9606 15916964 t lperfetto "Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif)" SIGNOR-137623 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Thr160 NKLRRYTtFSKRKTG 10753652 t llicata "Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors." SIGNOR-250639 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDCA5 protein Q96FF9 UNIPROT "up-regulates activity" phosphorylation Ser79 AVQSPRRsPRISFFL 9606 BTO:0000567 20551060 t miannu "Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy." SIGNOR-262969 IL20RA protein Q9UHF4 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 t gcesareni "Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain." SIGNOR-124486 PRKCA protein P17252 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 10816576 t lperfetto "Biochemical and morphological analyses indicate that threonine-phosphorylated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surfaceThe inhibitory effects of pkc are mediated by a single threonine residue (threonine 654) of egfr" SIGNOR-77421 GRIN1 protein Q05586 UNIPROT "NMDA receptor_2B" complex SIGNOR-C348 SIGNOR "form complex" binding 9606 BTO:0000938 12871085 t miannu "The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits" SIGNOR-264122 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120020 MAPKAP1 protein Q9BPZ7 UNIPROT PRKCE protein Q02156 UNIPROT "up-regulates activity" binding 9606 21806543 t miannu "In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC. " SIGNOR-276348 CDC25B protein P30305 UNIPROT CDK2 protein P24941 UNIPROT "up-regulates activity" dephosphorylation 9606 26474275 t miannu "CDC25B is also able to dephosphorylate and activate CDK2-Cyclin A and CDK2-Cyclin E complexes [ xref \u2013 xref ]." SIGNOR-277140 GSK3A protein P49840 UNIPROT STAT2 protein P52630 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser381 RKFNILTsNQKTLTP 9606 BTO:0002181 31843895 t miannu "GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation." SIGNOR-276760 CDK5 protein Q00535 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown phosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t lperfetto "In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation." SIGNOR-249194 ZDHHC9 protein Q9Y397 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" palmitoylation 9606 BTO:0000007 16000296 t miannu "Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein." SIGNOR-261352 PHC2 protein Q8IXK0 UNIPROT "Polycomb repressive complex 1" complex SIGNOR-C408 SIGNOR "form complex" binding 9606 31608994 t miannu "PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b" SIGNOR-266810 APLNR protein P35414 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256960 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251460 WNT5B protein Q9H1J7 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131885 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR TDG protein Q13569 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 24962565 t miannu "TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner" SIGNOR-272849 ACLY protein P53396 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI "down-regulates quantity by destabilization" "chemical modification" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-267101 2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol chemical CHEBI:93235 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258729 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr228 YPGGSDNyGSLSRVT -1 11382764 t lperfetto "Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302" SIGNOR-246484 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Ser577 RKPGLRRsPIKKVRK 9606 SIGNOR-C83 9840932 t lperfetto "The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5" SIGNOR-62353 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "down-regulates activity" phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t miannu "In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus." SIGNOR-256187 palbociclib chemical CHEBI:85993 ChEBI CDK6 protein Q00534 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205707 MC4R protein P32245 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256797 NEDD4L protein Q96PU5 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253463 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 18794113 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-180906 MAPKAPK2 protein P49137 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2" SIGNOR-166643 GDNF protein P39905 UNIPROT NRN1 protein Q9NPD7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252183 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "precursor of" -1 8994190 t Luana "Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues. " SIGNOR-269759 MYLIP protein Q8WY64 UNIPROT LDLR protein P01130 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 30896554 t miannu "The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells. " SIGNOR-271485 RARA protein P10276 UNIPROT CCNA1 protein P78396 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002136 11090075 t miannu "RARα is involved in the regulation of cyclin A1. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is negatively regulated by activated RARα." SIGNOR-249636 PRKN protein O60260 UNIPROT SNCA protein P37840 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000938 12666095 t lperfetto "Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R)." SIGNOR-249705 naltrexone chemical CHEBI:7465 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258767 CHMP3 protein Q9Y3E7 UNIPROT Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates -1 30989108 f miannu "ESCRT-III has been proposed to assemble inside the membrane neck formed at a late stage of a budding vesicle or an enveloped virus. The membrane neck needs to be constricted to proceed to membrane fission, thereby splitting the vesicle or virus from the cellular membrane. CHMP2A and CHMP3 are engaged late in ESCRT-III assembly, recruit VPS4 (31, 42), and block Snf7 (CHMP4) polymerization" SIGNOR-260845 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser978 SPLKRSHsLAKLGSL 9606 BTO:0000150 19567672 t llicata "Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions" SIGNOR-186471 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 t llicata "Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR" SIGNOR-252902 GNAQ protein P50148 UNIPROT TRIOBP protein Q9H2D6 UNIPROT "up-regulates activity" binding -1 17606614 t "We show that the C-terminal Rho-specific DH-PH cassette of Trio is similarly activated by Galpha(q)" SIGNOR-256494 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Thr64 ENLRRATtDLGRSLG -1 10467162 t lperfetto "Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect." SIGNOR-249019 Liprin-alpha proteinfamily SIGNOR-PF82 SIGNOR KIF1A protein Q12756 UNIPROT "up-regulates activity" binding 10116 BTO:0003102 30021165 t miannu "Kinesin-3 Family Member KIF1A Interacts with Liprin-α and TANC2. TANC2 and Liprin-α Recruit KIF1A-Driven DCVs in Dendritic Spines. Upon Ca2+/CaM binding, KIF1A is activated, allowing for DCV loading and motility. KIF1A-driven DCVs are recruited in dendritic spines by liprin-α and TANC2, which ensure a precise mechanism of synaptic tagging for the vesicles." SIGNOR-266892 ETV4 protein P43268 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24983502 f miannu "Transcriptional activation of oct4 by the ets transcription factor pea3 in nccit human embryonic carcinoma cells" SIGNOR-205173 MAD2L1BP protein Q15013 UNIPROT MCC complex SIGNOR-C382 SIGNOR "down-regulates quantity by destabilization" binding 9606 BTO:0000567 25092294 t miannu "We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4)." SIGNOR-265979 (8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol chemical CHEBI:92234 ChEBI DRD3 protein P35462 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258731 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser40 RQPSPSPsPTERAPA 9606 BTO:0001271 15093545 t llicata "We report here that as(2)o(3) treatment induces phosphorylation of the pml protein through a mitogen-activated protein (map) kinase pathway. Increased pml phosphorylation is associated with increased sumoylation of pml and increased pml-mediated apoptosis." SIGNOR-124248 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser381 RKFNILTsNQKTLTP 9606 BTO:0002181 31843895 t miannu "GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation." SIGNOR-276763 940929-33-9 chemical CID:49867937 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206724 2',2'-difluoro-2'-deoxyuridine chemical CHEBI:83486 ChEBI TYMS protein P04818 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0003207 25562513 t miannu "2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000. The specific TS inhibitor Raltitrexed (RTX) was included as a positive control. Using the in situ TS activity assay measuring the intracellular conversion of [5-(3)H]-2'-deoxyuridine or [5-(3)H]-2'-deoxycytidine to dTMP and tritiated water, it was observed that dFdC and dFdU inhibited TS." SIGNOR-259351 BCL10 protein O95999 UNIPROT CBM complex SIGNOR-C555 SIGNOR "form complex" binding 9606 15122200 t miannu "CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways." SIGNOR-276294 Stress_granules phenotype SIGNOR-PH124 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27920254 f miannu "Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis." SIGNOR-260867 ABL1 protein P00519 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Tyr15 EKIGEGTyGTVFKAK 9534 BTO:0000298 10896159 t gcesareni "Phosphorylation of Cdk5 by c-Abl occurs on tyrosine 15 (Y15), which is stimulatory for p35/Cdk5 kinase activity." SIGNOR-245288 MASTL protein Q96GX5 UNIPROT MASTL protein Q96GX5 UNIPROT "up-regulates activity" phosphorylation Ser875 TAQHLTVsGFSL 8355 phosphorylation:Thr194;Thr207 NMMDILTtPSMAKPR;PRQDYSRtPGQVLSL 22354989 t gcesareni "After this priming step, Gwl can intramolecularly phosphorylate its C-terminal tail at pS883; this site probably plays a role similar to that of the tail/Z motif of other AGC kinases." SIGNOR-243409 SRD5A1 protein P18405 UNIPROT 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI "up-regulates quantity" "chemical modification" 9606 15861399 t miannu "Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5Œ±-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions." SIGNOR-251534 PRDM1 protein O75626 UNIPROT CCL2 protein P13500 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 19915049 t lperfetto "Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression." SIGNOR-271679 CSF1 protein P09603 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 t gcesareni "Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta)." SIGNOR-72455 AURKB protein Q96GD4 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 19276349 t llicata "Here, we show that aurora a and b associate with and phosphorylate rassf1a on serine 203 aurora a regulates prometaphase progression by inhibiting the ability of rassf1a to suppress apc-cdc20 activity." SIGNOR-184561 CHEK1 protein O14757 UNIPROT TLK2 protein Q86UE8 UNIPROT "down-regulates activity" phosphorylation Ser750 PHIRKSVsTSSPAGA -1 12955071 t miannu "Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b)." SIGNOR-262740 Ub:E2 complex SIGNOR-C497 SIGNOR RNF169 protein Q8NCN4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271202 CDK1 protein P06493 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Ser382 DFIDAFAsPVEAEGT 9606 15125835 t lperfetto "Here we show that, at the onset of mitosis, cdk1 phosphorylates the peripheral golgi protein nir2 at multiple sites;of these, s382 is the most prominent. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis." SIGNOR-124638 SLC12A4 protein Q9UP95 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "down-regulates quantity" relocalization 21613606 t lperfetto "Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). " SIGNOR-264636 PRKAG2 protein Q9UGJ0 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "form complex" binding 9606 16054041 t gcesareni "Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits." SIGNOR-139176 AKT proteinfamily SIGNOR-PF24 SIGNOR CCDC88A protein Q3V6T2 UNIPROT unknown phosphorylation Ser1417 INRERQKsLTLTPTR 9606 16139227 t llicata "Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells." SIGNOR-140216 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16446360 t gcesareni "In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells." SIGNOR-143996 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 10090 21145499 t milica "Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component." SIGNOR-170364 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 14560030 t "Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling," SIGNOR-248666 SRC protein P12931 UNIPROT DLG4 protein P78352 UNIPROT up-regulates phosphorylation Tyr523 REDSVLSyETVTQME 9606 24981431 t llicata "These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission." SIGNOR-205120 FAM83G protein A6ND36 UNIPROT CSNK1A1L protein Q8N752 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273753 MEPCE protein Q7L2J0 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "down-regulates activity" binding 10090 BTO:0002572 32048991 t miannu "JMJD6 cleaves MePCE. we propose that JMJD6 is the cognate protease of MePCE and cleaves at the R171 site within MePCE. Experiments using purified JMJD6 showed that it could make a cut in an enzyme called MePCE, which belongs to the group of proteins that hold P-TEFb in its inactive form. The levels of activated Pol II were lower in cells without JMJD6 and higher in those without MePCE. Together, the results suggest that JMJD6 cuts MePCE to release P-TEFb, which then activates Pol II." SIGNOR-261038 PRKACA protein P17612 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation Ser21 LTEERDGsLNQSSGY 9606 20658524 t lperfetto "The serine 21 (s21) residue of fyn is a protein kinase a (pka) recognition site within an rxxs motif of the amino terminal sh4 domain of fyn. In addition, s21 is critical for fyn kinase-linked cellular signaling. Mutation of s21a blocks pka phosphorylation of fyn and alters its tyrosine kinase activity." SIGNOR-167147 S protein P59594 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 16310778 f Luana "We demonstrated that the adenovirus-mediated over-expression of SARS-CoV spike (S) protein and its C-terminal domain (S2) induce apoptosis in Vero E6 cells in a time- and dosage-dependent manner" SIGNOR-260219 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 15294014 f Luana "In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors." SIGNOR-260204 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 17453707 f Luana "SARS-CoV Nucleocapsid Protein Induced Apoptosis of COS-1 Mediated by the Mitochondrial Pathway" SIGNOR-260205 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 f Luana "Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells." SIGNOR-260199 M protein P59596 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 f Luana "Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells." SIGNOR-260198 3a protein P59632 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR "up-regulates activity" 9534 15958670 f Luana "These results indicated that the 3a protein induced apoptosis in Vero E6 cells." SIGNOR-260195 3b protein P59633 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR "up-regulates activity" 9534 16965829 f Luana "Over-expression of severe acute respiratory syndrome coronavirus 3b protein induces both apoptosis and necrosis in Vero E6 cells" SIGNOR-260194 6 protein P59634 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 18708124 f Luana "A SARS-CoV protein, ORF-6, induces caspase-3 mediated, ER stress and JNK-dependent apoptosis" SIGNOR-260203 7a protein P59635 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000018 15564512 f Luana "7a induces apoptosis via a caspase-dependent pathway and in cell lines derived from different organs, including lung, kidney, and liver. | The overexpression of HA-tagged 7a (7a-HA) induces apoptosis in 293T (human kidney epithelial) cells, as evidenced by an increase in caspase-3 protease activity, a hallmark of apoptosis, which is comparable to that caused by the overexpression of BAX, a proapoptotic member of the Bcl-2 family" SIGNOR-260197 7a protein P59635 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana "Cells expressing the ORF7a or ORF7b protein undergo apoptosis." SIGNOR-260209 GP5 protein P40197 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "form complex" binding 9606 BTO:0000132 16293600 t lperfetto "The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1." SIGNOR-261849 7b protein Q7TFA1 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana "Cells expressing the ORF7a or ORF7b protein undergo apoptosis." SIGNOR-260210 PARP1 protein P09874 UNIPROT MRE11 protein P49959 UNIPROT "up-regulates activity" relocalization 9606 19629035 t "PARP1 collaborates with Mre11 to promote replication fork restart after release from replication blocks, most likely by recruiting Mre11 to the replication fork to promote resection of DNA." SIGNOR-272478 CARM1 protein Q86X55 UNIPROT MDH1 protein P40925 UNIPROT "down-regulates activity" acetylation Arg230 FVTTVQQrGAAVIKA 9606 27840030 t lperfetto "Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization" SIGNOR-267639 MAPK10 protein P53779 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 t "Translocation from Nucleus to Cytoplasm" esanto "We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats." SIGNOR-74556 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 t lperfetto "Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively" SIGNOR-180763 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248367 CASP1 protein P29466 UNIPROT "NLRP1 inflammasome" complex SIGNOR-C224 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256406 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Tyr52 VQKKPTMyPEWKSTF -1 9692543 t "Lyn was found to phosphorylate Lyn-associated and recombinant PKC-delta in vitro and the tyrosine 52 phosphorylated PKC-delta was recruited to associate with the Lyn SH2 domain." SIGNOR-251408 FZD7 protein O75084 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 23290138 f "Simone Vumbaca" "We observed that overexpression of Fzd7 or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts" SIGNOR-255647 CRX protein O43186 UNIPROT RBP3 protein P10745 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 15277472 f miannu "KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl." SIGNOR-253821 APH1A protein Q96BI3 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR "form complex" binding 9606 25610395 t lperfetto "-Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)" SIGNOR-209714 arginine smallmolecule CHEBI:29016 ChEBI Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270370 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248297 MAP3K13 protein O43283 UNIPROT TRIM25 protein Q14258 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser12 CPLAEELsCSICLEP 9606 BTO:0002181 31186535 t miannu "Mechanistically, MAP3K13 phosphorylates the E3 ubiquitin ligase TRIM25 at Ser12 to decrease its polyubiquitination and proteasomal degradation." SIGNOR-277456 E4F1 protein Q66K89 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" ubiquitination Lys319 TSSSPQPkKKPLDGE 9606 BTO:0001938 17110336 t miannu "E4F1 Has an Intrinsic Ubiquitin E3 Ligase Activity that Drives K48-type Ubiquitylation of p53. These data demonstrate that E4F1 stimulates the ubiquitylation of p53 on the lysine cluster K319–K321, i.e., at sites distinct from those targeted by Hdm2. p53 forms Ubiquitylated by E4F1 Are Localized on Chromatin. In striking contrast with Ub-p53 forms stimulated by Hdm2, which are mainly cytosoluble and targeted to the proteasome, we found that E4F1-stimulated Ub-p53 forms are tightly associated with chromatin, suggesting that they could be involved in transcription." SIGNOR-271394 DUSP14 protein O95147 UNIPROT TAB1 protein Q15750 UNIPROT "down-regulates activity" dephosphorylation 9606 24403530 t miannu "DUSP14 directly interacted with TGF-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser (438), leading to TAB1 and TAK1 complex inactivation in T cells." SIGNOR-277147 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 21460634 t lperfetto "Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition." SIGNOR-216464 TJP1 protein Q07157 UNIPROT NHS protein Q6T4R5 UNIPROT "up-regulates activity" binding 10090 19447104 t miannu "NHS-A is a novel interactor of ZO-1 and is expected to have a role at tight junctions. Its recruitment to these junctions is dependent upon their assembly." SIGNOR-253567 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser24 APIRRRSsNYRAYAT 9606 15769444 t lperfetto "Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction." SIGNOR-134609 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT "down-regulates activity" cleavage Ser22 LLSYAVPsCGRSVEG -1 8753751 t lperfetto "Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments." SIGNOR-270547 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT "down-regulates activity" phosphorylation Thr119 HNLMRRStVSLLDTY 23871434 t "Phosphosite positions are derived from Figure S5" lperfetto "AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro" SIGNOR-275482 LIMK1 protein P53667 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser3 sGVAVSDG 9606 18079118 t gcesareni "Our results suggest that limk1-mediated cofilin phosphorylation is required for accurate spindle orientation by stabilizing cortical actin networks during mitosis" SIGNOR-159885 MC1R protein Q01726 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257085 GSK3B protein P49841 UNIPROT UNG protein P13051 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000812 27875297 t lperfetto "Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation" SIGNOR-264884 PKN2 protein Q16513 UNIPROT MEFV protein O15553 UNIPROT "down-regulates activity" phosphorylation Ser208 VRLRRNAsSAGRLQG 10090 BTO:0004732 27270401 t no miannu "PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome." SIGNOR-275464 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser463 PPISPASsDLSVAGS 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251246 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR EID1 protein Q9Y6B2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 26085330 t miannu "SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO)" SIGNOR-272431 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto "The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus" SIGNOR-252860 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser14 MGAELPSsPLAIEYV 9606 BTO:0000567 11416124 t miannu "In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro. " SIGNOR-275976 EPHA8 protein P29322 UNIPROT EPHA8 protein P29322 UNIPROT "up-regulates activity" phosphorylation Tyr616 FYAEPHTyEEPGRAG 9606 BTO:0000007 10498895 t "Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites." SIGNOR-251120 HSPB1 protein P04792 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 12855565 f gcesareni "These data demonstrate that hsp27 inhibits the release of smac" SIGNOR-103539 TLN1 protein Q9Y490 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257615 NR4A3 protein Q92570 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000815;BTO:0002552 30455429 f miannu "NR4A3 exhibits p53-independent anti-proliferative functions. Ectopic expression of NR4A3 inhibits the growth of MDA-MB-231 and H1299 cancer cell lines." SIGNOR-256201 CDK1 protein P06493 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Thr446 EGKISTItPQIQAFN 9606 14657031 t lperfetto "Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation" SIGNOR-119877 PRKCA protein P17252 UNIPROT CYTH2 protein Q99418 UNIPROT "down-regulates activity" phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 10531036 t lperfetto "ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'." SIGNOR-249023 SNW1 protein Q13573 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t gcesareni "We present evidence that skip interacts with the cbf1 corepressor complex and that skip has a role in orchestrating the conversion of cbf1 from an smrt-hdac-tethered transcriptional repressor to a notchic-tethered activation complex." SIGNOR-75785 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT "down-regulates activity" sumoylation Lys404 VSPTGIkNEKRGTS 9606 16442531 t "We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity." SIGNOR-256129 MAPK14 protein Q16539 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 19528229 t gcesareni "P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna." SIGNOR-186138 PAICS protein P22234 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "down-regulates quantity" "chemical modification" 9606 33179964 t miannu "The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS)." SIGNOR-267321 MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 t gcesareni "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." SIGNOR-161439 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20577053 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-166349 CTNNB1 protein P35222 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 10775268 t gcesareni "Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding" SIGNOR-76987 NPBWR1 protein P48145 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256818 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17442773 f miannu "Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The transcription factor CCAAT enhancer binding protein‐α (C/EBPα), a tumor suppressor gene and a crucial regulator of granulopoiesis through inhibition of c‐JUN, was downmodulated by NUP98‐HOXA9" SIGNOR-261501 "Immune complexes" stimulus SIGNOR-ST15 SIGNOR "Complement C1q" complex SIGNOR-C308 SIGNOR "up-regulates activity" binding -1 29449492 t lperfetto "We used IgG monoclonal antibodies (mAbs) oligomerized through antigen-binding on liposomes or preformed antibody complexes in solution and applied tomography and single-particle cryo–electron microscopy (cryo-EM) to resolve the mechanisms of C1 binding and activation.|Binding of C1 through its gC1q modules to mediators of inflammation, such as immunoglobulin G (IgG) or IgM antibodies (fig. S1, C and D), on cell surfaces activates the associated proteases and initiates the proteolytic cascade of complement" SIGNOR-263397 PYG proteinfamily SIGNOR-PF96 SIGNOR glycogen smallmolecule CHEBI:28087 ChEBI "down-regulates quantity" "chemical modification" 9606 3346228 t "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267953 "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR UHRF1 protein Q96T88 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000011 25533466 f miannu "We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis." SIGNOR-252250 DZIP3 protein Q86Y13 UNIPROT H2AZ2 protein Q71UI9 UNIPROT "up-regulates activity" monoubiquitination Lys121 IHKSLIGkKGQQKTA 9606 18206970 t miannu " 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation." SIGNOR-271756 GNAI1 protein P63096 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR "up-regulates activity" binding -1 10224115 t "G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics." SIGNOR-256538 GNAI1 protein P63096 UNIPROT ADCY6 protein O43306 UNIPROT "down-regulates activity" binding 7108 BTO:0001240 8119955 t "Marta Tosoni" "Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3" SIGNOR-278077 ABL1 protein P00519 UNIPROT ZNF746 protein Q6NUN9 UNIPROT "up-regulates activity" phosphorylation Tyr137 ETLVSLDyAISKPEV 9606 BTO:0000793 34581802 t miannu "C-Abl-mediated phosphorylation of PARIS at Y137 (within the Krüppel-associated box domain) drives its association with KAP1 and the repression of genes with diverse functions in pathways such as chromatin remodelling and p53-dependent cell death." SIGNOR-277626 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275754 Aldolase proteinfamily SIGNOR-PF75 SIGNOR "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "down-regulates quantity" "chemical modification" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266490 GEMIN2 protein O14893 UNIPROT "SMN complex" complex SIGNOR-C158 SIGNOR "form complex" binding 12065586 t lperfetto "SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry." SIGNOR-253116 ritonavir chemical CHEBI:45409 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258154 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR MYL4 protein P12829 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136697 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr700 LSSNPLMtPDILGSS 9606 BTO:0000567 9687510 t gcesareni "Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha" SIGNOR-59451 "Complement C1 complex" complex SIGNOR-C309 SIGNOR C2 protein P06681 UNIPROT "up-regulates activity" cleavage Ser20 LYPGLADsAPSCPQN 31331124 t lperfetto "C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex" SIGNOR-263421 RB1 protein P06400 UNIPROT E2F2 protein Q14209 UNIPROT down-regulates binding 9606 22569856 t gcesareni "Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins." SIGNOR-197328 COX5A protein P20674 UNIPROT "Cytochrome c oxidase-Mitochondrial respiratory chain complex IV" complex SIGNOR-C280 SIGNOR "form complex" binding 30030361 t lperfetto "Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits" SIGNOR-267751 PRKCA protein P17252 UNIPROT CDC42EP4 protein Q9H3Q1 UNIPROT "down-regulates activity" phosphorylation Ser80 SSKRSLLsRKFRGSK 9606 BTO:0001939 25086031 t miannu "Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes)." SIGNOR-263161 ESR2 protein Q92731 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253475 thalidomide chemical CHEBI:9513 ChEBI CRBN protein Q96SW2 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20223979 t miannu " Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. " SIGNOR-272207 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 11931757 t lperfetto "We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability." SIGNOR-217308 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2NL protein Q5JXB2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271336 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251617 LRP6 protein O75581 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 23209147 t Gianni "The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization." SIGNOR-262526 CARM1 protein Q86X55 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 24332853 f miannu "PRMT4 blocks myeloid differentiation of human hematopoietic stem/progenitor cells While PRMT4 promotes differentiation in several biological systems including T cell, adipocyte and muscle development, it blocks differentiation in the hematopoietic system, allowing HSPCs to maintain stemness. " SIGNOR-261968 APOA1 protein P02647 UNIPROT ABCA1 protein O95477 UNIPROT "up-regulates quantity by stabilization" binding 9606 12869555 t miannu "ApoA-I stabilization of ABCA1 is mediated by reduced PEST sequence phosphorylation, which in turn leads to decreased calpain proteolysis of ABCA1." SIGNOR-252101 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269385 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257056 LRRK2 protein Q5S007 UNIPROT RAB29 protein O14966 UNIPROT "up-regulates activity" phosphorylation Thr71 IAGQERFtSMTRLYY 9606 29212815 t miannu "In an attempt to mimic phosphorylation of Rab29 by LRRK2, we mutated the phosphorylation sites to Glu and observed that the Rab29[T71E,S72E] mutant failed to activate LRRK2 (Fig\u00a0 xref B).|To test whether phosphorylation of Rab29 at Thr71 and Ser72 by LRRK2 was required for activation of LRRK2, we mutated these sites both to Ala." SIGNOR-279475 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49C protein P0CI26 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271268 EIF3C protein Q99613 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266398 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 9606 BTO:0000574 10837024 t lperfetto "Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology" SIGNOR-77973 LTB4R protein Q15722 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256691 SIK2 protein Q9H0K1 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Ser91 ENLKKSLsCANLSTF 9606 24561619 t lperfetto "Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion" SIGNOR-204648 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI SH2B3 protein Q9UQQ2 UNIPROT "down-regulates activity" "chemical inhibition" -1 17620431 t miannu "Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. " SIGNOR-259169 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM33 protein Q9UPN9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271077 PKA proteinfamily SIGNOR-PF17 SIGNOR GAD1 protein Q99259 UNIPROT "down-regulates activity" phosphorylation Thr91 RDARFRRtETDFSNL 9606 BTO:0000142 15147202 t miannu "Here, we report the effect of phosphorylation on the two well-defined GAD isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 and GAD67. GAD65 was activated by phosphorylation, while GAD67 was inhibited by phosphorylation.We further demonstrate that protein kinase A (PKA) and protein kinase C isoform epsilon are the protein kinases responsible for phosphorylation and regulation of GAD67 and GAD65, respectively. We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF." SIGNOR-276009 CSNK2A2 protein P19784 UNIPROT HSPH1 protein Q92598 UNIPROT "down-regulates activity" phosphorylation Ser509 PTEENEMsSEADMEC -1 12558502 t llicata "Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro." SIGNOR-251008 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163752 Oxytocin protein P01178-PRO_0000020495 UNIPROT "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR up-regulates 9606 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268588 (S)-(-)-sulpiride chemical CHEBI:64119 ChEBI DRD3 protein P35462 UNIPROT "down-regulates activity" "chemical inhibition" 10029 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258733 MAPK1 protein P28482 UNIPROT MCRIP1 protein C9JLW8 UNIPROT "down-regulates activity" phosphorylation Thr30 PSSSEIFtPAHEENV 9606 25728771 t lperfetto "When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation" SIGNOR-264774 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT "down-regulates activity" phosphorylation Thr795 AAERPGGtPTPVIAY -1 19448668 t miannu "The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4." SIGNOR-262880 GSK3B protein P49841 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser140 EEEGERQsPPLEVSD 9606 BTO:0002181 33188146 t miannu "We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7." SIGNOR-277542 FOXC1 protein Q12948 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 21871448 t gcesareni "We demonstrate that physical interactions occur between wt1, foxc1/2 and rbpj, suggestive of the formation of multimeric transcriptional complexes." SIGNOR-176183 ASPG protein Q86U10 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "up-regulates quantity" "chemical modification" 9606 24657844 t miannu "Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia." SIGNOR-267538 MECP2 protein P51608 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 15870696 f miannu "Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters" SIGNOR-254571 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120044 GDF2 protein Q9UK05 UNIPROT ACVRL1 protein P37023 UNIPROT up-regulates binding 9606 17068149 t gcesareni "Finally, we demonstrate that bmp9 and bmp10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of alk1. Taken together, our results suggest that bmp9 and bmp10 are two specific alk1 ligands that may physiologically trigger the effects of alk1 on angiogenesis." SIGNOR-150260 FGF11 protein Q92914 UNIPROT SCN1A protein P35498 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253422 ECM stimulus SIGNOR-ST20 SIGNOR "A6/b4 integrin" complex SIGNOR-C174 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259034 PSMB8 protein P28062 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" 9606 BTO:0003445 19443843 t Gianni "Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment" SIGNOR-261974 FGF11 protein Q92914 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253414 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21761340 t lperfetto "The prostate-specific TMPRSS2 gene, while upregulated by AR activity in luminal cells, is also transcribed in basal populations, confirming that AR acts as an expression modulator." SIGNOR-253687 TOMM20 protein Q15388 UNIPROT "TOM40 complex" complex SIGNOR-C421 SIGNOR "form complex" binding 9606 BTO:0000567 18331822 t lperfetto "The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex." SIGNOR-267678 PRKACA protein P17612 UNIPROT TENT2 protein Q6PIY7 UNIPROT "down-regulates activity" phosphorylation Ser116 LSGERRYsMPPLFHT 9606 31057087 t miannu "We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition." SIGNOR-259402 (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin chemical CHEBI:272 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258783 MAPK14 protein Q16539 UNIPROT ELK3 protein P41970 UNIPROT up-regulates phosphorylation Ser357 IHFWSSLsPVAPLSP 9606 9130707 t gcesareni "Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase." SIGNOR-47681 baicalein chemical CHEBI:2979 ChEBI CYP2C9 protein P11712 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190236 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser25 PCLIIEDsQPESQVL 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" SIGNOR-100641 PRKN protein O60260 UNIPROT RHOT1 protein Q8IXI2 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 24647965 t miannu "We observe that Parkin efficiently ubiquitylates Miro1 at highly conserved lysine residues, 153, 230, 235, 330 and 572, upon phosphorylation by PINK1." SIGNOR-278561 PDPK1 protein O15530 UNIPROT PRKCG protein P05129 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-126072 BMP2 protein P12643 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 7791754 t lperfetto "Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor." SIGNOR-217532 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT "up-regulates activity" binding 9606 19880493 t lperfetto "IL-4 and IL-13 have overlapping but distinct effects on MFs, dependent on a common IL-4R, with profound changes in the expression of a range of cellular proteins and functions broadly implicated in the regulation of inflammation and repair." SIGNOR-249528 dactolisib chemical CHEBI:71952 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21803746 t "ATP-competitive inhibitor of PI3K and mTOR" gcesareni "The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific" SIGNOR-175706 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" phosphorylation Ser329 LGGLCDLsSRY 9606 12639913 t miannu "Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA" SIGNOR-250016 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159442 AKT proteinfamily SIGNOR-PF24 SIGNOR NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Ser600 PARQRIRsCVSAENF 9606 12409306 t esanto "Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity." SIGNOR-95247 PDX1 protein P52945 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000627 8866550 f "inferred from family member" miannu "The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription." SIGNOR-270264 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT "up-regulates activity" phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000567 18079698 t miannu "We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14." SIGNOR-276094 RPS6KB1 protein P23443 UNIPROT CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 t llicata "Mass spectrometry and mutagenesis analysis revealed that rsk and s6k1 phosphorylate cct_ ser-260 in vitro and in intact cells" SIGNOR-184926 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000142 8668348 t gcesareni "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." SIGNOR-42664 EPHB2 protein P29323 UNIPROT RRAS protein P10301 UNIPROT "down-regulates activity" phosphorylation Tyr66 DPTIEDSyTKICSVD 9606 10570155 t "Tyrosine 66 of R-Ras is phosphorylated by EphB2|. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. |Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated." SIGNOR-251125 MAPK14 protein Q16539 UNIPROT EEA1 protein Q15075 UNIPROT "up-regulates activity" phosphorylation Thr1392 CSAKNALtPSSKKPV 10090 BTO:0002572 16138080 t lperfetto "We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes" SIGNOR-140082 SPART protein Q8N0X7 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" binding 9606 19580544 t miannu "Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins." SIGNOR-261306 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser257 DSFESIEsYDSCDRL 9606 BTO:0000782 12475968 t lperfetto "Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition" SIGNOR-96334 "Complement C1 complex" complex SIGNOR-C309 SIGNOR C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263433 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNJ4 protein P48050 UNIPROT "up-regulates activity" phosphorylation Ser443 NISYRREsAI 9606 BTO:0000007 19635485 t miannu "Kir2.3 can be phosphorylated by PKAin vitro. We further show that the phosphorylation/dephosphorylation of Ser443 within the C-terminal Kir2.3 PDZ-binding motif RRESAI dynamically regulates the Kir2.3/TIP-1 association in heterologous HEK293T cells. These data suggest that TIP-1 may act as an important regulator for the endocytic pathway of Kir2.3." SIGNOR-263153 AKT2 protein P31751 UNIPROT XIAP protein P98170 UNIPROT up-regulates phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 14645242 t llicata "Here, we demonstrate that akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of xiap is also inhibited by akt." SIGNOR-119492 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr446 GTEPEPVySMEAADY 9606 12601080 t lperfetto "Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity" SIGNOR-98712 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 t gcesareni "We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism." SIGNOR-153622 GRPR protein P30550 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257421 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273058 KDM3B protein Q7LBC6 UNIPROT UCP1 protein P25874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0005964 19194461 t miannu "We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression." SIGNOR-266638 EDNRB protein P24530 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257254 CDK1 protein P06493 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr620 RAARFVStPFHEIMS 9606 17785528 t lperfetto "Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions" SIGNOR-157642 NDUFAB1 protein O14561 UNIPROT "NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1" SIGNOR-262161 RORA protein P35398 UNIPROT PCP2 protein Q8IVA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001011 19381306 t miannu "RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice." SIGNOR-266849 TRIM21 protein P19474 UNIPROT SQSTM1 protein Q13501 UNIPROT "down-regulates activity" ubiquitination Lys7 kAYLLGKE 9606 26942676 t miannu "TRIM21 directly ubiquitylates p62 at residue K7 to inhibit its oligomerization and sequestration function.|TRIM21 negatively regulates p62 mediated sequestration of Keap1 and antioxidant response." SIGNOR-278602 CHMP1A protein Q9HD42 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR "form complex" binding -1 26775243 t miannu "The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission." SIGNOR-265531 ING1 protein Q9UK53 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 14522900 f miannu " In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity." SIGNOR-254480 SRC protein P12931 UNIPROT VAMP7 protein P51809 UNIPROT "up-regulates activity" phosphorylation Tyr45 SENNKLTySHGNYLF 9534 BTO:0000298 23471971 t done miannu "We found that TI-VAMP is phosphorylated in vitro by c-Src kinase on tyrosine 45 of the Longin domain.Mimicking tyrosine 45 phosphorylation activates both t-SNARE binding and exocytosis of TI-VAMP." SIGNOR-273819 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 6772446 t "Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-." SIGNOR-253007 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr306 PSNHHAVyDVPPSVS 9606 12601080 t lperfetto "Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas." SIGNOR-98496 WWP1 protein Q9H0M0 UNIPROT KLF5 protein Q13887 UNIPROT "up-regulates activity" ubiquitination 9606 34035464 t miannu "WWP1 and Smurf2 were adopted to induce ubiquitination of endogenous KLF5 protein in cells.|WWP1 or Smurf2 degrades KLF5 by ubiquitination to repress fracture healing." SIGNOR-278683 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" binding -1 18025157 t "We show that PML-RARα physically interacts with Sp1 in the absence of DNA. In this report, we show that PML-RARα interacts with Sp1 and may interfere with the expression of genes that are not normally regulated by retinoic acid receptors." SIGNOR-255729 ALG11 protein Q2TAA5 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI "up-regulates quantity" "chemical modification" 9606 28575298 t lperfetto "The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum." SIGNOR-260417 DHX9 protein Q08211 UNIPROT mRNA_nuclear_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 f miannu "These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA." SIGNOR-260948 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 27383048 t miannu "Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP." SIGNOR-42980 V-ATPase complex SIGNOR-C560 SIGNOR cholesterol smallmolecule CHEBI:16113 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000584 31827278 t miannu "Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. In line with these observations, immunohistochemical staining of V-ATPase in human pancreatic ductal adenocarcinoma (PDAC) specimens revealed prominent staining at the cell periphery in neoplastic lesions, in con- trast to the predominantly cytoplasmic staining observed in adjacent normal tissues (Fig. 2e). Thus, mutant RAS-dependent plasma mem- brane V-ATPase displayed preferential accumulation in membrane ruffles, consistent with patterns observed in invasive breast, melanoma and pancreatic cancer cells" SIGNOR-277760 GATA1 protein P15976 UNIPROT RUNX1T1 protein Q06455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002731 20487545 f Regulation miannu "GATA-1 transcription factor binds and transactivates the ETO proximal promoter in an erythroid/megakaryocytic-specific manner. Thus, trans-acting factors that are essential in erythroid/megakaryocytic differentiation govern ETO expression." SIGNOR-251929 RB1 protein P06400 UNIPROT ANP32A protein P39687 UNIPROT "down-regulates activity" binding 9606 phosphorylation:Thr826 LPTPTKMtPRSRILV 15716273 t "We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation." SIGNOR-259083 GRK5 protein P34947 UNIPROT SNCB protein Q16143 UNIPROT "down-regulates activity" phosphorylation Ser118 LMEPEGEsYEDPPQE -1 10852916 t "GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes Œ≤-synuclein phosphorylation by both GRK2 and GRK5" SIGNOR-251203 LCK protein P06239 UNIPROT ACP1 protein P24666 UNIPROT "up-regulates activity" phosphorylation Tyr133 LIIEDPYyGNDSDFE 9534 9038134 t "In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation." SIGNOR-251367 D-ribofuranose smallmolecule CHEBI:47013 ChEBI "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "up-regulates quantity" "precursor of" 9606 25749547 t miannu "Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds." SIGNOR-267071 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 t milica "Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription." SIGNOR-198507 CDH11 protein P55287 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "up-regulates activity" binding 9606 10029089 t miannu "Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin" SIGNOR-265825 alemtuzumab antibody DB00087 DRUGBANK CD52 protein P31358 UNIPROT "down-regulates activity" binding 9606 BTO:0000782;BTO:0000776 15757437 t miannu "Alemtuzumab is a humanized monoclonal antibody against CD52, a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes, and on a large proportion of malignant lymphoid cells, but not on hematopoietic progenitor cells." SIGNOR-259883 SMARCE1 protein Q969G3 UNIPROT "Muscle cell-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C483 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex." SIGNOR-270731 PRKCI protein P41743 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr359 YLYEKANtPELKKSV 9606 BTO:0000551 21189248 t gcesareni "Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion." SIGNOR-170790 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI "up-regulates quantity" "precursor of" 9606 18767138 t lperfetto "Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate" SIGNOR-268246 MACROD2 protein A1Z1Q3 UNIPROT ADP-D-ribose(2-) smallmolecule CHEBI:57967 ChEBI "up-regulates quantity" "chemical modification" 9606 32257385 t miannu "MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins" SIGNOR-269840 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 t "inferred from 70% family members" gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-270206 SCF-FBW2 complex SIGNOR-C525 SIGNOR GCM1 protein Q9NP62 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 15640526 t miannu "FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system" SIGNOR-271528 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT "up-regulates activity" phosphorylation Thr402 TEAAQLStKSRAEGR 9606 BTO:0000007;BTO:0000567 12805220 t lperfetto "It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity." SIGNOR-101852 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1651 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248782 CCL21 protein O00585 UNIPROT CCR7 protein P32248 UNIPROT up-regulates binding 9606 BTO:0000671 11970971 t gcesareni "The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7." SIGNOR-117566 TFE3 protein P19532 UNIPROT WIPI1 protein Q5MNZ9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 24448649 f lperfetto "The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells" SIGNOR-276830 NTNG1 protein Q9Y2I2 UNIPROT LRRC4C protein Q9HCJ2 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 19467332 t miannu "The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively." SIGNOR-264047 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134533 GGCX protein P38435 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261232 PDGFRB protein P09619 UNIPROT NCK1 protein P16333 UNIPROT up-regulates binding 9606 10026169 t esanto "Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c)." SIGNOR-64737 ATP1A3 protein P13637 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 22797008 t miannu "The sodium/potassium transporting ATPase subunit alpha-3 (AT1A3; syn.: sodium pump subunit alpha-3; E.C. 3.6.3.9; UniProtKB ID: Q6PIC6) belongs to the cation transport ATPase (P-type) 3.A.3 family catalyzing hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action generates the electrochemical gradient of sodium and potassium ions thus providing energy for active transport of various nutrients. Three sodium/potassium transporting ATPase isoforms are expressed in the brain but AT1A3 is detectable in neurons exclusively." SIGNOR-265792 GRIK4 protein Q16099 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264345 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR ST7 protein Q9NRC1 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0004297 30945288 t miannu "We found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7)." SIGNOR-272309 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194545 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 21798082 f lperfetto "Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome." SIGNOR-252946 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser304 RASRRSDsASSEPVG 9606 19366211 t llicata "This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop." SIGNOR-185295 NEU1 protein Q99519 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "down-regulates activity" binding 9606 BTO:0003554 32164705 t miannu "NEU1 disrupts FN/ α5β1 interaction. taken together, strongly indicate that overexpressed NEU1 inhibits the Akt pathway by disrupting FN-integrin α5β1 interaction." SIGNOR-260658 INS protein P01308 UNIPROT APOB protein P04114 UNIPROT "down-regulates quantity by destabilization" 9606 23721961 f miannu "Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. Though insulin does not alter ApoB mRNA levels, it inhibits ApoB translation by promoting the trafficking of ApoB mRNA into P-bodies, aggregates of translationally repressed mRNAs" SIGNOR-252114 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 10102632 t lperfetto "Autophosphorylation of kdr in the kinase domain is required for maximal vegf-stimulated kinase activity and receptor internalizationthe intensity of vegf-induced autophosphorylation is significantly reduced when using receptor mutated at y996, confirming that this is a major site of autophosphorylation. Second, tyrosines 951 and 996 are the only two tyrosines in the receptor's kinase insert domain, and there is strong evidence from studies using the pdgfr and cfms that autophosphorylation of tyrosines in this domain leads to important signaling events." SIGNOR-66040 DRD5 protein P21918 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256914 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto "In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity." SIGNOR-251524 IL9 protein P15248 UNIPROT IL9R protein Q01113 UNIPROT up-regulates binding 9606 10642536 t fspada "Interleukin 9 (il-9) exerts its pleiotropic effects through the il-9 receptor (il-9r) complex, which consists of the il-9r alpha-chain, which determines the cytokine specificity, and the il-2 receptor gamma-chain" SIGNOR-73601 FBN1 protein P35555 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity" binding 9606 17242066 t "Regulation of localization" miannu "We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling." SIGNOR-251888 FEZF2 protein Q8TBJ5 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 23677067 f lperfetto "FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma." SIGNOR-268974 ZEB1 protein P37275 UNIPROT FBP1 protein P09467 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000762 30616754 t lperfetto "Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells|we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells." SIGNOR-267596 PTGER2 protein P43116 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256756 PTEN protein P60484 UNIPROT HCLS1 protein P14317 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11494141 f miannu "Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase)." SIGNOR-260052 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates phosphorylation Ser253 ETNVKMEsEGGADDS 9606 15687492 t gcesareni "A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c." SIGNOR-133528 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr771 ADIESSNyMAPYDNY 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179080 LCK protein P06239 UNIPROT LAX1 protein Q8IWV1 UNIPROT "up-regulates activity" phosphorylation Tyr193 SSEDSHDyVNVPTAE 9606 BTO:0000007 12359715 t miannu "Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85. " SIGNOR-273525 RIF1 protein Q5UIP0 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 15342490 f miannu "This result would suggest that Rif1 acts in an intra-S-phase checkpoint pathway that is separate from the Nbs1 pathway. Although a role for human Rif1 at telomeres is not excluded, our data show that the primary function of Rif1 is in the DNA-damage response. Rif1 localizes to DSBs in an ATM- and 53BP1-dependent manner and functions in the intra-S-phase checkpoint that serves to slow down DNA synthesis when DNA damage has occurred." SIGNOR-259060 MACROH2A1 protein O75367 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR down-regulates 16428466 f miannu "These data unambiguously identify mH2A as a strong transcriptional repressor and show that the repressive effect of mH2A is realized on at least two different transcription activation chromatin-dependent pathways: histone acetylation and nucleosome remodeling." SIGNOR-272930 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 t lperfetto "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45)" SIGNOR-227970 BMI1 protein P35226 UNIPROT "Polycomb repressive complex 1" complex SIGNOR-C408 SIGNOR "form complex" binding 9606 31608994 t miannu "PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b" SIGNOR-266812 nimodipine chemical CHEBI:7575 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" -1 18250364 t Luana "Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression. " SIGNOR-257765 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 15383283 t gcesareni "Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites." SIGNOR-129349 MAD2L1 protein Q13257 UNIPROT MCC complex SIGNOR-C382 SIGNOR "form complex" binding 9606 BTO:0000567 25092294 t miannu "The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20." SIGNOR-265973 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 18171681 t llicata "Plk1 phosphorylates ser(1337) and ser(1524) of topoiialpha plk1-associated phosphorylation is essential for the functions of topoiialpha in mitosis" SIGNOR-160237 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 t lperfetto "In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e." SIGNOR-244614 JNK proteinfamily SIGNOR-PF15 SIGNOR IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0004428 12510059 t lperfetto "Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylationOne of the specific Ser phosphorylation sites in IRS-1 that has been proposed to negatively modulate the insulin signal is Ser312 (numbered according to the human sequence). Prior studies have demonstrated that IRS-1 associates with and is phosphorylated by JNK in vitro on Ser312" SIGNOR-235777 PTK2 protein Q05397 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates quantity" phosphorylation 9606 19545541 t miannu "Taken together, our data suggest that FAK mediates the phosphorylation of IGF-1R and stabilizes the receptor.In this study we demonstrate that FAK, mainly known for its role in integrin signaling pathways, associates with and phosphorylates IGF-1R independently of IGF-1R 's intrinsic tyrosine kinase activity.|The impact of FAK on the expression levels of IGF-1R could be multilateral" SIGNOR-279565 ABL1 protein P00519 UNIPROT SNCA protein P37840 UNIPROT "up-regulates quantity" phosphorylation Tyr39 KTKEGVLyVGSKTKE 9606 29103051 t miannu "C-Abl interacts with alpha-synuclein and phosphorylates alpha-synuclein at Y39 (XREF_FIG) ." SIGNOR-279582 CSNK1D protein P48730 UNIPROT DCK protein P27707 UNIPROT "up-regulates activity" phosphorylation Ser74 EFEELTMsQKNGGNV 20637175 t lperfetto "We showed that recombinant CKI delta phosphorylated several residues of bacterially overexpressed dCK: Ser-74, but also Ser-11, Ser-15, and Thr-72. Phosphorylation of dCK by CKI delta correlated with increased activity reaching at least 4-fold. Site-directed mutagenesis demonstrated that only Ser-74 phosphorylation was involved in dCK activation by CKI delta," SIGNOR-275799 ceramide smallmolecule CHEBI:17761 ChEBI "ceramide 1-phosphate(2-)" smallmolecule CHEBI:84404 ChEBI "up-regulates quantity" "precursor of" 9606 34202192 t miannu "Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P)." SIGNOR-268501 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser239 GAKLRKVsKQEEASG 9606 12576312 t miannu "Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro" SIGNOR-250063 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT "up-regulates activity" phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 t miannu "In vitro kinase assay revealed that PDHA could be readily phosphorylated by active AMPK complex in a dose-dependent manner (Figure 6C). " SIGNOR-276835 STAT3 protein P40763 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR "form complex" binding 9606 19723038 t miannu "Sp1 and stat3 seem to synergistically augment renalase transcription." SIGNOR-187793 MCHR2 protein Q969V1 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257067 PTPN6 protein P29350 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 9733788 t tpavlidou "The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation." SIGNOR-59965 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" cleavage Asp326 NSEEDEMdSGTMVRA 9534 BTO:0004055 11517310 t lperfetto "In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus." SIGNOR-109874 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr296 MGYDDLDyGMMSDYG -1 11382764 t lperfetto "Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302" SIGNOR-246500 TUBA1B protein P68363 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu "We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching." SIGNOR-269727 DCAF7 protein P61962 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 "BTO:0002181; BTO:0003484" 16887337 f Giorgia "HAN11 and mDia1 repressed DYRK1A-dependent GLI1 transcriptional activity. The studies of SZ95 cells suggest that HAN11 reduces GLI1-dependent transcription by decreasing the nuclear pool of GLI1." SIGNOR-260634 LAT protein O43561 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-246050 MMP15 protein P51511 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272360 CDH15 protein P55291 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265854 RPA1 protein P27694 UNIPROT BRIP1 protein Q9BX63 UNIPROT "up-regulates activity" binding 9606 17596542 t irozzo "Our data are consistent with a model in which FANCJ associates with RPA in a DNA damage-inducible manner and through the protein interaction RPA stimulates FANCJ helicase to better unwind duplex DNA substrates. These findings identify RPA as the first regulatory partner of FANCJ." SIGNOR-259187 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT "up-regulates activity" phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000007 12138205 t "Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator." SIGNOR-251481 miR-132 mirna URS00001F4E81_9606 RNAcentral MECP2 protein P51608 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 23132946 f irozzo "In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability." SIGNOR-255884 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161585 EIF2AK2 protein P19525 UNIPROT "NLRP1 inflammasome" complex SIGNOR-C224 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22801494 t miannu "Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation." SIGNOR-263118 NCBP3 protein Q53F19 UNIPROT "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates activity" relocalization 9606 26382858 t lperfetto "The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization." SIGNOR-268364 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys373 SSHLKSKkGQSTSRH 9606 BTO:0000567 11070080 t gcesareni "P300 acetylates and activates the tumor suppressor p53 after dna damage." SIGNOR-84070 clofarabine chemical CHEBI:681569 ChEBI RRM2 protein P31350 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000664 1707752 t miannu "Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate" SIGNOR-258356 PLCB3 protein Q01970 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" 23994464 f apalma "The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release" SIGNOR-255014 LAMTOR5 protein O43504 UNIPROT LIN28B protein Q6ZN17 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23494474 f miannu "We found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells." SIGNOR-255251 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD2 protein Q15796 UNIPROT "up-regulates activity" acetylation Lys19 VKRLLGWkKSAGGSG 9606 BTO:0000567;BTO:0002181;BTO:0000552 17074756 t lperfetto "We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. To identify the specific lysine residue acetylated by p300, lys19, and lys20 in smad2(fl) were mutated individually and subjected to p300-mediated acetylation following expression in 293t cells. Mutation of lys19 blocked the p300-mediated acetylation of smad2(fl), whereas mutation of lys20 had no effect (fig. 2b), suggesting that lys19 is the preferred site for p300-mediated acetylation of smad2(fl)." SIGNOR-235899 RPA1 protein P27694 UNIPROT POLA1 protein P09884 UNIPROT "up-regulates activity" binding -1 9214288 t Federica "In our studies, we have shown that T antigen, DNA polymerase R, and the activation domain of VP16 all interact with overlapping regions of the 70-kDa subunit of RPA.| In the latter, both the direct protein-protein interaction and ssDNA-binding activities of RPA were needed for RPA to modulate polymerase processivity. We also found that SV40 T antigen inhibited the ability of RPA to increase processivity of DNA polymerase alpha, suggesting that this activity of RPA may be important for elongation but not during the initiation of DNA replication." SIGNOR-261272 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-A (a5-b1-g2) receptor" complex SIGNOR-C335 SIGNOR "up-regulates activity" "chemical activation" 9606 18790874 t brain lperfetto "Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS)." SIGNOR-263791 CHRM4 protein P08173 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256829 LRRK2 protein Q5S007 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000007 22012985 f gcesareni "We report that LRRK2 activates a calcium-dependent protein kinase kinase-² (CaMKK-²)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation." SIGNOR-237005 RNF168 protein Q8IYW5 UNIPROT H1-2 protein P16403 UNIPROT down-regulates polyubiquitination 9606 BTO:0000815 30517763 t miannu "ITCH biochemically antagonized RNF168 and RNF8 in polyubiquitination of histone H1.2 ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. Both RNF168 and RNF8 elicited higher Ubn levels of K46R-H1.2 compared to WT-H1.2, suggesting that Ubn of H1.2 by both E3 ligases occurs at a site apart from K46." SIGNOR-272927 PTPN1 protein P18031 UNIPROT BCR protein P11274 UNIPROT down-regulates dephosphorylation 9606 9566916 t "The effect has been demonstrated using P11274-1" gcesareni "These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo." SIGNOR-56818 CAMK2G protein Q13555 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275794 "Immune complexes" stimulus SIGNOR-ST15 SIGNOR FCGR3A protein P08637 UNIPROT "up-regulates activity" 9606 BTO:0000801 17558411 f lperfetto "After binding their antibody ligands, FcgRI and FcgRIII deliver activating signals through an association with the FcRg-chain (FcRg), a transmembrane adaptor protein with an immuno-receptor tyrosine-based activation motif in its cytoplasmic domain." SIGNOR-249523 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258188 NUAK1 protein O60285 UNIPROT LATS1 protein O95835 UNIPROT down-regulates phosphorylation Ser464 NIPVRSNsFNNPLGN 9606 19927127 t lperfetto "Moreover, we show that nuak1 phosphorylates lats1 at s464 and this has a role in controlling its stabilitycells that constitutively express nuak1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator lats1" SIGNOR-161792 P2RY1 protein P47900 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256800 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser215 SGRAREAsGAPTSSK 9606 BTO:0000938 17470458 t acerquone "The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor" SIGNOR-154631 pictrelisib chemical CHEBI:65326 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000149 21876152 t gcesareni "Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed" SIGNOR-176298 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159390 SIRT1 protein Q96EB6 UNIPROT NHLH2 protein Q02577 UNIPROT "up-regulates activity" deacetylation Lys49 EEAEGDGkGGSRAAL 10090 BTO:0000142 22169038 t miannu "SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter" SIGNOR-254830 IKBKB protein O14920 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t gcesareni "Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway" SIGNOR-124207 alvocidib chemical CHEBI:47344 ChEBI CDK4 protein P11802 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258172 GNB1 protein P62873 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" 15345719 f "In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation" SIGNOR-251107 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250936 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248684 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT "up-regulates activity" phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 t done miannu "p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation." SIGNOR-273952 AURKA protein O14965 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 23520446 t miannu "Because AURKA associated with EGFR, we next investigated whether AURKA phosphorylates EGFR at Thr654 and Ser1046.|Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells." SIGNOR-279590 CHUK protein O15111 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 SIGNOR-C14 9346241 t lperfetto "We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation" SIGNOR-52879 GNAI1 protein P63096 UNIPROT ADCY1 protein Q08828 UNIPROT "down-regulates activity" binding 9606 15922020 t "Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated." SIGNOR-256532 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT "up-regulates activity" phosphorylation Tyr398 QSHVEDLyVEGLPEG 9534 11373296 t lperfetto "These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation." SIGNOR-108342 KLF15 protein Q9UIH9 UNIPROT RBP3 protein P10745 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 15277472 f miannu "KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl." SIGNOR-253816 BID protein P55957 UNIPROT CYCS protein P99999 UNIPROT "up-regulates activity" 9606 9727492 f "Translocation from Mitochondria to Cytosol" lperfetto "TBID induces first the clustering of mitochondria around the nuclei and release of cytochrome c." SIGNOR-59224 STX1A protein Q16623 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR "form complex" binding 9606 BTO:0000938 30267828 t miannu "The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells." SIGNOR-263968 DRD2 protein P14416 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256980 GCM2 protein O75603 UNIPROT CASR protein P41180 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004712 BTO:0000975 18712808 f miannu "we show that both promoters (P1 and P2) of the calcium-sensing receptor (CASR) gene, a differentiation marker for the parathyroid gland, are transactivated by wild-type GCM2." SIGNOR-254199 MMP9 protein P14780 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272376 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB3 protein P13945 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257458 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 9606 12058027 t gcesareni "Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs." SIGNOR-89427 AR protein P10275 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 15861399 f miannu "AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation" SIGNOR-251540 MEN1 protein O00255 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16415155 f irozzo "We also found that menin is important for the proliferation of MLL oncoprotein-transformed myeloid cells, pointing to a paradoxically oncogenic role for the tumor suppressor menin in proliferation of transformed myeloid cells." SIGNOR-255895 enalapril chemical CHEBI:4784 ChEBI ACE protein P12821 UNIPROT "down-regulates activity" "chemical inhibition" 10116 7527095 t miannu "The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalaprilat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat." SIGNOR-258428 TTC5 protein Q8N0Z6 UNIPROT JMY protein Q8N9B5 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 15448695 t miannu "DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY" SIGNOR-262647 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation 9606 20230789 t "inferred from 70% family members" lperfetto "Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity" SIGNOR-270114 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000093 16582606 t lperfetto "In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue." SIGNOR-216729 CDK1 protein P06493 UNIPROT DIAPH1 protein O60610 UNIPROT "down-regulates activity" phosphorylation 9606 30816115 t miannu "In this study, we found that Cdk1 phosphorylated DIAPH1, which inhibited the interaction between DIAPH1 and profilin1 (PFN1) during metaphase.|Thus, the results suggest that the level of cortical F-actin has to be finely maintained by Cdk1 mediated positive and negative regulation of DIAPH1." SIGNOR-279598 IL12A protein P29459 UNIPROT IFNG protein P01579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10653850 f miannu "IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12" SIGNOR-260859 FRK protein P42685 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr391 PFLNSGTyHSRDEST 9606 BTO:0002035 35723276 t miannu "Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP. " SIGNOR-275455 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RHOA protein P61586 UNIPROT "up-regulates activity" phosphorylation Ser88 LMCFSIDsPDSLENI 9534 BTO:0000298 26816343 t miannu "We have recently reported that Rac1 is phosphorylated on threonine 108 (108T) by extracellular signal-regulated kinases (ERK) in response to epidermal growth factor (EGF) stimulation. Here, we provide evidence that RhoA is phosphorylated by ERK on 88S and 100T in response to EGF stimulation." SIGNOR-277202 "MITRAC complex" complex SIGNOR-C538 SIGNOR COX4I1 protein P13073 UNIPROT "up-regulates quantity" relocalization 23260140 t "Each association relies on the supply of subunits from either the cytosol or the mitochondrial matrix, suggesting that human TIM21 ushers nuclear-encoded proteins to assembly intermediates. In agreement with this, assembly of the early cytochrome c oxidase subunit COX4-1 requires TIM21, whereas it is dispensable for late-assembling subunits. The finding that TIM21 also interacts with complex I intermediates points to a more general role of TIM21 in respiratory-chain assembly. Furthermore, TIM21 appears to be tightly connected to MITRAC15, which, in contrast to TIM23 and MITRAC12, coimmunoprecipitates with TIM21 under all tested conditions. MITRAC15 associates with MITRAC and is required for complex IV but also complex I assembly." SIGNOR-272487 PPP1R3B protein Q86XI6 UNIPROT GYS1 protein P13807 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 t miannu "In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)" SIGNOR-271734 ARHGAP35 protein Q9NRY4 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260493 KPNB1 protein Q14974 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates relocalization 9606 10846168 t gcesareni "Here we show that the isolated smad 3 mh1 domain displays significant specific binding to importin beta. we propose that activation of all of the pathway-specific smad proteins (smads 1, 2, 3, 5, 8, and 9) exposes the conserved nls motif, which then binds directly to importin beta and triggers nuclear translocation." SIGNOR-78191 PBX2 protein P40425 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265778 PRKCA protein P17252 UNIPROT PRKD2 protein Q9BZL6 UNIPROT "up-regulates activity" phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 t lperfetto "Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead." SIGNOR-275954 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT "up-regulates activity" phosphorylation Ser108 WKLRARPsLTVTPRR 9606 BTO:0000567 21658950 t miannu "Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis." SIGNOR-263137 NEK11 protein Q8NG66 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser82 GSSESTDsGFCLDSP 9606 19734889 t lperfetto "Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites" SIGNOR-187867 PKC proteinfamily SIGNOR-PF53 SIGNOR KLHL3 protein Q9UH77 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser433 PMNTRRSsVGVGVVE 9534 BTO:0000298 25313067 t done miannu "We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation." SIGNOR-273780 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB4 protein Q9UN71 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265701 DLD protein P09622 UNIPROT OGDC complex SIGNOR-C397 SIGNOR "form complex" binding 9606 15953811 t miannu "The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH." SIGNOR-266256 PTEN protein P60484 UNIPROT DUSP1 protein P28562 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11494141 f miannu "Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase)." SIGNOR-260053 MAP3K14 protein Q99558 UNIPROT SLC9A1 protein P19634 UNIPROT "up-regulates activity" phosphorylation 9606 11369779 t miannu "The Nck-interacting kinase (NIK) phosphorylates the Na+-H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor.|We now show that NIK binds to and divergently activates the plasma membrane Na(+)-H(+) exchanger NHE1." SIGNOR-279632 WNT8B protein Q93098 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-132027 CNTFR protein P26992 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 10582086 f gcesareni "Clc/clf activates stat1 and stat3." SIGNOR-72774 RORC protein P51449 UNIPROT Th17 phenotype SIGNOR-PH94 SIGNOR up-regulates 9606 16990136 f "MARCO ROSINA" "Our results demonstrate that RORgt is the transcription factor that directs the differentiation of inflammatory Th17 cells" SIGNOR-255028 MAPK3 protein P27361 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 12169099 t gcesareni "Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein." SIGNOR-91383 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation 9606 SIGNOR-C14 19632174 t lperfetto "Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta." SIGNOR-187242 CSNK2A1 protein P68400 UNIPROT MAZ protein P56270 UNIPROT up-regulates phosphorylation Ser460 PTAVGSLsGAEGVPV 9606 BTO:0000567 10448092 t lperfetto "Site-specific mutagenesis of maz revealed that the serine residue at position 480 was the major site of phosphorylation by ckii both in vitro and in vivo. Phosphorylation of maz by ckii at this serine residue was required for maximum binding of maz to the pyrimidine-rich dna of the nuclease-hypersensitive element (nhe) in the 5'-end promoter region of the c-myc gene. Mutation of serine at position 480 to alanine eliminated the dna-binding activity of maz to this element." SIGNOR-70082 PPP5C protein P53041 UNIPROT CDC37 protein Q16543 UNIPROT "down-regulates activity" dephosphorylation Ser13 VWDHIEVsDDEDETH 9606 18922470 t "Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37." SIGNOR-248539 HCK protein P08631 UNIPROT WAS protein P42768 UNIPROT "up-regulates activity" phosphorylation Tyr291 AETSKLIyDFIEDQG 9534 BTO:0000298 12235133 t done miannu "Hck induces tyrosine phosphorylation of WASp. Here we show that the Src family kinase Hck induces phosphorylation of WASp-Tyr(291) independently of Cdc42 and that this causes a shift in the mobility of WASp upon SDS-PAGE. A phospho-mimicking mutant, WASp-Y291E, exhibited an enhanced ability to stimulate actin polymerization in a cell-free system and when microinjected into primary macrophages induced extensive filopodium formation with greater efficiency than wild-type WASp or a Y291F mutant. We propose that phosphorylation of Tyr(291) directly regulates WASp function." SIGNOR-273957 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000007 16461343 t miannu "Native ptpn22 dephosphorylated lck and zap70 at their activating tyrosine residues tyr-394 and tyr-493, respectively, but not at the regulatory tyrosines tyr-505 (lck) or tyr-319 (zap70)." SIGNOR-144345 FGA protein P02671 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR "form complex" binding -1 25427968 t lperfetto "Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively)." SIGNOR-263392 ERG protein P11308 UNIPROT ICAM2 protein P13598 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10574717 f miannu "The Ets family member Erg was found to be constitutively expressed in HUVEC, and TNF-(alpha) down-regulated Erg protein levels. Furthermore, an Erg cDNA transactivated the ICAM-2 promoter when transiently transfected into both HeLa cells and HUVEC." SIGNOR-253913 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t "The effect has been demonstrated using Q01196-8" lperfetto "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-244711 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 20219869 f apalma "Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6." SIGNOR-255357 PRKCD protein Q05655 UNIPROT YWHAZ protein P63104 UNIPROT "down-regulates activity" phosphorylation Ser58 VVGARRSsWRVVSSI 9606 12861023 t lperfetto "We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. | Experimentally, S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1." SIGNOR-249222 MAML1 protein Q92585 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 11101851 t "inferred from 70% of family members" gcesareni "Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4" SIGNOR-269934 TRIM38 protein O00635 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 22323536 t miannu "As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6. " SIGNOR-272009 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t miannu "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-255006 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 7578094 t lperfetto "These data are consistent with autophosphorylation on y-419 as predicted. Intermolecular autophosphorylation is consistent with the ability of srctk to dimerize, which is analogous to activation of receptor tyrosine kinases such as the egf receptor kinase in response to growth factors." SIGNOR-29369 GPR35 protein Q9HC97 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256717 HIF1A protein Q16665 UNIPROT NT5E protein P21589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000414 12370277 f miannu "Examination of the CD73 gene promoter identified at least one binding site for hypoxia-inducible factor-1 (HIF-1) and inhibition of HIF-1alpha expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 expression" SIGNOR-254423 PAK2 protein Q13177 UNIPROT MYLK protein Q15746 UNIPROT "down-regulates activity" phosphorylation Ser1760 RAIGRLSsMAMISGL -1 10748018 t miannu "PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991." SIGNOR-250223 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12565872 t "We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells" SIGNOR-253583 DHCR24 protein Q15392 UNIPROT DHCR7 protein Q9UBM7 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 25637936 t miannu "DHCR7 coimmunoprecipitates DHCR24. Overexpression of functional DHCR24 increases DHCR7 activity. Because knockdown of DHCR24 has no effect on DHCR7 mRNA (Fig. 3A), this implies that this phenomenon is occurring posttranscriptionally. Thus, the interaction between the two terminal steps of cholesterol synthesis appears to have functional consequences." SIGNOR-267249 KIF3B protein O15066 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272516 BTF3 protein P20290 UNIPROT EPHB2 protein P29323 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 17312387 f "In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis." SIGNOR-253949 MAPK9 protein P45984 UNIPROT EGLN2 protein Q96KS0 UNIPROT "up-regulates activity" phosphorylation Ser74 TATSTTAsPLRDGFG 9606 27263528 t miannu "Interestingly, we found that docetaxel induced JNK2 activation increased phosphorylation of PHD1 at Ser 74 and Ser 162 in hypoxic cancer cells (XREF_FIG)." SIGNOR-279078 GATA6 protein Q92908 UNIPROT RARB protein P10826 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000195 24317510 f lperfetto "Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2." SIGNOR-253154 CD274 protein Q9NZQ7 UNIPROT PDCD1 protein Q15116 UNIPROT up-regulates binding 9606 BTO:0000782 11015443 t miannu "Pd-l1, was found to bind pd-1 specifically. The functional significance of this interaction has been demonstrated in t cell assays, in which engagement of pd-1 by pd-l1 leads to the inhibition of tcr-mediated lymphocyte proliferation and cytokine secretion." SIGNOR-82604 CCNK protein O75909 UNIPROT CyclinK/CDK13 complex SIGNOR-C38 SIGNOR "form complex" binding 9606 22012619 t miannu "We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells" SIGNOR-176786 CHEK1 protein O14757 UNIPROT SYK protein P43405 UNIPROT down-regulates phosphorylation Ser295 GIISRIKsYSFPKPG 9606 22585575 t llicata "We found that chk1 phosphorylated the tumor suppressor spleen tyrosine kinase (l) (syk[l]) and identified the phosphorylation site at ser295. Furthermore, chk1 phosphorylation of syk(l) promoted its subsequent proteasomal degradation." SIGNOR-197528 ATR protein Q13535 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 16908529 t gcesareni "Finally, in vitro atr-mediated phosphorylation at the t2609 cluster was further confirmed by western blot analysis using phosphospecific antibodies against t2647 (fig. ?(Fig.7e),7e), suggesting that dna-pkcs could be the direct target of atr kinase." SIGNOR-148722 MRPL12 protein P52815 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262381 RANGAP1 protein P46060 UNIPROT MYCBP2 protein O75592 UNIPROT "down-regulates quantity by destabilization" relocalization 10090 26304119 t Monia "SUMOylated RanGAP1 Inhibits MYCBP2 Activity and Mediates Its Transport to the Nucleus. Surprisingly, we did not find MYCBP2-dependent ubiquitylation of SUMOylated RanGAP1 but instead a strong inhibition of the ubiquitin ligase activity of MYCBP2 in the presence of SUMOylated RanGAP1, as determined by the presence of ubiquitylated proteins. this effect was specific for SUMOylated RanGAP1, because the unmodified form of RanGAP1 did not affect MYCBP2-dependent protein ubiquitylation. , SUMOylated RanGAP1 inhibited the ubiquitin ligase activity of MYCBP2, and it is tempting to speculate that SUMOylated RanGAP1 inhibits the ubiquitin ligase activity of MYCBP2 to ensure MYCBP2 silencing during its transport to the nucleus" SIGNOR-261203 SRC protein P12931 UNIPROT TLR3 protein O15455 UNIPROT "up-regulates activity" phosphorylation Tyr759 EQFEYAAyIIHAYKD 9606 27514533 t miannu "Markedly, Src mediated late TLR3 Pi-Tyr759 leads to the nuclear accumulation of IRF3 and IRF7 and the increase of IFN-beta production.|Src can directly phosphorylate TLR3 Tyr759 in\nvitro and in vivo ." SIGNOR-279657 MDM2 protein Q00987 UNIPROT APEX1 protein P27695 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 21727086 t miannu "Once the reaction proceeds beyond the monoubiquitination stage, MDM2 polyubiquitinates APE1 for degradation." SIGNOR-278555 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser438 PGLLRRVsSTWTTTT 9606 19261611 t llicata "Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding." SIGNOR-184456 "STX11-VAMP8 SNARE complex" complex SIGNOR-C273 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR up-regulates 9606 BTO:0000782 22767500 f lperfetto "Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release." SIGNOR-261902 PROX1 protein Q92786 UNIPROT IFNG protein P01579 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20064070 f "Human PROX1 is involved in biologic functions closely tied to HIV infection, most notably as a negative regulator of interferon (IFN) gamma expression in T cells" SIGNOR-254506 thioridazine chemical CHEBI:9566 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258839 LPCAT1 protein Q8NF37 UNIPROT 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI "down-regulates quantity" "chemical modification" 9606 21498505 t miannu "Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. " SIGNOR-272762 ATF6 protein P18850 UNIPROT DDIT3 protein P35638 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31226023 t miannu "Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network" SIGNOR-260180 RAPGEF4 protein Q8WZA2 UNIPROT ABCC8 protein Q09428 UNIPROT "up-regulates quantity" binding 9606 21478675 t miannu " The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε." SIGNOR-278141 ponatinib chemical CHEBI:78543 ChEBI FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23468082 t miannu "Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family." SIGNOR-259277 FYN protein P06241 UNIPROT BSG protein P35613-2 UNIPROT "up-regulates activity" phosphorylation Tyr140 PVTDWAWyKITDSED 9606 BTO:0000849 32291412 t miannu "Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment." SIGNOR-273999 PRKCA protein P17252 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251620 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR SPI1 protein P17947 UNIPROT "down-regulates activity" binding 9606 BTO:0000318 18519037 t "We found that AML1-ETO is able to inhibit Sp1 transactivity. We also found that this inhibition of Sp1 transactivity by AML1-ETO is achieved by interaction between Sp1 and RUNT domain of AML1" SIGNOR-255671 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation" SIGNOR-252350 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 t lperfetto "Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation." SIGNOR-74296 TRIM23 protein P36406 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 28871090 t miannu "TRIM23 interacts with TBK1 and p62. TRIM23 GTPase activates TBK1 to phosphorylate p62. Biochemical characterization showed that TRIM23 binds with its C-terminal ARF domain to the N-terminal KD of TBK1, and that GTP hydrolysis activity of the ARF stimulates TBK1-mediated phosphorylation of p62 at S403 in its ubiquitin-associated (UBA) domain, which was shown to promote cargo recruitment and autophagic flux" SIGNOR-266654 CHD8 protein Q9HCK8 UNIPROT NEUROG1 protein Q92886 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 32839322 t Gianni "Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells" SIGNOR-268919 FOXO3 protein O43524 UNIPROT CITED2 protein Q99967 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 18158893 f gcesareni "Foxo3a induces expression of cited2" SIGNOR-160127 SLBP protein Q14493 UNIPROT H2AC20 protein Q16777 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265398 DAD1 protein P61803 UNIPROT "OST-B complex" complex SIGNOR-C536 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272067 MRPL1 protein Q9BYD6 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262384 LRP2 protein P98164 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity" binding 9606 BTO:0000142 26872844 t miannu "LRP2 Promotes SHH Activity in Neurogenic Niches of the Developing and Adult Brain. In the RDVM, LRP2 forms a co-receptor complex with PTCH1 facilitating SHH binding and internalization of SHH/PTCH1 complexes, a prerequisite for pathway activation (Fig. 3B)." SIGNOR-265257 BBS2 protein Q9BXC9 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262557 MRAP2 protein Q96G30 UNIPROT MC2R protein Q01718 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor." SIGNOR-252361 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1169 VQQDGKDyIPINAIL 9606 9299537 t lperfetto "Tyr-1169 and tyr-1213 on flt-1 were found to be auto-phosphorylated these results strongly suggest that tyr-1169 on flt-1 is a major binding site for plcgamma and important for flt-1 signal transduction within the cell" SIGNOR-50834 PRKACA protein P17612 UNIPROT MARK2 protein Q7KZI7 UNIPROT "down-regulates activity" phosphorylation Ser409 NPKQRRFsDQAAGPA 9606 BTO:0000007 25512381 t miannu "Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409. " SIGNOR-276870 MAPK14 protein Q16539 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser85 HQQPQSSsPVYGSSA 9606 14970194 t llicata "Here, we show that paxillin is phosphorylated by p38mapk in vitro and in nerve growth factor (ngf)-induced pc-12 cells. Ser 85 (ser 83 for endogenous paxillin) is identified as one of major phosphorylation sites by phosphopeptide mapping and mass spectrometry." SIGNOR-122108 CDK7 protein P50613 UNIPROT MBD4 protein O95243 UNIPROT "down-regulates activity" phosphorylation 9606 31466944 t miannu "The mechanistic basis for the phase-separation of MED1 is not well understood, and we hypothesize that this may be due to the phosphorylation of MED1 by CDK7 in response to growth stimuli or nuclear translocation of steroid hormone receptors, such as AR.|Together, we demonstrate that CDK7 inhibition selectively targets MED1 mediated, AR dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC." SIGNOR-279686 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser204 DSRPRSQsSKAAIPP 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262706 ULK1 protein O75385 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" phosphorylation 9606 29671878 t miannu "In the nucleation step of autophagy, The ULK1 complex phosphorylates and activates the Beclin-1-VPS34 complex." SIGNOR-279670 PLCG2 protein P16885 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni "Phosphorylation at Ser-146 by PKCδ increases p21 stability" SIGNOR-262963 "SAGA complex" complex SIGNOR-C465 SIGNOR H3C1 protein P68431 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269636 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 t "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis." SIGNOR-248383 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G3 protein O43432 UNIPROT "up-regulates activity" stabilization 9606 17581632 t lperfetto "EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit" SIGNOR-269157 CFHR1 protein Q03591 UNIPROT C3 protein P01024 UNIPROT "up-regulates activity" binding -1 cleavage:Arg748 ASHLGLArSNLDEDI 27814381 t "complement C3b fragment: PRO_0000005911" lperfetto "Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b" SIGNOR-263475 EGFR protein P00533 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 BTO:0000150 11483589 t lperfetto "We also show that the activated egf-r phosphorylates the muc1 cytoplasmic tail on tyrosine at a yekv motif that functions as a binding site for the c-src sh2 domain. The results demonstrate that egf-r-mediated phosphorylation of muc1 induces binding of muc1 to c-src in cells" SIGNOR-109538 testosterone smallmolecule CHEBI:17347 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000975 27702664 t lperfetto "The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively" SIGNOR-268667 F2RL3 protein Q96RI0 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257312 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR IDH1 protein O75874 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr157 GKVEITYtPSDGTQK 34929314 t lperfetto "During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome" SIGNOR-267621 GSK3B protein P49841 UNIPROT JUNB protein P17275 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 25303440 t miannu "GSK-3\u03b2 phosphorylation of JunB is therefore likely to be one of the critical events determining the difference in collagen deposition between normal and SSc fibroblasts.|In contrast, in normal fibroblasts, GSK-3beta is active and targets JunB for proteasomal degradation (XREF_FIG D)." SIGNOR-279721 SS18L1 protein O75177 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates relocalization 9606 BTO:0000938 15488321 t miannu "The calcium-responsive transactivator recruits creb binding protein to nuclear bodies." SIGNOR-129926 ABL1 protein P00519 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation 9606 17615370 t miannu "Abl silencing inhibits CAS mediated process and constriction in resistance arteries.|CAS phosphorylation was catalyzed by Abl in an in vitro study." SIGNOR-279671 S1PR2 protein O95136 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000007 10488065 t gcesareni "Edg-3 and edg-5 couple not only to gibut also to gqand g13." SIGNOR-70667 "Class II MHC" complex SIGNOR-C428 SIGNOR "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR "form complex" binding 9606 33374673 t scontino "The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR)." SIGNOR-267872 AHSA1 protein O95433 UNIPROT HSP90AA1 protein P07900 UNIPROT "up-regulates activity" binding 9606 16696853 t miannu "The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity" SIGNOR-252211 MAPK1 protein P28482 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 t "The effect has been demonstrated using O75030-9" gcesareni "The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation." SIGNOR-75030 RNF128 protein Q8TEB7 UNIPROT ARHGDIB protein P52566 UNIPROT "up-regulates quantity by stabilization" polyubiquitination 9606 BTO:0000661 17114425 t miannu "We found that RhoGDIα and RhoGDIβ are ubiquitin E3 substrates of GRAIL. GRAIL uses nonlysine 48-ubiquitin linkage in polyubiquitinating RhoGDI. GRAIL was subsequently demonstrated to bind and ubiquitinate RhoGDI, although GRAIL-mediated ubiquitination of RhoGDI did not result in proteosomal degradation. Our data suggest that ubiquitination of RhoGDI by GRAIL does not result in proteolytic degradation. In fact, GRAIL activity appeared to increase RhoGDI stability." SIGNOR-271621 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 12747827 t lperfetto "Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e." SIGNOR-236698 RAR proteinfamily SIGNOR-PF45 SIGNOR RXR proteinfamily SIGNOR-PF44 SIGNOR "up-regulates activity" binding 9606 1310351 t miannu "Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-256198 PAK1 protein Q13153 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation 9606 15037762 t gcesareni "Kinases targeted sequentially to the neck, cla4/pak and cdc5/polo, are responsible for stepwise phosphorylation and down-regulation of swe1." SIGNOR-123528 CDK3 protein Q00526 UNIPROT CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser273 PGQGGSTsAFEQLQR 9534 11733001 t miannu "P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed." SIGNOR-250679 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1B protein Q92523 UNIPROT "down-regulates activity" binding 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267115 CYCS protein P99999 UNIPROT Oxidative_phosphorylation phenotype SIGNOR-PH78 SIGNOR up-regulates 10090 23021218 f lperfetto "PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b)." SIGNOR-253100 EIF4G1 protein Q04637 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR "form complex" binding 9606 BTO:0000671 11408474 t miannu "Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f." SIGNOR-108518 ITGB1BP1 protein O14713 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257643 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 10567572 t gcesareni "G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2.." SIGNOR-72125 TUBGCP5 protein Q96RT8 UNIPROT "g-TuRC complex" complex SIGNOR-C282 SIGNOR "form complex" binding -1 31862189 t lperfetto "Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.”" SIGNOR-262329 PTH1R protein Q03431 UNIPROT SOST protein Q9BQB4 UNIPROT "down-regulates quantity" 28363951 f lperfetto "Furthermore, PTH acts on osteocytes to suppress the expression of sclerostin, an inhibitor of canonical Wnt signaling (Li, et al. 2005; Semenov, et al. 2005)). PTH action on sclerostin is primarily through cAMP signaling (Keller and Kneissel 2005) and mediated by Myocyte enhancer factor-2 (MEF2) transcriptional regulators (Leupin, et al. 2007). Using the cAMP signaling pathway in osteoblasts, PTH also inhibits the expression of Dickkopf 1 (Dkk1) (Guo et al. 2010a), which is another Wnt pathway inhibitor " SIGNOR-270552 HLTF protein Q14527 UNIPROT OCA2 protein Q04671 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000847 22234890 f miannu "The SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression." SIGNOR-254425 TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000007 17135271 t "These data establish a signaling cascade in which regulated site-specific Lys-63-linked TRAF6 auto-ubiquitination is the critical upstream mediator of IKK." SIGNOR-252099 CSNK2A1 protein P68400 UNIPROT SEC63 protein Q9UGP8 UNIPROT "up-regulates activity" phosphorylation Ser576 VSDKGSDsEEEETNR 9606 BTO:0000599 23287549 t lperfetto "Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62." SIGNOR-265267 JAK2 protein O60674 UNIPROT PRMT5 protein O14744 UNIPROT down-regulates phosphorylation Tyr297 NRPPPNAyELFAKGY 9606 21316606 t llicata "Oncogenic jak2 kinases phosphorylate prmt5 in_vivo phosphorylation of prmt5 by jak2v617f greatly impairs its methyltransferase activity" SIGNOR-171994 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT "down-regulates activity" dephosphorylation Ser988 PPLFPIKsFVKTKCK 9606 BTO:0000007 17603999 t "Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524." SIGNOR-248560 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser365 RLDRTGSsPTQGIVN 9606 15767678 t gcesareni "Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis." SIGNOR-134588 "Uridylate-specific endoribonuclease" protein P0C6X7-PRO_0000037321 UNIPROT EIF2AK2 protein P19525 UNIPROT "down-regulates activity" 9606 28158275 f miannu "Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation." SIGNOR-260348 MYLIP protein Q8WY64 UNIPROT VLDLR protein P98155 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 20427281 t miannu "Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation." SIGNOR-271487 NOTCH1 protein P46531 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 16554461 f gcesareni "Notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes." SIGNOR-145322 NEDD4 protein P46934 UNIPROT TUSC2 protein O75896 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys71 YEETIVTkNGQKRAK 9606 35167936 t miannu "NEDD4 Degrades TUSC2 to Promote Glioblastoma Progression.|NEDD4 E3 ubiquitin ligase polyubiquitinates TUSC2 at residue K71, and the TUSC2-K71R mutant is resistant to NEDD4-mediated proteasomal degradation." SIGNOR-278638 GDNF protein P39905 UNIPROT TUBA1A protein Q71U36 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization." SIGNOR-252174 SOX6 protein P35712 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003298 26893351 f "We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARŒ≥, C/EBPŒ± and MEST" SIGNOR-255822 CAMK2A protein Q9UQM7 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Ser1303 NKLRRQHsYDTFVDL BTO:0003036 8940188 t llicata "By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons." SIGNOR-250630 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TRIM71 protein Q2Q1W2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269247 CTNNBIP1 protein Q9NSA3 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10898789 t gcesareni "We identify a novel beta-catenin-interacting protein, icat, that was found to inhibit the interaction of beta-catenin with tcf-4 and represses beta-catenin-tcf-4-mediated transactivation." SIGNOR-79399 GARS1 protein P41250 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI "up-regulates quantity" "chemical modification" 9606 14660560 t miannu "Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA." SIGNOR-270804 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-66775 AMPK complex SIGNOR-C15 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser170 PSALNRTsSDSALHT 9606 21892142 t lperfetto "Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation" SIGNOR-216541 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 8119945 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-36279 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser77 PGPFATRsPLFIFMR 10090 12818176 t miannu "Mitochondrially localized JNKs but not their upstream activators MLKs or MKKs phosphorylated BIMEL at Ser65, potentiating its cytotoxicity without altering its subcellular distribution or integration into mitochondrial membranes. JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73" SIGNOR-250133 ASB8 protein Q9H765 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 31009856 t lperfetto "In turn, ASB8 facilitated K48-linked ubiquitination and degradation of IKKbeta via the ubiquitin-proteasome pathway, resulting in remarkable inhibition of I-kappa-B-alpha (IkappaBalpha) and of p65 phosphorylation, consequently suppressing NF-kappaB activity." SIGNOR-272253 BAD protein Q92934 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" binding 9606 BTO:0002552 17000778 t lperfetto "We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis" SIGNOR-149815 CSNK1A1 protein P48729 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 t llicata "Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. " SIGNOR-250794 FOXO6 protein A8MYZ6 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 21798082 f lperfetto "Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome." SIGNOR-236560 SRC protein P12931 UNIPROT GAK protein O14976 UNIPROT "up-regulates activity" phosphorylation Tyr412 KGDLDISyITSRIAV -1 28135906 t miannu "GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149." SIGNOR-263197 SPI1 protein P17947 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 20861919 f irozzo "In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation." SIGNOR-256085 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr185 KQCEQAVyQTILEED 10090 BTO:0000938 11279201 t lperfetto "Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons." SIGNOR-247072 SIRT7 protein Q9NRC8 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" deacetylation Lys38 PATGGVKkPHRYRPG 30653310 t lperfetto "Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37." SIGNOR-275882 EEF1A1 protein P68104 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269520 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163784 MAPK1 protein P28482 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t "We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction" SIGNOR-259920 PRKAA1 protein Q13131 UNIPROT GBF1 protein Q92538 UNIPROT down-regulates phosphorylation Thr1337 GKIHRSAtDADVVNS 9606 SIGNOR-C15 18063581 t lperfetto "These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration." SIGNOR-159639 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" cleavage Ile1512 KEFNPLViVGLSKDG -1 9242537 t lperfetto "Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex." SIGNOR-263633 HDAC1 protein Q13547 UNIPROT FSHR protein P23945 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23086931 f miannu "Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment." SIGNOR-254225 ERBB4 protein Q15303 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-252674 SLBP protein Q14493 UNIPROT H2AC4 protein P04908 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265397 ACLY protein P53396 UNIPROT "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "down-regulates quantity by destabilization" "chemical modification" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-268081 EIF2AK3 protein Q9NZJ5 UNIPROT OGT protein O15294 UNIPROT "up-regulates activity" phosphorylation 9606 33592173 t miannuccelli "Collectively, these results indicate that upon cold and \u03b2-adrenergic stimulation PERK-activated OGT catalyzes the O-GlcNAcylation of CK2\u03b1 and TOM70 which enhances MIC19 import into the mitochondria increasing cristae formation and cell respiration (Figure 7I).|Here, we report that the ER-resident kinase PERK is activated upon cold or \u03b2-adrenergic stimulation and directly phosphorylates OGT." SIGNOR-279736 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni "Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability." SIGNOR-157085 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRB3 protein P79483 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 t miannu "Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination." SIGNOR-271408 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-74823 HECTD3 protein Q5T447 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 28636940 t miannu " By western blot, we observed robust degradation of endogenous native CRAF in untransformed HEK293 cells treated with control siRNA 24 hr after the addition of AUY922, but this was substantially reduced in cells in which HECTD3 was knocked down, confirming that endogenous CRAF is a bona fide degradation target of HECTD3 " SIGNOR-272328 MUL1 protein Q969V5 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity" ubiquitination 9606 26018823 t miannu "MUL1 promotes ubiquitination of ULK1.|Overexpression of MUL1 and treatment with selenite promotes ULK1 degradation through the proteasome pathway." SIGNOR-278759 ADRA1D protein P25100 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257080 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120100 PRKAB1 protein Q9Y478 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition" SIGNOR-173044 ATM protein Q13315 UNIPROT UCHL3 protein P15374 UNIPROT "up-regulates activity" phosphorylation Ser75 EEEEKIKsQGQDVTS 27941124 t lperfetto "The deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. |Mutation of S75 (S75A) abolished the pSQ/TQ signal, suggesting that S75 is a major ATM phosphorylation site following DNA damage" SIGNOR-275910 MAPK9 protein P45984 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni "Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset." SIGNOR-164093 FUS protein P35637 UNIPROT GRIA4 protein P48058 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262806 CSNK1A1 protein P48729 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Ser159 GIPVRCYsAEVVTLW -1 10500146 t miannu "We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2." SIGNOR-275966 PICK1 protein Q9NRD5 UNIPROT GRIA2 protein P42262 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 25784538 t miannu "RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above." SIGNOR-264046 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr8 MPPYTVVyFPVRGRC 9606 BTO:0000150 19254954 t llicata "Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly," SIGNOR-184387 "A4/b7 integrin" complex SIGNOR-C187 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257728 RIPK4 protein P57078 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" phosphorylation Ser298 DGGIYIGsIMKGGAV 9606 23371553 t miannuccelli "Co-transfection of a RIPK4-GFP fusion increased the percentage of cells containing DVL2 puncta to more than 75% ( and ), suggesting that RIPK4 facilitates DVL2 signalosome formation.|Phosphorylation of DVL2 at Ser 298 and Ser 480 by RIPK4 favored canonical Wnt signaling." SIGNOR-279756 TLX1 protein P31314 UNIPROT RB1 protein P06400 UNIPROT "down-regulates activity" binding 9606 BTO:0000661 15897879 t 2 miannu "ectopic HOX11 expression resulted in hyperphosphorylation of the retinoblastoma protein (Rb), which correlated with inhibition of the major Rb serine/threonine phosphatase PP1." SIGNOR-240725 UBE2E2 protein Q96LR5 UNIPROT RNF19B protein Q6ZMZ0 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 16709802 t miannu "We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and" SIGNOR-271592 NOTCH1 protein P46531 UNIPROT TCFL5 protein Q9UL49 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f gcesareni "Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene." SIGNOR-149807 EPAS1 protein Q99814 UNIPROT KDM7A protein Q6ZMT4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271587 RARA protein P10276 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "up-regulates activity" binding 9606 15650024 t "inferred from family member" gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-267801 simvastatin chemical CHEBI:9150 ChEBI HMGCR protein P04035 UNIPROT "down-regulates activity" "chemical inhibition" -1 1433193 t miannu "Substitution of hydroxy and hydroxyalkyl functionality at C-7 of the hexahydronaphthalene nucleus of simvastatin has provided novel analogs. The synthetic strategy employed epoxidation or Lewis acid-catalyzed aldol reaction of the 8-keto silyl enol ether as a key reactive intermediate. These analogs were evaluated as potential hypocholesterolemic agents via initial determination of their ability to inhibit HMG-CoA reductase in vitro." SIGNOR-258348 "BRCA1-BARD1 complex" complex SIGNOR-C297 SIGNOR H4C1 protein P62805 UNIPROT "up-regulates activity" ubiquitination -1 12485996 t lperfetto "Strikingly, as well as H2AX, the nucleosome core histones H2A, H2B, H3 and H4 were all ubiquitylated efficiently by BRCA1/BARD1, while the linker histone H1 was not (Figure 3).| Generally, histone proteins are required for compaction of nuclear DNA into chromatin, and their modification is thought to loosen this compaction. Therefore, one might envisage that ubiquitylation of γH2AX by BRCA1/BARD1 at DNA breaks modulates local chromatin packaging to facilitate the action of DNA repair enzymes." SIGNOR-263234 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" dephosphorylation Tyr292 DTLNSDGyTPEPARI -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254732 ATM protein Q13315 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates phosphorylation Ser387 SDDSRTAsQLDEFQE 9606 16931761 t lperfetto "Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism" SIGNOR-149082 CSF2RB protein P32927 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "form complex" binding 9606 BTO:0000876 BTO:0001103 9680354 t apalma "The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors." SIGNOR-255583 GNG12 protein Q9UBI6 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 t gcesareni "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin." SIGNOR-252681 MAP3K7 protein O43318 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates phosphorylation 9606 9480845 t gcesareni "Overexpression oftak1together with its activator protein,tak1binding protein 1 (tab1), induced thenucleartranslocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene." SIGNOR-55719 PTGFR protein P43088 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256953 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000562 17075052 t gcesareni "The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment." SIGNOR-150347 HTR2C protein P28335 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256877 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1125 APSRDPHyQDPHSTA 9606 8845374 t lperfetto "The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site" SIGNOR-44247 MAPK1 protein P28482 UNIPROT CTNND1 protein O60716 UNIPROT "down-regulates activity" phosphorylation Thr906 SLDNNYStPNERGDH 9615 BTO:0000837 32010791 t miannu " Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation." SIGNOR-277505 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1A protein P35348 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258462 MMP2 protein P08253 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates cleavage 9606 10652271 t gcesareni "We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-beta (tgf-beta), which constitutes a novel mechanism of tgf-beta activation" SIGNOR-74384 PMP22 protein Q01453 UNIPROT ITGA6 protein P23229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21518455 f Regulation miannu "Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression." SIGNOR-251897 SPI1 protein P17947 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR "up-regulates activity" 10090 BTO:0000725 8079170 f "Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor." SIGNOR-259954 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser107 NPMRRIHsLPQKLLG 9606 BTO:0002181 34363019 t miannu "Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. " SIGNOR-276738 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-118861 PIK-90 chemical CID:6857685 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206226 GRB10 protein Q13322 UNIPROT IGF1R protein P08069 UNIPROT down-regulates binding 9606 21659604 t gcesareni "Grb10 negatively regulates growth factor signaling. It binds the insulinand insulin-like growth factor 1 (igf-1) receptors, and mice without grb10 are larger and exhibit enhanced insulin sensitivity" SIGNOR-174062 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273144 KIT protein P10721 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS -1 21135090 t "KIT is responsible for the permanent phosphorylation of all three STAT proteins. STAT1, -3, and -5 were phosphorylated on their activation-specific Tyr701, Tyr704, and Tyr694, respectively, following KIT stimulation." SIGNOR-251365 SMARCA4 protein P51532 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18234970 f miannu "An increased association of the chromatin remodeling factor, Brg-1, to the ABCG2 promoter was observed consistently in S1 and H460 cells where ABCG2 expression was activated by romidepsin treatment" SIGNOR-255150 SRC protein P12931 UNIPROT JUP protein P14923 UNIPROT "up-regulates activity" phosphorylation Tyr644 RNEGTATyAAAVLFR 9606 14517306 t lperfetto "Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcriptionFor instance, Src, which mainly phosphorylates Tyr86 in beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin." SIGNOR-247310 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT "up-regulates activity" phosphorylation Ser558 GSSQGRNsPAPAVTA 10090 BTO:0000964 34048556 t lperfetto "Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity." SIGNOR-268343 HACE1 protein Q8IYU2 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates quantity" ubiquitination Lys147 PQGLAMAkEIGAVKY 9606 23864022 t miannu "GTP-bound Rac1 is ubiquitylated by Hace1 at lysine (K)-147 (ref. xref ).|This indicates that Hace1 binds and targets Rac1 once the latter has been recruited to the complex." SIGNOR-278810 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT "up-regulates activity" phosphorylation Tyr37 LINLGKNyEKAVNAM -1 21840312 t miannu "Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility." SIGNOR-263041 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser231 KSNIVLLsAEEKKEQ 9606 BTO:0000776 7678037 t llicata "These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-251011 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr31 GGGSMGDyMAQEDDW 9606 23454549 t lperfetto "Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin" SIGNOR-192195 ULK1 protein O75385 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates phosphorylation 9606 21460634 t lperfetto "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity." SIGNOR-217484 ATM protein Q13315 UNIPROT BID protein P55957 UNIPROT "down-regulates activity" phosphorylation 9606 23069655 t lperfetto "Taken together, these results are consistent with the idea that at low levels of DNA damage ATM phosphorylates Bid to keep it away from the mitochondria resulting in low levels of ROS.|Thus, Bid accumulation at the mitochondria, which is negatively regulated by ATM, triggers a metabolic change in mitochondria that includes an increase in ROS and perhaps changes in other metabolites that signal back to the nucleus to regulate gene transcription leading to cell cycle progression (XREF_FIG)." SIGNOR-279790 MAPK14 protein Q16539 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" phosphorylation Ser87 AAAGPALsPVPPVVH 9606 19336399 t gcesareni "The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38mapk" SIGNOR-184936 Ub:E2 complex SIGNOR-C497 SIGNOR SHPRH protein Q149N8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271119 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269373 MAPK8 protein P45983 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 15538382 t lperfetto "Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment." SIGNOR-130385 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp78 PNVVAARdVPEGMQN 9606 11741536 t gcesareni "Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis." SIGNOR-256434 DLG4 protein P78352 UNIPROT "Postsynaptic density assembly" phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 17243894 f miannu "PSD-95 (the best-studied scaffold protein of the PSD, which binds to NR2 subunits of NMDA receptors) was found to be highly abundant in the adult forebrain PSD" SIGNOR-264230 CASK protein O14936 UNIPROT TBR1 protein Q16650 UNIPROT up-regulates binding 9534 BTO:0000298 10749215 t miannu "Here we report that, through its guanylate kinase domain, CASK interacts with Tbr-1, a T-box transcription factor that is involved in forebrain development. CASK enters the nucleus and binds to a specific DNA sequence (the T-element) in a complex with Tbr-1. CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development." SIGNOR-266835 IL12B protein P29460 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 7527811 t fspada "Characterization of the p40 proteins for binding and bioactivity showed that both the p40 monomer and dimer inhibited 125i-labeled il-12 binding to il-12r, but the 80-kda species, having a 50% inhibitory concentration (ic50) of 20 to 70 ng/ml, was at least 20-fold more effective than the monomer. The results suggest that the il-12 p40 subunit contains the essential epitopes for receptor binding." SIGNOR-27690 ILK protein Q13418 UNIPROT MYL12B protein O14950 UNIPROT "up-regulates activity" phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 11278951 t lperfetto "Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19).Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activa" SIGNOR-106427 MYC protein P01106 UNIPROT HNRNPA1 protein P09651 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20010808 t "We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2," SIGNOR-268690 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT "up-regulates activity" phosphorylation Ser45 LGIRSSKsAGALEEG 9606 BTO:0002524 30631047 t miannu "Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Function assay of ARMC10 and ARMC10 phosphorylation at S45." SIGNOR-277806 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT "up-regulates activity" relocalization 9606 23119004 t lperfetto "Binding of igf to igf-ir activates pi3k to generate pip3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including akt and pdk1." SIGNOR-252642 ruxolitinib chemical CHEBI:66919 ChEBI JAK1 protein P23458 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258276 TGFB1 protein P01137 UNIPROT SLC5A5 protein Q92911 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14623893 f miannu "The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression" SIGNOR-259912 PAMPs stimulus SIGNOR-ST11 SIGNOR MPO-ANCA complex SIGNOR-C474 SIGNOR "up-regulates quantity" 9606 BTO:0000133 15972951 f lperfetto "In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. |using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus." SIGNOR-270586 SLC36A1 protein Q7Z2H8 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI "up-regulates quantity" relocalization 9606 12748860 t lperfetto "Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut." SIGNOR-264739 MAPK9 protein P45984 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 t llicata "These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells." SIGNOR-115835 AKT1 protein P31749 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 12588998 t gcesareni "Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro" SIGNOR-265320 SNX9 protein Q9Y5X1 UNIPROT EGFR protein P00533 UNIPROT down-regulates 9606 11799118 f gcesareni "We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation." SIGNOR-114167 LAS1L protein Q9Y4W2 UNIPROT "Rix1 complex" complex SIGNOR-C373 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22190735 t miannu "LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes." SIGNOR-265467 paclitaxel chemical CHEBI:45863 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" "chemical inhibition" 9606 28298489 t miannu "Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a ""pseudo"" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap." SIGNOR-259449 POU5F1 protein Q01860 UNIPROT LEFTY2 protein O00292 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254940 PP1 proteinfamily SIGNOR-PF54 SIGNOR PYG proteinfamily SIGNOR-PF96 SIGNOR "down-regulates activity" dephosphorylation 9606 BTO:0002049 22225877 t "GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation" SIGNOR-267961 TFAP2A protein P05549 UNIPROT CRABP2 protein P29373 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002828 17187826 f miannu "Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16." SIGNOR-255400 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT "down-regulates activity" monoubiquitination Lys686 HQGKRNPkSPLACTN 9606 21791603 t miannu "Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709)." SIGNOR-272731 SUZ12 protein Q15022 UNIPROT SUZ12/EED complex SIGNOR-C76 SIGNOR "form complex" binding 9606 16712789 t miannu "Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2." SIGNOR-146761 BLK protein P51451 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000776 32323266 t scontino "The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases." SIGNOR-268214 CHEK1 protein O14757 UNIPROT E2F7 protein Q96AV8 UNIPROT "down-regulates activity" phosphorylation 9606 29363506 t miannu "Chk1 inhibits the transcriptional repressor function of E2F7 and E2F8 to promote cell cycle progression and prevent apoptosis.|Here, we demonstrate that Chk1 phosphorylates both E2F7 and E2F8 in response to DNA damage." SIGNOR-279692 "Pituitary adenylate cyclase-activating peptide-27" smallmolecule CHEBI:80303 ChEBI ADCYAP1R1 protein P41586 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257445 HIPK1 protein Q86Z02 UNIPROT PAGE4 protein O60829 UNIPROT "up-regulates activity" phosphorylation Thr51 PGQEREGtPPIEERK 9606 24559171 t Manara "Here, we have identified homeodomain-interacting protein kinase 1 (HIPK1), also a component of the stress-response pathway, as a kinase that phosphorylates PAGE4 at T51 | We show that phosphorylation of PAGE4 is critical for its transcriptional activity since mutating this T residue abolishes its ability to potentiate c-Jun transactivation." SIGNOR-260929 hsa-miR-129-1-3p mirna URS00004CCDA3_9606 RNAcentral BDKRB2 protein P30411 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003878 25008064 t Parnian "Expression of BDKRB2 was negatively related to miR-129-1-3p. Luciferase reporter assay showed that BDKRB2 was the target of the miR-129-1-3p. In summary, miR-129-1-3p inhibits the BGC-823 cell migration by targeting BDKRB2." SIGNOR-278003 TLN1 protein Q9Y490 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257628 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 20110348 t gcesareni "Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a." SIGNOR-163680 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2L6 protein O14933 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271353 ECSIT protein Q9BQ95 UNIPROT MAVS protein Q7Z434 UNIPROT "up-regulates activity" binding 9606 22588174 t Giorgia "ECSIT interacts with IPS-1|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation" SIGNOR-260371 ABL1 protein P00519 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 23383209 t miannu "Previously, we showed that c-Abl and Arg promote phosphorylation of the STAT3 transcription factor (Y705) in a variety of cancer cell lines , .|Since c-Abl and Arg activate STAT3, we investigated whether c-Abl and Arg regulate NF-kappaB signaling." SIGNOR-279675 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 14976552 t lperfetto "We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli" SIGNOR-217472 LMTK2 protein Q8IWU2 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12393858 t gcesareni "Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity." SIGNOR-94631 HMGA2 protein P52926 UNIPROT CCNA2 protein P20248 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14645522 f miannu "Transcriptional activation of the cyclin a gene by the architectural transcription factor hmga2" SIGNOR-119496 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257915 Alkannin chemical CHEBI:2578 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000093;BTO:0000018 21516121 t "inferred from family member" lperfetto "Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2." SIGNOR-270284 SPOP protein O43791 UNIPROT DEK protein P35659 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E)." SIGNOR-272826 "Elongator complex" complex SIGNOR-C466 SIGNOR TUBA3D protein P0DPH8 UNIPROT "up-regulates activity" acetylation 9606 BTO:0000007 19185337 t miannu "Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. α-Tubulin Acetylation Promotes Radial Migration and Branching of Cortical Projection Neurons" SIGNOR-269715 SCN8A protein Q9UQD0 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253406 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GRIP1 protein Q9Y3R0 UNIPROT "up-regulates activity" phosphorylation Ser734 SLKGKPLsEAIHLLQ -1 11301320 t miannu "Here we show that epidermal growth factor regulates the activities of the p160 GRIP1 through the extracellular signal-regulated kinase (ERK) family of mitogen-activated protein kinases. ERKs phosphorylate GRIP1 at a specific site, Ser-736, the integrity of which is required for full growth factor induction of GRIP1 transcriptional activation and coactivator function." SIGNOR-263056 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763 12193595 t miannu "Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction." SIGNOR-91726 MDM2 protein Q00987 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001109 10640274 t miannu "We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation." SIGNOR-271385 "CHIR 99021" chemical CHEBI:91091 ChEBI GSK3A protein P49840 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190997 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRA protein P01903 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys244 FIIKGLRkSNAAERR 9606 19117940 t miannu "Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination." SIGNOR-271412 CXCL1 protein P09341 UNIPROT CXCR2 protein P25025 UNIPROT "up-regulates activity" binding 9606 38309677 t miannu "CXCL1 produces cellular chemotactic activity by binding to the CXC chemokine receptor 2 (CXCR2). In PC, this chemokine has been associated with a variety of carcinogenic mechanisms, including oncogene-induced senescence (OIS), angiogenesis, cancer metastasis, and immunosuppressive microenvironments " SIGNOR-277717 TNFRSF10B protein O14763 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 t amattioni "Fadd binds to ligated trailr1 or trail-r2" SIGNOR-98565 MAP3K7 protein O43318 UNIPROT RAB8A protein P61006 UNIPROT "up-regulates activity" phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 t lperfetto "In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease" SIGNOR-260266 UCHL5 protein Q9Y5K5 UNIPROT "INO80 complex" complex SIGNOR-C498 SIGNOR "form complex" binding 9606 25016522 t miannu "Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication." SIGNOR-270852 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000478 26214522 f Luana " We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models." SIGNOR-264552 CASP1 protein P29466 UNIPROT "NLRP3 inflammasome" complex SIGNOR-C225 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256409 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto "We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein." SIGNOR-216957 UBC protein P0CG48 UNIPROT PRKN protein O60260 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 26161729 t lperfetto "Mechanism of phospho-ubiquitin-induced PARKIN activation|PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN|Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator." SIGNOR-249692 KDM1A protein O60341 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 28720390 f gianni "The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia." SIGNOR-268728 (R)-carnitine smallmolecule CHEBI:16347 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI "up-regulates quantity" "precursor of" 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267118 SRC protein P12931 UNIPROT SLC6A4 protein P31645 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr47 SGQISNGySAVPSPG 10116 BTO:0000132 21992875 t miannu "We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT. " SIGNOR-276385 F9 protein P00740 UNIPROT F7 protein P08709 UNIPROT "up-regulates activity" cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 t lperfetto "The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa." SIGNOR-263522 MAPK1 protein P28482 UNIPROT IL16 protein Q14005 UNIPROT up-regulates phosphorylation Ser845 SIRQRISsFETFGSS 9606 14768064 t lperfetto "The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response." SIGNOR-121852 CDK1 protein P06493 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr176 HLFGFPPtPPKEVSP 9606 BTO:0000007 25670854 t miannu "GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1). " SIGNOR-276884 LEF1 protein Q9UJU2 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19620402 f miannu "We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPalpha." SIGNOR-254551 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser201 PLQRQPSsPGPTPRN 9606 BTO:0001103 10212242 t lperfetto "Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates." SIGNOR-67065 MDC1 protein Q14676 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19230643 t gcesareni "Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1." SIGNOR-184141 PRKACA protein P17612 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Thr316 GTASSRKtLWNQELY -1 21880142 t miannu "PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266308 FZD2 protein Q14332 UNIPROT DVL3 protein Q92997 UNIPROT "up-regulates activity" binding 9606 23151663 t areggio "Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. " SIGNOR-258962 ANAPC5 protein Q9UJX4 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252005 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr3 tSQKHRDF 9606 16495336 t gcesareni "We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell" SIGNOR-144791 NR0B2 protein Q15466 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 9606 11368516 f "inferred from family member" gcesareni "Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation." SIGNOR-270298 GABBR1 protein Q9UBS5 UNIPROT "GABA-B receptor" complex SIGNOR-C336 SIGNOR "form complex" binding 9606 BTO:0000007 9872316 t brain lperfetto "Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2." SIGNOR-263742 PRKACA protein P17612 UNIPROT DYNLRB1 protein Q9NP97 UNIPROT up-regulates phosphorylation Ser73 LTFLRIRsKKNEIMV 9606 23333499 t llicata "Our results show that km23-1 is required for camp-responsive element (cre) transcriptional activation by tgf_, with s73-km23-1 being required for the cre-dependent tgf_ stimulation of fibronectin (fn) transcription." SIGNOR-200456 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR ACTA1 protein P68133 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136175 NFATC4 protein Q14934 UNIPROT PTGS2 protein P35354 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21871017 t miannu "NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration" SIGNOR-264027 PTPRG protein P23470 UNIPROT SHC1 protein P29353 UNIPROT "down-regulates activity" dephosphorylation Tyr349 EEPPDHQyYNDFPGK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254723 UQCRB protein P14927 UNIPROT "CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262194 PYGB protein P11216 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI "down-regulates quantity" "chemical modification" 9606 3346228 t "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267395 APP protein P05067 UNIPROT GSK3A protein P49840 UNIPROT up-regulates 9606 BTO:0000938 16446437 f gcesareni "These results suggest a direct relationship between app proteolytic processing, but not amyloid-_, in gsk-3_ activation and tau phosphorylation in human neurons." SIGNOR-144057 CCR5 protein P51681 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 20219869 t areggio "The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2." SIGNOR-255119 PRKCZ protein Q05513 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser177 AKELDQGsLCTSFVG 9606 10022904 t lperfetto "Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation." SIGNOR-249015 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A13 protein Q9NSD5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207066 Hypoxia stimulus SIGNOR-ST25 SIGNOR NPTX1 protein Q15818 UNIPROT up-regulates 10090 BTO:0000938 15115814 f lperfetto "We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death." SIGNOR-261431 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4523 GSRHSLAsTDEKREL 9606 15272003 t lperfetto "Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc." SIGNOR-127211 DDR1 protein Q08345 UNIPROT DDR1 protein Q08345 UNIPROT "up-regulates activity" phosphorylation Tyr513 LLLSNPAyRLLLATY 9606 BTO:0000007;BTO:0000356 9659899 t llicata "The discoidin domain receptor tyrosine kinases are activated by collagen | Here, we present evidence that stimulating DDR1- and DDR2-expressing cells with various types of collagen induces receptor autophosphorylation." SIGNOR-251086 CDC7 protein O00311 UNIPROT MCM7 protein P33993 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni "We propose that phosphorylation of mcm4/6 s/tp sites, which are already phosphorylated in g1, allows initial mcm2-7 phosphorylation by ddk and initiation from the first origins of replication ( fig. 7ai )." SIGNOR-169506 PRKACA protein P17612 UNIPROT CAPN2 protein P17655 UNIPROT down-regulates phosphorylation Thr370 GNWRRGStAGGCRNY 9606 11909964 t llicata "Activation of m-calpain (calpain ii) by epidermal growth factor is limited by protein kinase a phosphorylation of m-calpain.These Data point to a novel mechanism of negative control of calpain activation, direct phosphorylation by pka." SIGNOR-116248 SLBP protein Q14493 UNIPROT H2BC1 protein Q96A08 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265393 DLG1 protein Q12959 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" binding 9606 BTO:0000782 17187070 t Barakat "Dlgh1 immunoprecipitates were specifically enriched for activated p38 phosphorylated at Thr180 and Tyr182; phosphorylated p38 was not detected in the unbound fraction from stimulated samples" SIGNOR-274143 ZNF774 protein Q6NX45 UNIPROT "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR "up-regulates activity" binding 9606 BTO:0000578 31659254 t miannu "Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription." SIGNOR-265558 BTRC protein Q9Y297 UNIPROT NFKBIB protein Q15653 UNIPROT "down-regulates quantity by destabilization" binding 9534 BTO:0004055 10514424 t miannu "Interaction with beta-TrCP is also necessary for ubiquitination of IkappaBbeta upon stimulation of cells, and deletion of the F-box in beta-TrCP abolishes its ability to ubiquitinate IkappaBbeta. Therefore, these results indicate that beta-TrCP plays a critical role in the activation of NF-kappaB by assembling the ubiquitin ligase complex for both phosphorylated IkappaBalpha and IkappaBbeta.β-TrCP recognizes IκBα phosphorylated at Ser-32 and Ser-36 through its WD40 domain, whereas the F-box motif recruits additional proteins including Skp1 and Cullin to form the Skp1-cullin-F-box (SCF) ubiquitin ligase complex" SIGNOR-272554 MAPK3 protein P27361 UNIPROT PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation Ser12 ESPLCPLsPLEAGDL 9606 10187842 t lperfetto "We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution." SIGNOR-249473 KANSL1 protein Q7Z3B3 UNIPROT "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR "form complex" binding 9606 BTO:0000007 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex." SIGNOR-267164 KIF5B protein P33176 UNIPROT GABBR1 protein Q9UBS5 UNIPROT "up-regulates activity" relocalization 10090 17532644 t SARA "GABABR1 co-immunoprecipitated with Marlin-1 and kinesin-I, providing evidence for the existence of a complex between these proteins. Kinesin-I modulates GABAB receptor transport." SIGNOR-260990 PEX12 protein O00623 UNIPROT UBE2D1 protein P51668 UNIPROT "up-regulates activity" binding -1 19687296 t miannu "Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle." SIGNOR-253024 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1110 GSVQNPVyHNQPLNP 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-236516 JUN protein P05412 UNIPROT SERPINA3 protein P01011 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002600 11027208 f miannu "We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1." SIGNOR-254808 RGMA protein Q96B86 UNIPROT NEO1 protein Q92859 UNIPROT "down-regulates activity" binding 10090 18485097 t miannu "Netrin-1-neogenin interactions mediate chemoattractive axon guidance, while RGMa-neogenin interactions repel axons. " SIGNOR-268388 ETS1 protein P14921 UNIPROT VWF protein P04275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9444957 f miannu "Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells." SIGNOR-253915 TAF3 protein Q5VWG9 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263930 BMI1 protein P35226 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20551323 f gcesareni "One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf" SIGNOR-259359 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR SLBP protein Q14493 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr62 RRPESFTtPEGPKPR 9606 BTO:0000567 18490441 t lperfetto "Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase" SIGNOR-265259 NFE2 protein Q16621 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000426 16287851 f "Regulation of expression" miannu "NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells." SIGNOR-251839 MAFA protein Q8NHW3 UNIPROT NKX6-1 protein P78426 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17149590 f miannu "the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA." SIGNOR-254564 ECM stimulus SIGNOR-ST20 SIGNOR "AD/b2 integrin" complex SIGNOR-C172 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259055 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser301 SSSPNNLsPTGWSQP 10090 BTO:0000944 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-249443 CASP6 protein P55212 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto "In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329." SIGNOR-261745 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-252319 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Ser311 EYTIKSHsSLPPNNS 9606 15611134 t lperfetto "Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311." SIGNOR-132455 DICER1 protein Q9UPY3 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR "form complex" binding 9606 23661684 t miannu SIGNOR-143105 PLCG1 protein P19174 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 12645577 t gcesareni "Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199." SIGNOR-99310 PTPRG protein P23470 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" dephosphorylation Tyr413 TAPESLAyNKFSIKS -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254691 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser44 ESEESQDsSDSIGSS 9606 20730097 t lperfetto "We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf4" SIGNOR-167572 CENPC protein Q03188 UNIPROT "CENP-A nucleosome" complex SIGNOR-C321 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 20566683 t miannu "CENP-C is required for centromere assembly. CENP-C and CENP-N bind to different sites on the same CENP-A nucleosomes. CENP-C, like CENP-N, interacts directly and specifically with CENP-A nucleosomes." SIGNOR-263706 PKA proteinfamily SIGNOR-PF17 SIGNOR DNM1L protein O00429 UNIPROT "down-regulates activity" phosphorylation Ser637 VPVARKLsAREQRDC -1 31063459 t lperfetto "For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission" SIGNOR-262551 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser636 SGDYMPMsPKSVSAP 10090 15306821 t lperfetto "Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin." SIGNOR-127912 OAT protein P04181 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "down-regulates quantity" "chemical modification" 9606 14617280 t miannu "Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)" SIGNOR-256032 "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "glycerone phosphate(2-)" smallmolecule CHEBI:57642 ChEBI "up-regulates quantity" "precursor of" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-268075 CAMK4 protein Q16566 UNIPROT NOS1 protein P29475 UNIPROT "down-regulates activity" phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 t llicata "It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation." SIGNOR-250713 "NMDA receptor_2A" complex SIGNOR-C347 SIGNOR DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11052931 t miannu "Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor" SIGNOR-264222 EPAS1 protein Q99814 UNIPROT KDM4B protein O94953 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271584 MKNK1 protein Q9BUB5 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Ser121 VSSGSRSsTRTSTSS 9606 19864419 t llicata "The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability." SIGNOR-188893 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC1 protein Q96A08 UNIPROT "down-regulates activity" monoubiquitination Lys36 KKRKRTRkESYSIYI 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271992 GABRD protein O14764 UNIPROT "GABA-A (a4-b2-d) receptor" complex SIGNOR-C326 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263746 PRKD1 protein Q15139 UNIPROT KAT7 protein O95251 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr331 LRLQGQItEGSNMIK 9606 BTO:0002181 33014433 t miannu "We show that PKD1 directly interacts and phosphorylates KAT7 at Thr97 and Thr331 in vitro and in vivo. PKD1-mediated phosphorylation of KAT7 enhances its expression levels and stability by reducing its ubiquitination-mediated degradation. " SIGNOR-277828 ULK2 protein Q8IYT8 UNIPROT FBP1 protein P09467 UNIPROT "down-regulates activity" phosphorylation Ser63 HLYGIAGsTNVTGDQ 9606 BTO:0000007 27153534 t done miannu "Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown)." SIGNOR-274040 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" sumoylation Lys594 GNWRGMLKTSKAEEL 9606 BTO:0000007 19638400 t Barakat "Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms." SIGNOR-274128 PRKCA protein P17252 UNIPROT F3 protein P13726 UNIPROT up-regulates phosphorylation Ser285 RKAGVGQsWKENSPL 9606 23195225 t lperfetto "We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. The phosphorylation of ser253 is known to be mediated by protein kinase c_" SIGNOR-199872 FBXW8 protein Q8N3Y1 UNIPROT "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR "up-regulates activity" binding 9606 BTO:0001109 17205132 t miannu "FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1. We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8." SIGNOR-271631 MARK2 protein Q7KZI7 UNIPROT KIF13B protein Q9NQT8 UNIPROT "down-regulates activity" phosphorylation Ser1381 KLSRRSIsSPNVNRL 9534 BTO:0000298 20194617 t miannu "We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410." SIGNOR-262955 glutamine smallmolecule CHEBI:28300 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 BTO:0000567 22749528 f Luana "Leucine and Glutamine Activate Glutaminolysis and mTORC1" SIGNOR-268008 PRKCA protein P17252 UNIPROT NF2 protein P35240 UNIPROT "down-regulates activity" phosphorylation 9606 24481838 t miannu "PKC\u03b1\nnormally phosphorylates and inactivates NF2.|PKCalpha normally phosphorylates and inactivates NF2." SIGNOR-280081 "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI "up-regulates quantity" "precursor of" 10843999 t lperfetto "The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP." SIGNOR-271825 ADAM17 protein P78536 UNIPROT EREG protein O14944 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF" SIGNOR-259843 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT "up-regulates activity" phosphorylation Thr100 TNTYYLQtFGHNTMD 9606 BTO:0000007 21321328 t miannu " We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A)." SIGNOR-276311 CDC34 protein P49427 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR "up-regulates activity" binding 9606 25425648 t miannu "The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases." SIGNOR-277334 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT "up-regulates activity" phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 12817019 t lperfetto "Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase." SIGNOR-102511 CSNK1A1 protein P48729 UNIPROT BHLHE40 protein O14503 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser243 GSDTDTDsGYGGESE 9606 BTO:0002181 25202122 t miannu "CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation. " SIGNOR-276851 ADORA2B protein P29275 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257414 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna" SIGNOR-171034 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr120 QFDAAHPtNVQRLAE 9606 BTO:0001130 19141652 t lperfetto "This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity." SIGNOR-183388 arginine smallmolecule CHEBI:29016 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 BTO:0000567 27126896 f Luana " Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation." SIGNOR-268013 CCL5 protein P13501 UNIPROT CCR5 protein P51681 UNIPROT "up-regulates activity" binding 9606 BTO:0000584 38339310 t miannu "CCL5, also known RANTES (regulated on activation, normal T cell expressed and secreted), is a potent chemoattractant for a variety of leukocytes, including T cells, mono- cytes, NK cells, and basophils, signaling via the CCR1, CCR3, and CCR5 cell surface receptors [59]. Among these receptors, CCL5 has the highest affinity for CCR5." SIGNOR-277726 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248653 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates activity" phosphorylation Ser567 VLSDNDRsLLERWTR 9606 BTO:0000567 20667468 t miannu "Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803." SIGNOR-259823 CSNK2B protein P67870 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-251053 FYN protein P06241 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto "To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation." SIGNOR-249337 HCRTR1 protein O43613 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257012 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT "down-regulates activity" binding 9606 21976273 t miannu "Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS)." SIGNOR-252420 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Ser246 CPRLRIFsHPNVLPV 9606 17420447 t lperfetto "We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin." SIGNOR-154303 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates "chemical activation" 9606 23450633 t gcesareni "S1p action on yap in 293a (or hacat) cells is mediated by s1p2 rather than s1p1 or s1p3 (of ? Ve known s1p receptors) and lpa receptors 1 and 3 (of six)." SIGNOR-192117 TOMM22 protein Q9NS69 UNIPROT "TOM40 complex" complex SIGNOR-C421 SIGNOR "form complex" binding 9606 BTO:0000567 18331822 t lperfetto "The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex." SIGNOR-267679 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser129 VNTRAGPsQHSSPAV 9606 BTO:0000671 12628002 t lperfetto "Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)" SIGNOR-99127 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UHRF1 protein Q96T88 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser639 QQEGGFAsPRTGKGK -1 22411829 t miannu "Importantly, the S652ph antibody identifies phosphorylated UHRF1 in mitotic cells and consistently S652 can be phosphorylated by the M phase-specific kinase CDK1-cyclin B in vitro. UHRF1 S652 phosphorylation significantly reduces UHRF1 interaction with USP7 in vitro and in vivo, which is correlated with a decreased UHRF1 stability in the M phase of the cell cycle. In contrast, UHRF1 carrying the S652A mutation, which renders UHRF1 resistant to phosphorylation at S652, is more stable. " SIGNOR-276408 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 f "Alessandro Palma" "It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits" SIGNOR-254955 THRB protein P10828 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates activity" binding 9606 BTO:0001073 29407449 t scontino "We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2." SIGNOR-267256 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP50 protein Q9UKX7 UNIPROT "down-regulates activity" phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t llicata "Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin." SIGNOR-188131 PTPN11 protein Q06124 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t "Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B" SIGNOR-248671 AS-605240 chemical CID:5289247 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189921 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr751 SKDESVDyVPMLDMK -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248414 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR PAX7 protein P23759 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103;BTO:0002314 22493066 t lperfetto "Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells NICD regulates Pax7 through interaction with RBP-J_, which binds to two consensus sites upstream of the Pax7 gene." SIGNOR-219365 S1PR2 protein O95136 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256871 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRNB3 protein Q05901 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000227 28901280 t miannu "Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes." SIGNOR-264258 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t gcesareni "...expression of GRK4ƒŽ‚ drastically increased the basal level of32P incorporation into B2R.[ƒ‚€‚]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation." SIGNOR-249674 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 19118012 t gcesareni "Phosphorylation by activated jnk protects c-jun from ubiquitination;phosphorylation of c-jun on ser73 by jnk is sufficient to protect c-jun from ubiquitination c-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk). Phosphorylation by activated jnk protects c-jun from ubiquitination, thus by prolonging its half-life targets of the jnk signal transduction pathway include the transcription factors atf2 and c-jun apoptosis, altered;apoptosis, induced;transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts) transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts)" SIGNOR-183017 ADSS1 protein Q8N142 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI "down-regulates quantity" "chemical modification" 9606 10496970 t miannu "Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP." SIGNOR-267344 Ub:E2 complex SIGNOR-C497 SIGNOR ANAPC11 protein Q9NYG5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271110 FBXL5 protein Q9UKA1 UNIPROT NABP2 protein Q9BQ15 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25249620 t miannu "Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation. " SIGNOR-272460 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser5 sPPLRDVD 9606 SIGNOR-C17 14749395 t lperfetto "Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21." SIGNOR-121605 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT "up-regulates activity" phosphorylation Ser83 EEGTFRSsIRRLSTR -1 15621037 t miannu "PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA." SIGNOR-263117 CHRM3 protein P20309 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256739 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 t lperfetto "Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised" SIGNOR-146585 HNRNPU protein Q00839 UNIPROT NHLH2 protein Q02577 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 17174306 f lperfetto "In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs." SIGNOR-262286 EYA3 protein Q99504 UNIPROT Six1/Dach complex SIGNOR-C122 SIGNOR "up-regulates activity" dephosphorylation 10090 14628042 t llicata "The phosphatase function of Eya switches the function of Six1-Dach from repression to activation," SIGNOR-238032 RPS6KB1 protein P23443 UNIPROT PDPK1 protein O15530 UNIPROT "down-regulates activity" phosphorylation Ser549 VWRQRYQsHPDAAVQ 9606 35318320 t miannu "Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT." SIGNOR-273844 AATF protein Q9NY61 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 23146908 t "Chromatin immunoprecipitation in combination with siRNA-mediated knockdown revealed that recruitment of AATF and ZIPK to the PSA enhancer was dependent on AR, whereas recruitment of TSG101 was dependent on AATF." SIGNOR-253669 Flesinoxan chemical CID:57347 PUBCHEM HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8""5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3)." SIGNOR-258950 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT "down-regulates activity" phosphorylation Ser189 LLGVDLGsMDEEEEI 10090 BTO:0000944 14754904 t miannu "Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions." SIGNOR-262729 KDM6B protein O15054 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 f lperfetto "IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization." SIGNOR-249563 MARK4 protein Q96L34 UNIPROT MAPT protein P10636-5 UNIPROT "down-regulates activity" phosphorylation Thr231 KKVAVVRtPPKSPSS -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273932 GDNF protein P39905 UNIPROT DNM2 protein P50570 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization." SIGNOR-252173 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser1424 SYELPARsQIGQKSP 10090 29301787 t lperfetto "Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466" SIGNOR-272269 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR methionine smallmolecule CHEBI:16811 ChEBI "down-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270397 BTRC protein Q9Y297 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates ubiquitination 9606 10228155 t gcesareni "Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels." SIGNOR-67374 PRKACA protein P17612 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 t miannu "HTH1 was phosphorylated at Ser40 by PKA. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. phosphorylationof hTH1‚4 at Ser40, to a stoichiometry of up to 1.0 molphosphate per mol TH subunit, dramatically increases their binding to 14-3-3 proteins." SIGNOR-250061 FBXO6 protein Q9NRD1 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 19716789 t miannu " Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint." SIGNOR-271881 CEBPA protein P49715 UNIPROT S100A9 protein P06702 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001370 9706399 t "Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells." SIGNOR-254041 MTF1 protein Q14872 UNIPROT MCAT protein Q8IVS2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15378601 f miannu "MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase." SIGNOR-254600 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser54 QPLPPRPsPAALPGG 23871434 t lperfetto "WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85" SIGNOR-275480 SLC25A13 protein Q9UJS0 UNIPROT "aspartic acid" smallmolecule CHEBI:22660 ChEBI "up-regulates quantity" relocalization 9606 12084073 t miannu "Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane." SIGNOR-265157 LRP5 protein O75197 UNIPROT LPR5/6 complex SIGNOR-C219 SIGNOR "form complex" binding 9606 27821587 t miannu "Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands." SIGNOR-256176 NOTCH1 protein P46531 UNIPROT ZMIZ1 protein Q9ULJ6 UNIPROT "up-regulates activity" binding 10090 BTO:0001825 26522984 t miannu "The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions" SIGNOR-263937 COL21A1 protein Q96P44 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "up-regulates activity" binding 35267698 t lperfetto "Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]." SIGNOR-272347 EEF1A2 protein Q05639 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269529 "ISGF3 complex" complex SIGNOR-C124 SIGNOR EIF2AK2 protein P19525 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27712625 f miannu "The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum." SIGNOR-260158 DMD protein P11532 UNIPROT DGC complex SIGNOR-C217 SIGNOR "form complex" binding 9606 15117830 t apalma "The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink)." SIGNOR-255998 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260581 RET protein P07949 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 16153436 t gcesareni "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-140298 "oxotremorine M" chemical CHEBI:38322 ChEBI CHRM1 protein P11229 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258656 ACE protein P12821 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT "up-regulates quantity" cleavage 9606 32201502 t MIANNU "Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I" SIGNOR-260236 WIPF1 protein O43516 UNIPROT WASL protein O00401 UNIPROT "up-regulates activity" binding 9606 10878810 t lperfetto "Recruitment of N-WASP to vaccinia is mediated by WASP-interacting protein (WIP), whereas in Shigella WIP is recruited by N-WASP. Our observations show that vaccinia and Shigella activate the Arp2/3 complex to achieve actin-based motility, by mimicking either the SH2/SH3-containing adaptor or Cdc42 signalling pathways to recruit the N-WASP-WIP complex." SIGNOR-261880 ASPG protein Q86U10 UNIPROT "L-asparagine zwitterion" smallmolecule CHEBI:58048 ChEBI "down-regulates quantity" "chemical modification" 9606 24657844 t miannu "Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia." SIGNOR-267537 DCAF15 protein Q66K64 UNIPROT RBM39 protein Q14498 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001109 31819272 t miannu "Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation." SIGNOR-272203 PBK protein Q96KB5 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16982762 t gcesareni "Pbk/topk could phosphorylate histone h3 at ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone h3 modification." SIGNOR-265364 PRKAA1 protein Q13131 UNIPROT HIPK2 protein Q9H2X6 UNIPROT "up-regulates activity" phosphorylation Ser121 LMRRSTVsLLDTYQK -1 23871434 t miannu "These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J)." SIGNOR-276467 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15306821 t lperfetto "Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulates insulin." SIGNOR-127904 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation 9606 20230789 t "inferred from 70% family members" lperfetto "Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity" SIGNOR-270203 SRF protein P11831 UNIPROT NKX3-1/SRF complex SIGNOR-C25 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001260 10993896 t lperfetto "A novel complex element containing a juxtaposed nkx-binding site (nke) and an srf-binding element (sre) in the proximal promoter region was found to be necessary for the nkx3-1/srf coactivation of smga transcription." SIGNOR-82090 GAMT protein Q14353 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR up-regulates -1 26319512 f Luana "GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system" SIGNOR-265794 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni "A dominant-negative mutant of high cell density-enhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation." SIGNOR-101279 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257500 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" binding 9606 BTO:0001938;BTO:0000567 25784705 t SARA "PKR directly interacts with G3BP1 through the NTF2-like and PXXP domains of G3BP1. The recruitment of inactive PKR to SGs through this interaction correlates with its activation" SIGNOR-260981 BBS7 protein Q8IWZ6 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262556 indometacin chemical CHEBI:49662 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" -1 9057869 t miannu "Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM)." SIGNOR-258606 FGF13 protein Q92913 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253411 Shikonin chemical CHEBI:81068 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000093;BTO:0000018 21516121 t "inferred from family member" lperfetto "Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2." SIGNOR-270289 WASL protein O00401 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 20498093 t lperfetto "Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes." SIGNOR-261003 PPP2CB protein P62714 UNIPROT MYC protein P01106 UNIPROT down-regulates dephosphorylation Ser62 LLPTPPLsPSRRSGL 9606 16987807 t esanto "Phosphorylation at ser-62 by pro-directed kinases (p-k) is a prerequisite for gsk3-dependent phosphorylation of thr-58. This triggers binding of pin1, subsequently protein phosphatase 2a (pp2a)-dependent dephosphorylation of ser-62, and then recruitment of scf-fbw7 to the thr-58-phosphorylated myc. Scf-fbw7 polyubiquitinylates myc (branching through lys-48), leading to its proteasomal degradation." SIGNOR-149726 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" phosphorylation Ser282 NSLQRVPsYDSFDSE BTO:0003637 12475968 t llicata "Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1 " SIGNOR-250686 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" "chemical inhibition" 25309440 t "inferred from 70% of family members" lperfetto "Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway." SIGNOR-269849 IGF1 protein P05019 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 17200203 f "Regulation of expression" miannu "Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts" SIGNOR-251862 AKT proteinfamily SIGNOR-PF24 SIGNOR CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 t lperfetto "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-244210 GART protein P22102 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI "down-regulates quantity" "chemical modification" 9606 34283828 t miannu "In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR)." SIGNOR-267298 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." SIGNOR-244251 Ub:E2 complex SIGNOR-C497 SIGNOR UBR5 protein O95071 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271299 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT "up-regulates activity" phosphorylation Ser1773 AAHGKRPsIGNLEHV -1 19074150 t miannu "We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry." SIGNOR-263109 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159365 CEBPB protein P17676 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 15044620 f miannu "C/EBPbeta activates the endogenous MDR1 gene of MCF-7 cells, and this activation was associated with a novel C/EBPbeta interaction region within the proximal MDR1 promoter (-128 to -75)." SIGNOR-253771 XBP1 protein P17861 UNIPROT XBP1 protein P17861 UNIPROT "up-regulates activity" binding -1 12805554 t miannu "E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins" SIGNOR-224199 MTA1 protein Q13330 UNIPROT COP1 protein Q8NHY2 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0001938 19805145 t miannu "MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism" SIGNOR-271892 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 t "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-248567 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr162 QLAAKLAyLQILSEE 9606 BTO:0001282 16373505 t "PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation." SIGNOR-251113 SMAD5 protein Q99717 UNIPROT HAND1 protein O96004 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268941 RPS12 protein P25398 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262440 BIRC5 protein O15392 UNIPROT CPC complex SIGNOR-C554 SIGNOR "form complex" binding 9606 23175282 t miannu "It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A)." SIGNOR-275424 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser523 MEKEDYHsLYQSHL 9606 10347209 t llicata "We conclude that pkc-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein. our results strongly suggest that direct phosphorylation of tyrosinase by pkc-_ leads to its activation." SIGNOR-67866 SOD1 protein P00441 UNIPROT "ER stress" stimulus SIGNOR-ST9 SIGNOR up-regulates 10090 18519638 f "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)" "SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK" SIGNOR-262788 PTAFR protein P25105 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257387 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2D3 protein P61077 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271348 INSR protein P06213 UNIPROT IRS4 protein O14654 UNIPROT "up-regulates activity" phosphorylation 10090 25905389 t lperfetto "The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok." SIGNOR-217897 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 SIGNOR-C110 11955436 t gcesareni "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." SIGNOR-116524 AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT "up-regulates activity" phosphorylation Ser1261 PMKKLHVsTINLQKA 10090 BTO:0002572 31186373 t miannu "AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. AMPK associates with and phosphorylates mTOR within mTORC2., these data indicate that AMPK phosphorylates mTOR on Ser1261 within mTORC2, an event that correlates with increased mTORC2 autophosphorylation and downstream signaling." SIGNOR-262535 USP45 protein Q70EL2 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR "up-regulates activity" deubiquitination 9606 BTO:0001938 25538220 t miannu "USP45 associates with the ERCC1–XPF endonuclease. USP45 interacts specifically with ERCC1–XPF via its N-terminal 61 residues. USP45 deubiquitylates ERCC1. USP45 promotes survival of cells exposed to agents that induce DNA damage responses controlled by ERCC1–XPF endonuclease" SIGNOR-268504 "prostaglandin F2alpha" smallmolecule CHEBI:15553 ChEBI Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 20219869 f apalma "Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle" SIGNOR-256213 UBE2D2 protein P62837 UNIPROT TRIM9 protein Q9C026 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 20085810 t miannu "Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N" SIGNOR-271420 "CHEVI complex" complex SIGNOR-C269 SIGNOR SEC22B protein O75396 UNIPROT "up-regulates activity" relocalization 9606 27319744 t lperfetto "VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles" SIGNOR-261832 HRH1 protein P35367 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257050 AKT1 protein P31749 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates activity" phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 t lperfetto "Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor." SIGNOR-252542 CADPS protein Q9ULU8 UNIPROT SNAP25 protein P60880 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu "CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1" SIGNOR-264338 FABP4 protein P15090 UNIPROT "Fatty acid" stimulus SIGNOR-ST19 SIGNOR "up-regulates quantity" relocalization 9606 28457600 t miannu "Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs)." SIGNOR-264458 belinostat chemical CHEBI:61076 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257744 SRC protein P12931 UNIPROT SH3GL1 protein Q99961 UNIPROT unknown phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t llicata "These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp." SIGNOR-139154 ESRRA protein P11474 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253790 SMO protein Q99835 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 10090 BTO:0002572 16885213 t gcesareni "We found that Smo, by virtue of what appears to be constitutive activity, activates all members of the G(i) family but does not activate members of the G(s), G(q), and G(12) families. The activation is suppressed by cyclopamine and other inhibitors of Hedgehog signaling and is enhanced by the Smo agonist purmorphamine." SIGNOR-148487 regorafenib chemical CHEBI:68647 ChEBI ABCB1 protein P08183 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26254357 t miannu "It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG2" SIGNOR-259182 TRIM33 protein Q9UPN9 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 25639486 t miannu "TRIM33 ubiquitylates nuclear beta-catenin.|Tumour suppressor TRIM33 targets nuclear beta-catenin degradation." SIGNOR-278578 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni "Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation." SIGNOR-184198 PCDHA6 protein Q9UN73 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-265666 SHANK3 protein Q9BYB0 UNIPROT "Postsynaptic density assembly" phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 f miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function." SIGNOR-264607 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT "down-regulates activity" phosphorylation Tyr731 PYDTLHIyGYEGSES 10029 BTO:0000246 16027153 t lperfetto "cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity." SIGNOR-246466 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Ser540 KVMARSLsPPPELEE 10090 BTO:0000944 15851026 t lperfetto "Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation." SIGNOR-249454 FERMT2 protein Q96AC1 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 24165133 t miannu "Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton." SIGNOR-266102 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNJ1 protein P48048 UNIPROT "up-regulates activity" phosphorylation Ser4 sSRNVFDT -1 12221079 t miannu "We conclude that ROMK1 is a substrate of PKC and that serine residues 4 and 201 are the two main PKC phosphorylation sites that are essential for the expression of ROMK1 in the cell surface." SIGNOR-275989 BRAF protein P15056 UNIPROT NFE2L2 protein Q16236 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29731393 f miannu "Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2" SIGNOR-267362 ZNF239 protein Q16600 UNIPROT RBP3 protein P10745 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12409453 f miannu "We have demonstrated that MOK2 can bind to the 8 bp present in the IRBP promoter and repress transcription from this promoter by competing with the CRX activator for DNA binding." SIGNOR-255629 SRC protein P12931 UNIPROT PIP5K1C protein O60331 UNIPROT up-regulates phosphorylation Tyr649 TDERSWVySPLHYSA 9606 15738269 t lperfetto "Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation." SIGNOR-134459 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268709 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser231 KSNIVLLsAEEKKEQ 9606 7678037 t llicata "These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-250915 ACTL6B protein O94805 UNIPROT "Brain-specific SWI/SNF SMARCA2 variant" complex SIGNOR-C485 SIGNOR "form complex" binding 9606 BTO:0000142 11790558 t miannu " Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core." SIGNOR-270749 METTL3 protein Q86U44 UNIPROT USP13 protein Q92995 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 36528756 t lperfetto "Furthermore, N6-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m6A reader IGF2BP2." SIGNOR-275839 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser188 QNRYSFYsTCSGQKA -1 23444369 t miannu "Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry." SIGNOR-273490 RNF125 protein Q96EQ8 UNIPROT DDX58 protein O95786 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0005029 17460044 t miannu "Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production." SIGNOR-271647 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269341 MYCT1 protein Q8N699 UNIPROT CCNE2 protein O96020 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30283340 f miannu "MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2." SIGNOR-261733 ABL1 protein P00519 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Tyr292 RLGHCHTyWAVSEEL 9606 BTO:0000007 30842273 t miannu "The data in this study show that IRF3 is physically associated with c-Abl in vivo and directly binds to c-Abl in vitro. IRF3 is phosphorylated by c-Abl and c-Abl-related kinase, Arg, mainly at Y292." SIGNOR-277440 NR3C1 protein P04150 UNIPROT TIMELESS protein Q9UNS1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19805059 t miannu "GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription" SIGNOR-268052 FN1 protein P02751 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 15721307 t lperfetto "Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway." SIGNOR-253304 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12393875 t "inferred from 70% family members" gcesareni "We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac." SIGNOR-269964 PRKCG protein P05129 UNIPROT NRGN protein Q92686 UNIPROT "up-regulates activity" phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto "Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM." SIGNOR-248915 eIF4F_complex complex SIGNOR-C44 SIGNOR Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 30459806 f gianni "The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation" SIGNOR-268530 TRIM13 protein O60858 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21333377 t miannu "Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro." SIGNOR-271851 PRKACA protein P17612 UNIPROT DSP protein P15924 UNIPROT "down-regulates activity" phosphorylation Ser2849 RSGSRRGsFDATGNS 9606 BTO:0000567 7525582 t miannu "HeLa cells treated with forskolin indicated that stimulation of protein kinase A in transfected cells could decrease the interaction of DP.AN.SerC23 with keratin IF networks. phosphorylation of Ser-C23 could destabilize interactions that occur either directly through this 20 residue sequence or that are dependent on its correct conformation" SIGNOR-250353 SMARCA4 protein P51532 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t miannu "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-132922 IHH protein Q14623 UNIPROT PTCH1 protein Q13635 UNIPROT "down-regulates activity" binding 9606 BTO:0001253 9811851 t lperfetto "Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH." SIGNOR-61311 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000007 15466476 t lperfetto "Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases." SIGNOR-129690 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni "This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway." SIGNOR-141803 PRKCZ protein Q05513 UNIPROT PPP1R14A protein Q96A00 UNIPROT "up-regulates activity" phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto "A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP." SIGNOR-249261 PLK2 protein Q9NYY3 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 t lperfetto "Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein." SIGNOR-182155 CC2D1A protein Q6P1N0 UNIPROT HTR1A protein P08908 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000938 20171170 t nucleus lperfetto "Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor." SIGNOR-268295 MAPK1 protein P28482 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 t gcesareni "Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3" SIGNOR-169875 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257979 procaterol chemical CHEBI:135209 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257864 SNIP1 protein Q8TAD8 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR down-regulates binding 9606 10887155 t lperfetto "In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4" SIGNOR-217661 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr699 DPEGGVDyKNIHLEK 9606 15297464 t lperfetto "Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins." SIGNOR-127536 CBX5 protein P45973 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264489 CASP3 protein P42574 UNIPROT GRIPAP1 protein Q4V328 UNIPROT "up-regulates activity" cleavage 9606 17761173 t Giorgia "These results suggest that the region of GRASP‐1 downstream of the Caspase‐3‐cleavage site is capable of activating the JNK signaling pathway by enhancing the phosphorylation of JNK. these results suggest that full length GRASP‐1 does not enhance JNK pathway activity, possibly due to the inhibitory effect of the N‐terminal fragment on the C‐terminal fragment. In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein." SIGNOR-260641 COMMD5 protein Q9GZQ3 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 30021164 f miannu "In this study, we identified a specific and crucial role for COMMD5 in the endocytic trafficking machinery, and especially we determined COMMD5 as an actin- and tubulin-binding protein. Our results provide further insight into the essential role of COMMD5 on every aspect of cellular processes, from membrane receptor trafficking to cytoskeleton organization, cell migration, and junctions. Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks." SIGNOR-261693 ACP1 protein P24666 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr857 DIMRDSNyISKGSTF 9606 12149261 t "Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation|On the basis of these results, we propose a key role for LMW-PTP in PDGF-r down-regulation through the dephosphorylation of the activation loop Tyr-857, thus determining a general negative regulation of all downstream signals, with the exception of those elicited by internalized receptors." SIGNOR-248452 Ub:E2 complex SIGNOR-C497 SIGNOR LONRF1 protein Q17RB8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271156 ULK1 protein O75385 UNIPROT DENND3 protein A2RUS2 UNIPROT "up-regulates activity" phosphorylation Ser490 ELAPRNSsLRLTDTA 9606 25925668 t lperfetto "ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12." SIGNOR-264731 IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 11416002 t lperfetto "To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1" SIGNOR-235487 IFNG protein P01579 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates binding 9606 7673114 t gcesareni "Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (43 45) is required for signal transduction" SIGNOR-31013 PTPN12 protein Q05209 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 18482983 t "we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin" SIGNOR-248659 EGFR protein P00533 UNIPROT PKIA protein P61925 UNIPROT up-regulates phosphorylation Tyr8 MTDVETTyADFIASG 9606 1956339 t lperfetto "The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency." SIGNOR-22455 F2RL2 protein O00254 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257409 TDP2 protein O95551 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 21980489 t miannu "TTRAP associates with TRAF6.The TAK1-TTRAP-TRAF6 complex is stabilized by ubiquitylation and recruited to TβRI." SIGNOR-277189 SREBF2 protein Q12772 UNIPROT LDLR protein P01130 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21123766 t miannu "Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes." SIGNOR-254453 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120128 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser173 MLETLSQsPPKGVTI 10090 BTO:0000664 17475908 t miannu "All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells." SIGNOR-262668 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t gcesareni "Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase." SIGNOR-33141 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser53 LPPFEDEsEGLLGTE 9606 19647517 t lperfetto "Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry" SIGNOR-187400 IQSEC2 protein Q5JU85 UNIPROT ARF6 protein P62330 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10090 BTO:0000142 18164504 t miannu "Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6." SIGNOR-264906 RAB4A protein P20338 UNIPROT RUFY1 protein Q96T51 UNIPROT "up-regulates activity" binding 9606 20534812 t Giulio "Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4" SIGNOR-261280 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser181 NPLLRKEsAPPSLRR -1 15738054 t lperfetto "We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro." SIGNOR-249273 BKM120 chemical CHEBI:71954 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190392 RGCC protein Q9H4X1 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" binding 9606 BTO:0001685 11687586 t miannu "RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity." SIGNOR-262726 MAD2L1BP protein Q15013 UNIPROT TRIP13 protein Q15645 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 25092294 t miannu "We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4)." SIGNOR-265971 MYCBP2 protein O75592 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001321 32814769 t miannu "We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop." SIGNOR-267147 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0001271 8622703 t lperfetto "We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr." SIGNOR-40615 ERBB3 protein P21860 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 14967450 t gcesareni "All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3." SIGNOR-121971 PRKCA protein P17252 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser259 FPLRKTAsEPNLKVR 10116 BTO:0002320 15367659 t lperfetto "We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E" SIGNOR-249268 PRKCD protein Q05655 UNIPROT TACSTD2 protein P09758 UNIPROT "down-regulates activity" phosphorylation Ser322 GELRKEPsL 9606 BTO:0001109 31177095 t done miannu " Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation." SIGNOR-273820 GRID1 protein Q9ULK0 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264951 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu50 RANTFLEeVRKGNLE -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263676 CILK1 protein Q9UPZ9 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 22356909 t lperfetto "Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division." SIGNOR-217562 "NMDA receptor_2D" complex SIGNOR-C350 SIGNOR CTTN protein Q14247 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000142 14684878 t miannu "Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors." SIGNOR-266602 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000586 16293724 f lperfetto "We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt" SIGNOR-235914 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1C protein Q8TCG5 UNIPROT "down-regulates activity" binding 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267116 DNAJB9 protein Q9UBS3 UNIPROT HSPA5 protein P11021 UNIPROT "up-regulates activity" binding -1 12356756 t miannu "When BAP was added to BiP (2:1 molar ratio of BAP:BiP), it increased the ATPase activity of BiP by about 2-fold, which was similar to the increase observed when the J domain of ERdj4 was added to BiP (Fig.5). When both BAP and the J domain were added to BiP, the rate of ATP hydrolysis by BiP was stimulated by about 4-fold over basal levels, indicating that both BAP and ERdj4 positively regulate the ATPase activity of BiP" SIGNOR-261044 MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 f "Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin" SIGNOR-255466 EGFR protein P00533 UNIPROT KCNJ4 protein P48050 UNIPROT "up-regulates activity" phosphorylation Tyr234 YMTQEGEyLPLDQRD -1 21486282 t miannu "These results demonstrate that the EGF receptor tyrosine kinase up-regulates the K(IR) 2.3 channel via phosphorylation of the Y234 residue of the WT protein. " SIGNOR-276322 TP53 protein P04637 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 11714700 t gcesareni "This study identifies the anti-apoptotic survivin gene as a p53-repressed gene;notably, survivin repression by p53 is shown to be distinct from p53-dependent growth arrest." SIGNOR-111971 PRKCI protein P41743 UNIPROT NUMB protein P49757 UNIPROT down-regulates phosphorylation 9606 17609107 t esanto "Numb is regulated by phosphorylation since the protein is released from ccss and no longer binds integrins when phosphorylated by atypical protein kinase c (apkc)." SIGNOR-156765 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser381 CIPTAGMsPSRSNTI 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249395 Ub:E2 complex SIGNOR-C497 SIGNOR PDZRN4 protein Q6ZMN7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271036 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265803 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9335504 t llicata "The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1." SIGNOR-52670 GBAF complex SIGNOR-C467 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 f miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269790 "SAGA complex" complex SIGNOR-C465 SIGNOR H3Y1 protein P0DPK2 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkATAWQAP 9606 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269631 CD163 protein Q86VB7 UNIPROT hb:hp complex SIGNOR-C149 SIGNOR "down-regulates quantity by destabilization" binding 9606 11854029 t miannu "CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis." SIGNOR-251823 MECP2 protein P51608 UNIPROT TET1 protein Q8NFU7 UNIPROT "up-regulates activity" binding 28594324 t lperfetto "MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naı ̈ve but dissociate during conditioning|Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing." SIGNOR-277701 SIRT6 protein Q8N6T7 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 25083875 t miannu "SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids." SIGNOR-268158 KDM4B protein O94953 UNIPROT BBC3 protein Q9BXH1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001109 28073943 f miannu "JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B." SIGNOR-263732 WNT3A protein P56704 UNIPROT FZD1 protein Q9UP38 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 10601008 t gcesareni "Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes." SIGNOR-73036 ALDOB protein P05062 UNIPROT "glycerone phosphate(2-)" smallmolecule CHEBI:57642 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266484 PSMA2 protein P25787 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263367 CADPS protein Q9ULU8 UNIPROT VAMP2 protein P63027 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu "CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly." SIGNOR-264340 MTHFR protein P42898 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI "down-regulates quantity" "chemical modification" 9606 10720211 t lperfetto "Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine." SIGNOR-268228 OBSCN protein Q5VST9 UNIPROT ANK2 protein Q01484 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0003324 19840192 t miannu "Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins." SIGNOR-266726 PKG proteinfamily SIGNOR-PF77 SIGNOR 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266507 WNK1 protein Q9H4A3 UNIPROT SLC12A2 protein P55011 UNIPROT "up-regulates activity" phosphorylation Thr1023 QKKQGKNtIDVWWLF 9606 BTO:0000007 36318922 t miannu "Combining these biochemical studies with the live cell imaging data, these results collectively suggest that the entire CTD is necessary for WNK1 to drive optimal SPAK/OSR1 activation and downstream NKCC1/KCC phosphorylation via PS." SIGNOR-277859 PRKAA1 protein Q13131 UNIPROT SYN1 protein P17600 UNIPROT "down-regulates activity" phosphorylation Ser9 NYLRRRLsDSNFMAN 9606 10880969 t lperfetto "It has been reported that site 1 of syn i can be phosphorylated by pka. Pka-mediated synapsin i ser9 phosphorylation occurs in response to cgs 21680 treatment. Results show that the adenosine a2a receptor agonist, cgs 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase a activation, which in turn increased synapsin i phosphorylation" SIGNOR-78891 Oxytocin protein P01178-PRO_0000020495 UNIPROT "GABA-A (a6-b1-g2) receptor" complex SIGNOR-C334 SIGNOR up-regulates 9606 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268586 MAP4K1 protein Q92918 UNIPROT CARD11 protein Q9BXL7 UNIPROT "up-regulates activity" phosphorylation Ser556 TKMQPPRsRSSIMSI -1 19706536 t miannu "HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro." SIGNOR-276259 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 33941852 f "Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. " SIGNOR-268623 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 t gcesareni "PKA activated Src both in vitro and in vivo by phosphorylating Src on serine 17 within its amino terminus" SIGNOR-247988 tazarotene chemical CHEBI:32184 ChEBI RARB protein P10826 UNIPROT "up-regulates activity" "chemical activation" 9534 19058965 t Luana "Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. " SIGNOR-258028 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 SIGNOR-C16 12105215 t gcesareni "To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-90438 MAT2B protein Q9NZL9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001938 30942439 f miannu "MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen" SIGNOR-261242 MRAP protein Q8TCY5 UNIPROT MC5R protein P33032 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252368 FFAR1 protein O14842 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257184 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 22975381 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-192057 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS2 protein Q9NRM7 UNIPROT up-regulates 9606 23075495 f gcesareni "On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz." SIGNOR-199199 STOML2 protein Q9UJZ1 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" binding 9606 18641330 t Giorgia "In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling." SIGNOR-260378 BGJ-398 chemical CHEBI:63451 ChEBI FGFR4 protein P22455 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190272 2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine chemical CHEBI:91330 ChEBI ATM protein Q13315 UNIPROT "down-regulates activity" "chemical inhibition" -1 18794134 t Gianni "A targeted compound library was screened for potential inhibitors of the ATM kinase, and CP466722 was identified." SIGNOR-261975 DPYD protein Q12882 UNIPROT thymine smallmolecule CHEBI:17821 ChEBI "down-regulates quantity" "chemical modification" 10499634 t "Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil." SIGNOR-253989 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser365 KDCERRFsRSDQLKR 9606 9366517 t llicata "Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo." SIGNOR-53172 SPI1 protein P17947 UNIPROT miR-146a mirna URS000075D8A0_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 10090 21730352 f miannu "We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation." SIGNOR-256243 DDX5 protein P17844 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 18829551 t miannu "P68 is a nuclear protein and interacts with ar / p68 co-occupies the active psa promoter at are regions and enhances ar transcriptional activity" SIGNOR-181456 ERG protein P11308 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22140532 f miannu "ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability." SIGNOR-254065 CPSF3 protein Q9UKF6 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 30507380 f lperfetto "Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes." SIGNOR-268336 AKT1 protein P31749 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr39 LKKIRLDtETEGVPS 9606 18354084 t lperfetto "Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity." SIGNOR-178058 PTPN14 protein Q15678 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 BTO:0000586 22710723 t lperfetto "We show that p130 crk-associated substrate (p130cas) is a direct substrate of ptpn14 and that ptpn14 specifically regulates p130cas phosphorylation at tyrosine residue 128 (y128) in colorectal cancer (crc) cells. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation" SIGNOR-197923 CAST protein P20810 UNIPROT CAPN2 protein P17655 UNIPROT "down-regulates activity" binding 9606 BTO:0000590 25969760 t lperfetto "In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain" SIGNOR-251609 RUNX3 protein Q13761 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 19800882 t gcesareni "To investigate the possible mechanism of the down-regulation of hes-1 by runx3, we performed western blot and reporter assay and found that runx3 suppressed intracellular domain of notch1 (icn1)-mediated transactivation of notch signaling while it did not alter the expression of icn1 and recombination signal binding protein-j kappa (rbp-j) in smmc7721 cells." SIGNOR-188338 RELA protein Q04206 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR "form complex" binding 9606 BTO:0000671 9056676 t miannu "Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel." SIGNOR-46948 CDK1 protein P06493 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates phosphorylation Ser552 DLEVLTSsPTRNLNG 9606 24013421 t llicata "Here, we report that cyclin-dependent kinase 1 (cdk1) phosphorylates the histone h2a deubiquitinase ubp-m at serine 552 (s552p), and, importantly, this phosphorylation is required for cell cycle progression." SIGNOR-202678 ATF4 protein P18848 UNIPROT FGF21 protein Q9NSA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22233381 f miannu "These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation." SIGNOR-253748 CDX2 protein Q99626 UNIPROT MEP1A protein Q16819 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22326557 t "TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis|" SIGNOR-253965 E2F1 protein Q01094 UNIPROT TLR3 protein O15455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 22310660 f lperfetto "Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is upregulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells." SIGNOR-254136 JUN protein P05412 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255767 WNT7A protein O00755 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" 9606 BTO:0001103 21902831 f gcesareni "Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors." SIGNOR-176575 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation 9606 12510059 t "inferred from 70% family members" gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-270132 TH protein P07101 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI "up-regulates quantity" "chemical modification" 9606 NBK536726 t brain lperfetto "Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH)." SIGNOR-263991 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 14579029 t gcesareni "Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632" SIGNOR-118877 NR3C1 protein P04150 UNIPROT ATP1B1 protein P05026 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 9694812 t miannu "Together these data indicate that the 21-base pair sequence represents a true MRE/GRE and that optimal activation of the human Na/K-ATPase beta1 promoter is controlled by mineralocorticoid and glucocorticoid hormones. It appears that an interaction of MR with GR on the beta1 promoter effectively down-regulates transcription." SIGNOR-254864 MAPKAPK2 protein P49137 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser326 LTIPPRFsIAPSSLD 9606 18695677 t llicata "Here, we have identified mk2 as a major plk1 kinase toward ser326, whose phosphorylation is critical to recruit ?-Tubulin to centrosomes and subsequent establishment of functional bipolar spindles. To our knowledge, this is the first direct evidence to demonstrate that the essential function of plk1 in centrosome maturation and bipolar spindle formation is controlled by its upstream kinase." SIGNOR-179968 RORA protein P35398 UNIPROT NTRK2 protein Q16620 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 28608249 t lperfetto "Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005)." SIGNOR-265137 CFL1 protein P23528 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR "down-regulates quantity" binding 9606 BTO:0000132 27871158 t lperfetto "Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers." SIGNOR-261836 PTEN protein P60484 UNIPROT ABTB1 protein Q969K4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11494141 f miannu "Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase)." SIGNOR-260050 TGFB1 protein P01137 UNIPROT TFAP4 protein Q01664 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 21228219 f miannu "TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts." SIGNOR-255428 CDK9 protein P50750 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Ser211 VAQTPMPsEYQNMTV 9606 23603988 t lperfetto "We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr." SIGNOR-201923 PAX6 protein P26367 UNIPROT GCG protein P01275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000120 12783165 f miannu "In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3." SIGNOR-254905 MEF2D protein Q14814 UNIPROT ASH2L protein Q9UBL3 UNIPROT up-regulates 9606 BTO:0000887 18026121 f gcesareni "Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d." SIGNOR-159334 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" phosphorylation Ser637 HSLLERYsVNEGLVA 9606 BTO:0000567 phosphorylation:Thr550 PPINGSStPNPKIAS 19509060 t lperfetto "Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation." SIGNOR-272991 LPCAT4 protein Q643R3 UNIPROT "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "chemical modification" 9606 21498505 t miannu "Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. " SIGNOR-272771 MBL2 protein P11226 UNIPROT MASP2 protein O00187 UNIPROT "up-regulates activity" binding 9606 9087411 t lperfetto "The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5)." SIGNOR-263415 NMBR protein P28336 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways." SIGNOR-107025 ADIPOQ protein Q15848 UNIPROT ADIPOR2 protein Q86V24 UNIPROT up-regulates binding 9606 16622416 t milica "Two adiponectin receptors, adipor1 and adipor2, have recently been identified." SIGNOR-146173 alanine smallmolecule CHEBI:16449 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264746 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 10567431 t lperfetto "Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size." SIGNOR-217056 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT "up-regulates activity" phosphorylation Tyr821 QEPDEILyVNMDEGG -1 9178760 t llicata "Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins" SIGNOR-250592 NTRK1 protein P04629 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 10708759 t esanto "Autophosphorylated trka binds directly to plc?, Abl, and shc." SIGNOR-75402 "bisphenol F" chemical CHEBI:34575 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -1 31995776 t miannu "This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. ." SIGNOR-268734 trimipramine chemical CHEBI:9738 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9537821 t miannu "At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. " SIGNOR-258742 RPS6KA2 protein Q15349 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 20385620 t gcesareni "Rsk2 is activated by treatment with tumor necrosis factor-alfa (tnf-alfa) and directly phosphorylates ikbalfa at ser-32, leading to ikbalfa degradation." SIGNOR-164790 PRKAA1 protein Q13131 UNIPROT TBC1D1 protein Q86TI0 UNIPROT down-regulates phosphorylation Ser237 RPMRKSFsQPGLRSL 9606 BTO:0001760 SIGNOR-C15 17995453 t gcesareni "In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar" SIGNOR-159048 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EGR1 protein P18146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11085989 f miannu "We also show for the first time that leptin rapidly stimulates the mRNA expression of the zinc finger transcription factor, Egr-1, in the hypothalamus of mice. Our transfection results suggest that this regulation by leptin occurs by activation of theegr-1 promoter via activation of SHP-2 and of the ERK pathway. " SIGNOR-263507 IL23R protein Q5VWK5 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni "Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12." SIGNOR-87808 PALB2 protein Q86YC2 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates binding 9606 BTO:0000150 16793542 t miannu "Palb2 colocalizes with brca2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions." SIGNOR-147217 MAPK9 protein P45984 UNIPROT MFN2 protein O95140 UNIPROT down-regulates phosphorylation Ser27 HMAEVNAsPLKHFVT 9606 22748923 t lperfetto "Jnk phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (e3) huwe1/mule/arf-bp1/hecth9/e3histone/lasu1 to mitofusin 2, with the bh3 domain of huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2these data establish that mfn2 is phosphorylated on ser27 in response to a variety of cellular stresses and implicate jnk in this process" SIGNOR-198054 MAPK3 protein P27361 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 t lperfetto "We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309." SIGNOR-184180 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273050 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr286 LQIDDNEyAYLKAII 9606 22308320 t lperfetto "Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function." SIGNOR-195896 NLK protein Q9UBE8 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000150 17563747 t gcesareni "Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna." SIGNOR-155828 ATP smallmolecule CHEBI:15422 ChEBI P2RX7 protein Q99572 UNIPROT up-regulates "chemical activation" 9606 18827222 t mrosina "Pericellular ATP activates P2XRs on the T cell in an autocrine fashion (step 4) and perhaps also P2X7 receptors on the APC in a paracrine fashion resulting in IL-1beta processing and release (step 5)." SIGNOR-254965 NCF2 protein P19878 UNIPROT "Phagocyte NADPH oxidase complex" complex SIGNOR-C557 SIGNOR "form complex" binding 9606 37263099 t miannu "NADPH oxidase is composed of essential protein components in its active state: membranous subunits, including p22-phox and gp91-phox, and cytoplasmic subunits, including p47-phox, p67-phox, p40-phox, and RAC2 (in neutrophils), among which NCF4 encodes the cytoplasmic subunit p40-phox" SIGNOR-277632 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT "down-regulates activity" phosphorylation Ser941 NVRSKVGsTENIKHQ -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250171 SNTB1 protein Q13884 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates 10090 BTO:0002314 BTO:0001103 29681515 t apalma "[...] suggesting that, during an asymmetric cell division, p38gamma localization would be basally restricted by the DGC complex via its interaction with beta-1-syntrophin." SIGNOR-255903 TRAF6 protein Q9Y4K3 UNIPROT LGMN protein Q99538 UNIPROT "up-regulates quantity by stabilization" polyubiquitination 9606 BTO:0000815 24610907 t miannu "We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. We now present evidence that AEP is a substrate for TRAF6 ubiquitination, resulting in AEP/TRAF6/HSP90α complex formation." SIGNOR-272853 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89264 DOK1 protein Q99704 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257671 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 12198243 t gcesareni "Here we show that shp can interact with the liver x receptors lxralpha (nr1h3) and lxrbeta (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter" SIGNOR-92060 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249462 CAV1 protein Q03135 UNIPROT HMGA1 protein P17096 UNIPROT "up-regulates activity" relocalization 9606 22706202 t miannu "CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization." SIGNOR-254428 WDR62 protein O43379 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" relocalization 10090 30566428 t lperfetto "In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis" SIGNOR-271715 "MLL Fusion" "fusion protein" SIGNOR-FP14 SIGNOR MECOM protein Q03112 UNIPROT "up-regulates quantity by expression" methylation 10090 BTO:0001271 22553314 t miannu "We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia." SIGNOR-260107 F2 protein P00734 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 25297919 t lperfetto "Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1." SIGNOR-261859 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser419 S-->N 9606 25605940 t miannu "We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here." SIGNOR-276476 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation Tyr261 GLVTTLHyPAPKCNK 9606 15735735 t lperfetto "The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization" SIGNOR-134400 APC-c complex SIGNOR-C150 SIGNOR AURKA protein O14965 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0004055 12023018 t miannu "We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity." SIGNOR-272612 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219337 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 BTO:0000938 12367505 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." gcesareni "Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27." SIGNOR-94021 YWHAZ protein P63104 UNIPROT GEM protein P55040 UNIPROT "up-regulates quantity by stabilization" binding 9534 BTO:0000298 14701738 t miannu "In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase" SIGNOR-261725 DUSP5 protein Q16690 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 10224087 t gcesareni "Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway" SIGNOR-67355 INTS4 protein Q96HW7 UNIPROT DYNC1H1 protein Q14204 UNIPROT "up-regulates quantity" 9606 BTO:0000567 23904267 f Monia "We propose a model in which nuclear localized Integrator complex, including ASUN, mediates 3′-end processing of snRNA, which in turn is required for normal processing of mRNA encoding a key regulator(s) of cytoplasmic dynein localization. When Integrator activity is compromised (e.g., by knockdown of an essential subunit), production of critical transcript(s) during interphase is impaired, leading to reduction of perinuclear dynein at G2/M." SIGNOR-261186 UBE2D2 protein P62837 UNIPROT PEX5 protein P50542 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 19687296 t miannu "Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle." SIGNOR-253023 "CCT365623 (hydrochloride)" chemical CID:139266765 PUBCHEM LOX protein P28300 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000195 31070916 t "Simone Vumbaca" "Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy." SIGNOR-261121 MAPK8 protein P45983 UNIPROT MFN2 protein O95140 UNIPROT "down-regulates quantity" phosphorylation Ser27 HMAEVNASPLKHFVT 9606 BTO:0001938 22748923 t Barakat "We demonstrate that a critical component of the mitochondrial fusion apparatus, the mitofusin Mfn2, is a target for phosphorylation in response to a variety of cellular stresses. We provide direct evidence that JNK mediates this phosphorylation." SIGNOR-274138 ITGB1 protein P05556 UNIPROT KCNH2 protein Q12809 UNIPROT "up-regulates activity" binding 9606 35442831 t miannu "One such mechanism is operant in colorectal cancer (CRC) cells. On integrin-dependent CRC cell adhesion, the Kv11.1/β1 integrin complex recruits the PI3K p85 subunit, which stimulates AKT phosphorylation and thus regulates autophagy" SIGNOR-277614 IFNAR complex SIGNOR-C243 SIGNOR CCL2 protein P13500 UNIPROT "up-regulates quantity by expression" 10090 32283152 f miannu "The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages." SIGNOR-260851 GHSR protein Q92847 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257429 CDKN2AIP protein Q9NXV6 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18292944 f fstefani "Carf interacts with hdm2 and undergoes degradation by an hdm2-dependent proteasome pathway, and ii) it acts as a transcriptional repressor of hdm2." SIGNOR-160971 SP1 protein P08047 UNIPROT CBS protein P35520 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12427542 f miannu "We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter." SIGNOR-254812 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT "down-regulates quantity by destabilization" cleavage Glu612 IKTEEISeVKMDAEF -1 8943232 t lperfetto "The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261766 PTPRB protein P23467 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t gcesareni "Inally, mrna tissue distribution of these ptps by rt-pcr analysis and coexpression of the wild-type ptps to test their ability to dephosphorylate ligand-activated ghr suggest ptp-h1 and ptp1b as potential candidates involved in ghr signaling." SIGNOR-104580 WARS1 protein P23381 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 14660560 t miannu "Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471)" SIGNOR-270512 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr131 KENLIREyVKQTWNL 9606 BTO:0000776 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246601 imiquimod chemical CHEBI:36704 ChEBI TLR7 protein Q9NYK1 UNIPROT "up-regulates activity" "chemical activation" 9606 15661881 t miannu "Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively." SIGNOR-259244 CDK1 protein P06493 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation 9606 16682949 t gcesareni "We found that nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative cdc2 phosphorylation sites in nde1 and found that alteration of these sites diminishes phosphorylation by cdc2 in vitro and affects the stability of su48-nde1 interactions and the centrosomal localization of nde1." SIGNOR-146734 veliparib chemical CHEBI:62880 ChEBI PARP2 protein Q9UGN5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189224 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser679 SPDSMNAsRLSQPGQ 9606 BTO:0000007 10195894 t "Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response." SIGNOR-251277 AKT2 protein P31751 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni "Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation." SIGNOR-164302 DAB2IP protein Q5VWQ8 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 27858941 t miannu "The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP." SIGNOR-254745 COL1A1 protein P02452 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 f "Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I" SIGNOR-254662 ERG protein P11308 UNIPROT ERG protein P11308 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001106 21536859 f miannu "We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer." SIGNOR-253925 PTP4A3 protein O75365 UNIPROT ITGB1 protein P05556 UNIPROT "down-regulates activity" dephosphorylation Tyr783 DTGENPIyKSAVTTV 9606 23092334 t miannu "In this study, we demonstrate that PRL-3 directly binds to integrin \u03b21 and dephosphorylates integrin \u03b21-Y783, a key residue for integrin \u03b21 function [ ].|These results indicate that PRL-3 dephosphorylates integrin \u03b21 in vitro and in vivo." SIGNOR-277050 CDK5R1 protein Q15078 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 10604467 t "Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular location and alters its substrate specificity." SIGNOR-268153 HHAT protein Q5VTY9 UNIPROT SHH protein Q15465 UNIPROT up-regulates palmitoylation 9606 18534984 t gcesareni "Both the shh precursor and mature protein are n-palmitoylated by hhatn-palmitoylation of cys-24 by hhat is required for n-product multimerization and full activity" SIGNOR-161548 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 9606 15952796 t lperfetto "We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling." SIGNOR-138167 IGF1R protein P08069 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" binding -1 7541045 t lperfetto "In our present work, we show that both IRS-1 and SHC interact directly with the juxtamembrane region of the IGFIR in a phosphotyrosine-dependent manner. |We propose a model in which IGFIR autophosphorylation of Tyr-950 forms a direct binding site for the amino-terminal receptor binding domains of SHC and IRS-1. This interaction is presumed to facilitate tyrosine phosphorylation of SHC on Tyr-317 leading to GRB2/SOS interaction" SIGNOR-262587 CDK1 protein P06493 UNIPROT ERCC6L protein Q2NKX8 UNIPROT up-regulates phosphorylation Thr1063 VKQFDAStPKNDISP 9606 17218258 t lperfetto "Following phosphorylation of pich on the cdk1 site t1063, plk1 is recruited to pich and controls its localization. Starting in prometaphase, pich accumulates at kinetochores and inner centromeres." SIGNOR-152133 MAP3K7 protein O43318 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 9278437 t lperfetto "Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway." SIGNOR-50618 p38 proteinfamily SIGNOR-PF16 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 t "inferred from 70% family members" gcesareni "Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target" SIGNOR-270124 Gbeta proteinfamily SIGNOR-PF4 SIGNOR WWC1 protein Q8IX03 UNIPROT unknown phosphorylation 9606 BTO:0000149 24269383 t "inferred from 70% family members" llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-270121 PPP1CB protein P62140 UNIPROT NF2 protein P35240 UNIPROT up-regulates dephosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto "When serine 518 is dephosphorylated by the myosin phosphatase mypt-1-pp1?, The tumor suppressor function of merlin is activated, inhibiting the ras signaling pathway and leading to growth arrest" SIGNOR-159836 "Daunorubicin hydrochloride" chemical CHEBI:31456 ChEBI TOP2B protein Q02880 UNIPROT "down-regulates activity" "chemical inhibition" 9606 1963303 t miannu "DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives." SIGNOR-259323 FBXO3 protein Q9UK99 UNIPROT SQSTM1 protein Q13501 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272444 WNK3 protein Q9BYP7 UNIPROT SLC12A7 protein Q9Y666 UNIPROT "down-regulates activity" phosphorylation 21613606 t lperfetto "We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs" SIGNOR-264630 GRB2 protein P62993 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 BTO:0001271 8402896 t "GRB2 binds BCR-ABL with SH2 domain" gcesareni "We demonstrate that bcr-abl exists in a complex with grb-2 in vivo. Binding of grb-2 to bcr-abl is mediated by the direct interaction of the grb-2 sh2 domain with a phosphorylated tyrosine, y177, within the bcr first exon." SIGNOR-39049 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser633 SFDTHFRsPSSSVGS 9606 12620228 t llicata "Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth." SIGNOR-98980 PRKCB protein P05771 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 t lperfetto "These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels." SIGNOR-249087 UBE3A protein Q05086 UNIPROT RAD23A protein P54725 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 10373495 t miannu " Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B." SIGNOR-272550 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 f "Alessandro Palma" "It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits" SIGNOR-254957 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT "up-regulates activity" phosphorylation Tyr596 KLPGLRTyVDPHTYE 9606 11870224 t "Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3" SIGNOR-251115 TRPV4 protein Q9HBA0 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000443 23021218 f lperfetto "TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance." SIGNOR-253095 MAPK8 protein P45983 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 15192708 t "The effect has been demonstrated using Q43561-2" gcesareni "Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway.Mutational analysis revealed that t155 but not t94 or t140 is the site of jnk-mediated phosphorylation (figure 2b). Erk also phosphorylated lat at t155 (figure 2c), whereas p38, which was able to phosphorylate atf2, failed to induce threonine phosphorylation of lat (figure 2d). These results indicate that lat is directly phosphorylated by erk and jnk at the same site, t155." SIGNOR-125774 SHH protein Q15465 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887 17688959 f lperfetto "Most importantly, we report that shh induces mapk/erk and phosphoinositide 3-kinase (pi3k)-dependent akt phosphorylation and that activation of both signaling pathways is essential for shh's signaling in muscle cells. However, the effect of shh on akt phosphorylation is more robust than that on mapk/erk, and data suggest that shh influences these pathways in a manner similar to igf-i." SIGNOR-244446 TBX3 protein O15119 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25211658 t lperfetto "TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS" SIGNOR-249603 HES5 protein Q5TA89 UNIPROT ATOH1 protein Q92858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 30030829 f lperfetto "The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production" SIGNOR-265145 "AP-3 complex" complex SIGNOR-C247 SIGNOR "AP-3/clathrin vescicle" complex SIGNOR-C250 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260668 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 10090 15486195 t miannu "Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination." SIGNOR-250132 ARHGAP5 protein Q13017 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260461 "IPP complex" complex SIGNOR-C380 SIGNOR ACTB protein P60709 UNIPROT "up-regulates activity" relocalization 27590440 t lperfetto "Apart from binding with integrins on the membrane, IPP complex can interact with the cytoskeleton as well as many signaling proteins inside the cell. Up to now, dozens of IPP complex-related proteins have been identified. One of these proteins is parvin that binds to F-actin, thus connecting ECM with cytoskeleton.17 In the following, we will discuss PINCH-interacting proteins and their roles." SIGNOR-265768 protriptyline chemical CHEBI:8597 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9537821 t miannu "At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter." SIGNOR-258736 MAPK1 protein P28482 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates phosphorylation Ser250 SSSGVPYsPAIPNKR 9606 22595671 t lperfetto "Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling." SIGNOR-197543 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 20626350 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." gcesareni "Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27." SIGNOR-166633 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257936 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUNB protein P17275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9694870 f lperfetto "Here we report the identification of Smad Binding Elements (SBEs) composed of the sequence CAGACA in the promoter of the JunB gene, an immediate early gene that is potently induced by TGF-beta, activin, and bone morphogenetic protein (BMP) 2. Two JunB SBEs are arranged as an inverted repeat that is transactivated in response to Smad3 and Smad4 co-overexpression and shows inducible binding of a Smad3- and Smad4-containing complex in nuclear extracts from TGF-beta-treated cells." SIGNOR-59476 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR PPP2R5B protein Q15173 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23135275 t miannu "Here, we report that KLHL15-Cul3 specifically targets B'β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B'β." SIGNOR-272019 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCC8 protein Q09428 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000783 35065096 t miannu "Activated PKA and EPAC enhance insulin granular exocytosis by insulin granular priming and phosphorylates sulfonylurea receptor (SUR1) KATP channel subunit and thereby closes KATP-channels in the plasma membrane [13,43,82], leading to membrane depolarization, and opening of the voltage gated Ca2+-channels. This leads to an increased influx of extracellular Ca2+, which triggers fusion of intracellular insulin-containing granules with the plasma membrane and thereby insulin secretion." SIGNOR-278146 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Ser1035 DHQTPPTsPVQGTTP 9606 24089523 t lperfetto "Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1" SIGNOR-202698 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 15225553 t lperfetto "Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174." SIGNOR-126654 CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR AR protein P10275 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser310 TEDTAEYsPFKGGYT 9534 17698582 t "phosphorylation site remapping based on Fig 7D" lperfetto "We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1)." SIGNOR-273125 KPNA3 protein O00505 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 t gcesareni "Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7." SIGNOR-165280 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser155 FPLRKTVsEPNLKLR -1 15738054 t lperfetto "We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro." SIGNOR-249275 PRKCD protein Q05655 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Ser221 QAQRFRFsPMGVDHM 9606 20086103 t lperfetto "Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur." SIGNOR-163524 "Viral protein" proteinfamily SIGNOR-PF88 SIGNOR Ubiquitinated-Viral_Protein complex SIGNOR-C427 SIGNOR "form complex" binding 9606 25688236 t scontino "MHC class I antigen presentation pathway. Proteins with ubiquitin tags (red spheres) are degraded by proteasomes and the resulting peptides are transported into the endoplasmic reticulum (ER) by TAP|Many viruses have mechanisms of interfering with MHC class I processing, including direct interaction of viral proteins with immunoproteasome subunits." SIGNOR-267765 SLC35A1 protein P78382 UNIPROT "sialic acid" smallmolecule CHEBI:26667 ChEBI "up-regulates quantity" relocalization 9606 34384782 t miannu "The CMP-sialic acid transporter SLC35A1 and UDP-galactose transporter SLC35A2 are two well-characterized nucleotide sugar transporters with distinctive substrate specificities. Nucleotide sugar transporters (NSTs) transport nucleotide sugars from the cytosol into the lumen of the endoplasmic reticulum or the Golgi apparatus, where the nucleotide sugars serve as substrates for protein glycosylation and glycosphingolipid synthesis." SIGNOR-268466 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR BLM protein P54132 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser175 SFVTPPQsHFVRVST 9606 BTO:0002181 26028025 t miannu "We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates." SIGNOR-276910 SNAI2 protein O43623 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 20509143 f miannu "SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness." SIGNOR-255154 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser6 sQLDSDFS 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" SIGNOR-100649 GSK3B protein P49841 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr265 ATYHHNStTTWTGSR 10090 BTO:0000944 25373906 t miannu "In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region. " SIGNOR-276442 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258005 lurasidone chemical CHEBI:70735 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10030 20404009 t Luana "In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype." SIGNOR-257839 HOXB6 protein P17509 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000664 15269212 t Luana "HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion." SIGNOR-261637 FBXO6 protein Q9NRD1 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 19716789 t miannu " Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint." SIGNOR-271879 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser85 PLPDAGAsPAPSRCC 23871434 t lperfetto "WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85" SIGNOR-275481 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEYL protein Q9NQ87 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 11044625 f gcesareni "The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j." SIGNOR-254339 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A2-B2 complex SIGNOR-C137 SIGNOR "up-regulates activity" "chemical activation" 9606 15036565 t gcesareni "One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)" SIGNOR-243961 "all-cis-5,8,11,14,17-icosapentaenoic acid" smallmolecule CHEBI:28364 ChEBI FBN1 protein P35555 UNIPROT "up-regulates quantity by expression" 9606 16467281 f "Regulation of expression" miannu "It was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin." SIGNOR-251910 MAPK3 protein P27361 UNIPROT DEPTOR protein Q8TB45 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser235 MELLNEKsPSSQETH -1 35216969 t miannu "Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay." SIGNOR-277587 PXN protein P49023 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" 9606 BTO:0000182 phosphorylation:Tyr88 PQSSSPVyGSSAKTS 27447856 f lperfetto "Together, our data suggest that phosphorylation of paxillin Y88 activates AKT through the paxillin-p130Cas-p85/PI3K-AKT signaling axis and promotes colorectal tumorigenesis" SIGNOR-263979 DYRK2 protein Q92630 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000150 22307329 t lperfetto "Degradation of c-jun/c-myc is a critical process for the g(1)/s transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 ? (gsk3?). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this gsk3? Modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase dyrk2 functions as a priming kinase of c-jun and c-myc.The finding that kinase-active dyrk2 phosphorylated gst_c-jun210_310-wt by detection with an anti_phospho_c-jun(ser243) antibody demonstrated that dyrk2 is a ser243 kinase in vitro" SIGNOR-195771 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR "form complex" binding 9606 23397623 t miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270912 GOT2 protein P00505 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "down-regulates quantity" "chemical modification" 9606 31422819 t miannu "This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-268059 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT "up-regulates activity" phosphorylation Ser299 FLELVVSsDKREARQ 9606 17006539 t gcesareni "A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK." SIGNOR-149948 COL4A5 protein P29400 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t "Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)" SIGNOR-254669 CSNK2A1 protein P68400 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" phosphorylation Ser692 IPDDDEDsYEIFEPP -1 9525959 t llicata "Factor Va, the essential cofactor for prothrombinase, is phosphorylated on the acidic COOH terminus of the heavy chain of the cofactor, at Ser692, by a platelet membrane-associated casein kinase II (CKII). | The phosphorylated cofactor has increased susceptibility to inactivation by activated protein C, since phosphorylated factor Va was found to be inactivated approximately 3-fold faster than its native counterpart." SIGNOR-250862 Gbeta proteinfamily SIGNOR-PF4 SIGNOR POLR2A protein P24928 UNIPROT down-regulates phosphorylation 9606 14662762 t "inferred from 70% family members" lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-270039 ABL1 protein P00519 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Tyr143 SPAGRSIyNSFYVYC 9606 BTO:0000142 20823226 t llicata "Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function." SIGNOR-167853 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273914 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763 12193595 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-91738 PRKAA2 protein P54646 UNIPROT HNF4A protein P41235 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser313 GKIKRLRsQVQVSLE 10029 BTO:0000246 12740371 t miannu "AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. Phosphorylation of HNF4α on Ser-304 reduces protein stability." SIGNOR-250322 EXOC3 protein O60645 UNIPROT "Exocyst_EXOC6 variant" complex SIGNOR-C492 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270786 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249278 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM64C protein A6NLI5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271272 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 10090 20610653 f miannu "Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors." SIGNOR-260329 "2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester" chemical CHEBI:95001 ChEBI CETP protein P11597 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191265 EXOSC8 protein Q96B26 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR "form complex" binding -1 24189234 t miannu "The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40)." SIGNOR-261384 ARHGAP35 protein Q9NRY4 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260492 ACACB protein O00763 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI "down-regulates quantity" "chemical modification" 9606 20952656 t miannu "ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA" SIGNOR-267106 MFGE8 protein Q08431 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 10116 31958465 f miannu "We demonstrated that Milk fat globule-EGF factor8 (MFGE8) is protective against Ang-II-induced atrial fibrosis and atrial fibrillation. In vitro, silencing of MFGE8 by small interfering RNA significantly increased Ang-II-induced atrial fibrosis, whereas administration of recombinant human MFGE8 (rhMFGE8) attenuated the atrial fibrosis." SIGNOR-260646 CAPN1 protein P07384 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains" SIGNOR-251584 "Late macropinosomes" phenotype SIGNOR-PH229 SIGNOR "Lysosome fusion" phenotype SIGNOR-PH231 SIGNOR up-regulates 9606 39000072 f miannu "The fusion of matured macropinosomes with lysosomes is promoted by TRPML1, and degradation of macropinosomes is inhibited by mTORC1." SIGNOR-277787 SRC protein P12931 UNIPROT TNK2 protein Q07912 UNIPROT "up-regulates activity" phosphorylation 9606 26677978 t miannu "Dasatinib sensitivity in samples from patients with TNK2 mutations ( xref ) could result from either direct inhibition of TNK2 kinase activity itself, or indirectly through inhibition of SRC kinases by dasatinib, since SRC can activate TNK2 by directly phosphorylating the TNK2 activation loop ( xref ).|In addition to phosphorylation in response to EGFR signaling, TNK2 can also be activated by other receptor tyrosine kinases ( xref ), and phosphorylation of the TNK2 activation loop by SRC is required for its kinase activity ( xref )." SIGNOR-279082 SREBF2 protein Q12772 UNIPROT ABCG8 protein Q9H221 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21123766 f miannu "these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α." SIGNOR-254456 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT unknown phosphorylation Ser696 PNKELPPsPEKKTKP 9606 BTO:0000567 10791892 t miannu "We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region" SIGNOR-277461 ITGB8 protein P26012 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257729 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 30230471 f lperfetto "In keeping with the overall improvement in insulin sensitivity we found that insulin-induced IR Y1162/Y1163 tyrosine phosphorylation and activation and downstream PI3K/AKT signaling in the liver (as monitored by AKT Ser-473 phosphorylation) were dramatically enhanced by POMC TCPTP deficiency (Figure 4h).|This would suggest that TCPTP deletion, or decreased TCPTP in POMC neurons in response to feeding, represses HGP by enhancing IR signaling and permitting POMC neurons to be activated by insulin." SIGNOR-276956 SIK2 protein Q9H0K1 UNIPROT SIK2 protein Q9H0K1 UNIPROT "up-regulates activity" phosphorylation Ser343 RLKSHRSsFPVEQRL -1 27478041 t miannu "SIK2 S358 Autophosphorylation Is a Marker of SIK2 Activity" SIGNOR-277268 CYP1B1 protein Q16678 UNIPROT 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000093 8790407 t Luana "These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens." SIGNOR-269754 TRIM13 protein O60858 UNIPROT TRIM13 protein O60858 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 31744379 t miannu " In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1). " SIGNOR-272219 GSK3B protein P49841 UNIPROT BLM protein P54132 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr171 ETSKSFVtPPQSHFV 9606 BTO:0002181 26028025 t miannu "We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates." SIGNOR-276906 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 10090 BTO:0000887 24145169 f "The BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling" SIGNOR-256487 IL12A protein P29459 UNIPROT IFNG protein P01579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10653850 f miannu "IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12" SIGNOR-260861 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding -1 BTO:0000567 16729043 t lperfetto "We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K." SIGNOR-236327 CD40LG protein P29965 UNIPROT IGSF6 protein O95976 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 9809579 f miannu "CD40L activation of dendritic cells down-regulates DORA, a novel member of the immunoglobulin superfamily" SIGNOR-261727 "hydrogen peroxide" smallmolecule CHEBI:16240 ChEBI MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 f gcesareni "These findings suggest that c-src mediated bmk1 activation by h(2)o(2) may counteract ischemic cellular damage probably through the activation of mef2c transcription factor." SIGNOR-113758 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Ser51 ADGHRGPsAAFAPAA 9606 33388549 t miannu "P -Ser9 GSK-3\u03b2 phosphorylates Ser43, Ser51, and Ser493 residues of src, regulating src activity." SIGNOR-278443 AURKA protein O14965 UNIPROT SOX8 protein P57073 UNIPROT "up-regulates activity" phosphorylation Ser327 SAPSASAsPTETGPP 9606 BTO:0000410 32550913 t miannu "We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance." SIGNOR-273548 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 21658387 t lperfetto "Lrrk2 directly phosphorylates akt1 as a possible physiological substrate. These data establish that lrrk2 can protect neurons from apoptotic insult through a survival pathway in which lrrk2 signals to activate akt. Lrrk2-mediated phosphorylation of akt1 (ser473)" SIGNOR-244410 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499-2 UNIPROT down-regulates phosphorylation Ser579 YQSTIPQsPSPAPDD 9606 10828059 t "The effect has been demonstrated using Q08499-5" llicata "The pde4d2 isoform is inhibited by erk2 phosphorylation" SIGNOR-77563 EGR1 protein P18146 UNIPROT HSD11B2 protein P80365 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15659537 f miannu "Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50." SIGNOR-253876 EDNRA protein P25101 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0000671 10199825 t gcesareni "We studied the ability of et receptors to activate galfa13 using an assay for g protein alfa-chain activation that is based on the fact that an activated (gtp-bound) alfa-chain is resistant to trypsinization compared with an inactive (gdp-bound) alfa-chain." SIGNOR-66856 CCT137690 chemical CID:25154041 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190895 mTORC1 complex SIGNOR-C3 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 21659604 t lperfetto "The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase." SIGNOR-217063 FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18612045 f lperfetto "Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity" SIGNOR-235367 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Thr74 SVLTGKLtTVFLPIV -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263587 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 12576312 t lperfetto "Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of rhoa and is inhibited by cgmp-dependent protein kinase phosphorylation. Three phosphorylation sites have been identified in vasp: ser157, ser239, and thr278, all of which can be phosphorylated by either pka or pkg in vitro" SIGNOR-98139 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 16782899 t llicata "Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain" SIGNOR-147183 S1PR3 protein Q99500 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257330 IKBKE protein Q14164 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" phosphorylation 9606 15489227 t miannu "Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro." SIGNOR-217379 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 8385099 t "The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor." SIGNOR-252692 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000007 12475979 t "When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365))," SIGNOR-248703 NOD1 protein Q9Y239 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000567 19898471 f miannu "Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria." SIGNOR-252404 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-154261 PTPRG protein P23470 UNIPROT DAB1 protein O75553 UNIPROT "down-regulates activity" dephosphorylation Tyr198 EDVEDPVyQYIVFEA -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254697 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT "up-regulates activity" phosphorylation Ser1217 PIKNLHSsHSSGLMD 9606 BTO:0000565 28630147 t miannu "Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C)." SIGNOR-266420 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" binding 9606 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-236152 FOXJ1 protein Q92949 UNIPROT TEKT2 protein Q9UIF3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000939 23822649 t miannu "FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1)." SIGNOR-266937 N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91439 ChEBI TBK1 protein Q9UHD2 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190795 SLBP protein Q14493 UNIPROT H2AW protein Q7L7L0 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265409 glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" "chemical inhibition" 9606 32745890 t miannu "Glucose deprivation, activates the glucose level–sensing kinase, AMPK, which in turn influences Rac1-dependent macropinocytosis. In this context macropinosomes take up necrotic cell debris as a rich nutrient source to fuel tumor cell growth" SIGNOR-277765 UTS2R protein Q9UKP6 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257377 SLC6A3 protein Q01959 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 30465801 t miannu "Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles." SIGNOR-269189 MAD2L2 protein Q9UI95 UNIPROT FZR1 protein Q9UM11 UNIPROT "down-regulates activity" binding -1 11459826 t miannu "The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1" SIGNOR-264902 AKT1 protein P31749 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t llicata "Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis." SIGNOR-164884 WNT1 protein P04628 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131571 PIK3R1 protein P27986 UNIPROT PIK3CD protein O00329 UNIPROT "up-regulates activity" binding 9534 14665640 t lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242643 KLHL9 protein Q9P2J3 UNIPROT CEBPD protein P49716 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000527 25303533 t miannu "KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ." SIGNOR-272459 TFE3 protein P19532 UNIPROT LAMP1 protein P11279 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 24448649 f lperfetto "Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A)." SIGNOR-276825 YAP1 protein P46937 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23075495 f gcesareni "Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis." SIGNOR-256669 MDM2 protein Q00987 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 BTO:0001938 12646252 t gcesareni "These data strongly suggest thatmdm2functions as the ubiquitin ligase toward hnumb and that it induces its degradation in intact cells." SIGNOR-99497 MAPK8 protein P45983 UNIPROT BMF protein Q96LC9 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 12591950 t miannu "Activated JNK causes BimL and Bmf phosphorylation in vivo. It is known that UV radiation causes the release of Bim and Bmf from dynein and myosin V motor complexes and that these proteins cause Bax/Bak-dependent apoptosis . The results of this study demonstrate that JNK can engage this apoptotic pathway by phosphorylation of BH3-only proteins, including Bim and Bmf." SIGNOR-250116 ATR protein Q13535 UNIPROT PARP1 protein P09874 UNIPROT "down-regulates activity" phosphorylation Ser179 FRPEYSAsQLKGFSL 9606 BTO:0000018 33811702 t miannu "Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site-specific phosphorylation inactivates PARP1, inhibiting ionophore-induced necrosis." SIGNOR-277551 RBX1 protein P62877 UNIPROT "BAF250b E3 ligase" complex SIGNOR-C522 SIGNOR "form complex" binding 9606 BTO:0000567 20086098 t miannu "In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro" SIGNOR-271439 PRKCA protein P17252 UNIPROT PITPNC1 protein Q9UKF7 UNIPROT "up-regulates activity" phosphorylation Ser274 SVRSAPSsAPSTPLS 9534 BTO:0000298 21728994 t done miannu "Only BIM-I caused a reduction in 14-3-3 binding (Figure 3B), suggesting that PKC could be responsible for one or both of the serine phosphorylations, pSer274 and pSer299." SIGNOR-273800 CDK1 protein P06493 UNIPROT PPP1R13L protein Q8WUF5 UNIPROT "up-regulates activity" phosphorylation Ser113 LHPYSPLsPKGRPSS 9606 30105797 t done miannu "Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53. " SIGNOR-273586 RPS6KA1 protein Q15418 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 7838153 t gcesareni "Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii." SIGNOR-34113 HP protein P00738 UNIPROT HBB protein P68871 UNIPROT "down-regulates quantity" binding 9606 9315856 t "Regulation of binding" miannu "Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers." SIGNOR-251815 MTOR protein P42345 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 29789464 f Luana "The mTOR complexes are essential to neurogenesis and the establishment of neural circuits. | Activation of mTOR complexes exerts profound effects on all the processes of neurogenesis, including dendrite formation." SIGNOR-265771 TCF7L1 protein Q9HCS4 UNIPROT NANOG protein Q9H9S0 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001581 16894029 t Luana "These experiments showed that Tcf3 is associated with chromatin in the Nanog promoter regions and that the DNA-binding activity of Tcf3 was required for repression." SIGNOR-266081 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 BTO:0000017 28192398 t miannu "We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation. " SIGNOR-277341 EID1 protein Q9Y6B2 UNIPROT EP300 protein Q09472 UNIPROT "down-regulates activity" binding 11073990 t lperfetto "Inhibition of MyoD may be explained by EID-1's ability to bind and inhibit p300's histone acetylase activity, an essential MyoD coactivator." SIGNOR-253377 SPEN protein Q96T58 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 12374742 t gcesareni "We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen." SIGNOR-94201 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000763;BTO:0000149 10197981 t llicata "Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain." SIGNOR-66742 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 11404076 t gcesareni "Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip." SIGNOR-86125 NOG protein Q13253 UNIPROT BMPR2 protein Q13873 UNIPROT "down-regulates activity" binding 9031 SIGNOR-C29 12478285 t "Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function" lperfetto "Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955). Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors" SIGNOR-219225 TNF protein P01375 UNIPROT NOD2 protein Q9HC29 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18647246 f miannu "NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B." SIGNOR-252407 SMARCD3 protein Q6STE5 UNIPROT "Muscle cell-specific SWI/SNF ARID1B variant" complex SIGNOR-C482 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270705 SSTR4 protein P31391 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256959 STUB1 protein Q9UNE7 UNIPROT PRKN protein O60260 UNIPROT "up-regulates activity" binding -1 12150907 t miannu "In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6). " SIGNOR-272888 SYK protein P43405 UNIPROT LAX1 protein Q8IWV1 UNIPROT "up-regulates activity" phosphorylation Tyr373 SNEDSSDyENVLTAK 9606 BTO:0000007 12359715 t miannu "Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85. " SIGNOR-273535 MID1IP1 protein Q9NPA3 UNIPROT ACACA protein Q13085 UNIPROT "up-regulates activity" binding 10029 BTO:0000457 20952656 t miannu "Recently, we reported the discovery that MIG12, a 183 amino acid protein, binds to ACC1 and ACC2, which induces polymerization and subsequently increases the enzymatic activity of the protein" SIGNOR-267111 STAT3 protein P40763 UNIPROT S100A9 protein P06702 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18809714 f miannu "Accumulation of myeloid-derived suppressor cells (MDSCs) associated with inhibition of dendritic cell (DC) differentiation is one of the major immunological abnormalities in cancer and leads to suppression of antitumor immune responses. The molecular mechanism of this phenomenon remains unclear. We report here that STAT3-inducible up-regulation of the myeloid-related protein S100A9 enhances MDSC production in cancer." SIGNOR-261931 NR1I2 protein O75469 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000003 18540626 f miannu "Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals." SIGNOR-254834 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" dephosphorylation Ser114 HISPAQGsPKPPPAA -1 29945972 t miannu "MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation." SIGNOR-277880 FOXO1 protein Q12778 UNIPROT POMC protein P01189 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000614 28270795 f miannu "Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations." SIGNOR-263503 WNT5A protein P41221 UNIPROT FZD4 protein Q9ULV1 UNIPROT "up-regulates activity" binding 9606 16602827 t areggio "We show that in addition to its inhibitory function, Wnt5a can also activate beta-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4." SIGNOR-258954 PTH1R protein Q03431 UNIPROT CYP24A1 protein Q07973 UNIPROT "up-regulates quantity" 28363951 f lperfetto "These PTH actions are mainly mediated by Gsalpha signaling, which induces the expression of the gene encoding 25-hydroxyvitamin D 1alpha-hydroxylase (Cyp27b1) and destabilizes the transcript encoding vitamin D 24-hydroxylase (Cyp24a1)" SIGNOR-270555 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto "Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals." SIGNOR-235995 "8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid" chemical CID:92577 PUBCHEM PTPN11 protein Q06124 UNIPROT "down-regulates activity" "chemical inhibition" -1 19233143 t lperfetto "In this study, we screened protein tyrosine phosphatases (PTPs) by in vitro phosphatase assays to identify PTPs that are inhibited by 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), a potent inhibitor of SHP-1 and SHP-2 PTPs." SIGNOR-261977 CYCS protein P99999 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9390557 t lperfetto "Caspase-9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cytochrome c and datp, an event that leads to caspase-9 activation." SIGNOR-53585 PRKAA1 protein Q13131 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser486 DDEITEAKsGTATPQRS -1 17023420 t "We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators" SIGNOR-256114 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT "up-regulates activity" phosphorylation Ser45 LGIRSSKsAGALEEG 9606 BTO:0002524 30631047 t miannu "Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Function assay of ARMC10 and ARMC10 phosphorylation at S45." SIGNOR-277792 KLHL22 protein Q53GT1 UNIPROT PLK1 protein P53350 UNIPROT "down-regulates activity" binding -1 23455478 t miannu "Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors. " SIGNOR-272108 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 7925415 t lperfetto "Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-34691 PHLPP1 protein O60346 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" dephosphorylation Ser338 RPRGQRDsSYYWEIE 10090 24530606 t gcesareni "PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression." SIGNOR-237449 AMOT protein Q4VCS5 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates relocalization 9606 BTO:0000567 21205866 t "AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity." gcesareni "Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition." SIGNOR-175776 LRRC4 protein Q9HBW1 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 9606 BTO:0000142 25526788 f miannu "The overexpression of LRRC4/NGL-2 suppresses glioma cell growth, angiogenesis and invasion through complicated signaling regulation networks." SIGNOR-264060 CLP1 protein Q92989 UNIPROT "CFII complex" complex SIGNOR-C387 SIGNOR "form complex" binding 9606 BTO:0000567 30139799 t lperfetto "Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1." SIGNOR-266120 CIITA protein P33076 UNIPROT HLA-DOB protein P13765 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11823510 f "Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA." SIGNOR-254015 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT "down-regulates activity" phosphorylation Ser253 QEALQKLsDVTLVPV 33850055 t lperfetto "TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o" SIGNOR-275646 SEC23A protein Q15436 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265289 P4HB protein P07237 UNIPROT ERN1 protein O75460 UNIPROT "down-regulates activity" binding 32149426 t lperfetto "The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a ""foldase"" into a ""holdase"", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity." SIGNOR-275573 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT "up-regulates activity" binding 9606 11502070 t lperfetto "The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd." SIGNOR-109719 GNG2 protein P59768 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR "form complex" binding 9606 23994464 t apalma "Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit" SIGNOR-255005 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0000222 BTO:0000887;BTO:0001103 18676376 t gcesareni "The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c." SIGNOR-179796 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" binding 9606 22252525 t gcesareni "The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor." SIGNOR-195414 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR TP53 protein P04637 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 11950834 t irozzo "Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro.Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control." SIGNOR-256285 SETDB1 protein Q15047 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR "form complex" binding 10090 21952300 t FFerrentino "The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43." SIGNOR-253522 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001289 21489980 f miannu "Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. We propose that methylation of the TM promoter is responsible for silencing of TM expression in MM tissue, a process that is regulated by PARP1." SIGNOR-254893 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1242 ATSMFDDyQGDSSTL 9606 9722576 t lperfetto "Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor." SIGNOR-59754 MARCHF8 protein Q5T0T0 UNIPROT SLC3A2 protein P08195 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 21757542 t miannu "Taken together, these findings demonstrate that MARCH8 directly ubiquitinates CD98, and this likely leads to its routing to late endosomes for degradation." SIGNOR-272755 CAMK2G protein Q13555 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275795 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF6 protein O60337 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271248 NEFM protein P07197 UNIPROT "Neurofilament L/M" complex SIGNOR-C207 SIGNOR "form complex" binding 9606 19468066 t miannu "Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H" SIGNOR-255271 CPT1B protein Q92523 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI "down-regulates quantity" "chemical modification" 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267127 ATM protein Q13315 UNIPROT KHSRP protein Q92945 UNIPROT up-regulates phosphorylation Ser670 GPGAPPGsQPDYSAA 9606 21329876 t lperfetto "The atm kinase directly binds to and phosphorylates ksrp, leading to enhanced interaction between ksrp and pri-mirnas and increased ksrp activity in mirna processing" SIGNOR-172127 "bis(2-ethylhexyl) phthalate" chemical CHEBI:17747 ChEBI HCAR2 protein Q8TDS4 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 27551952 t miannu "We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR)." SIGNOR-268772 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser83 YSGSEGDsESGEEEE -1 2046671 t llicata "Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro. We report here that serine 83 appears to be the residue phosphorylated by CKII but that three other serines in this region can also be involved in phosphorylation and the enhancement of DNA-binding activity." SIGNOR-250958 SNRPD3 protein P62318 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270662 BCR protein P11274 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260526 CSNK1A1 protein P48729 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Ser12 FSLHDALsGSGNPNP -1 8253806 t llicata "L-29, a soluble lactose-binding lectin, is phosphorylated on serine 6 and serine 12 in vivo and by casein kinase I." SIGNOR-250789 WNT11 protein O96014 UNIPROT FZD6 protein O60353 UNIPROT "up-regulates activity" binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni "Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors." SIGNOR-141431 S1PR3 protein Q99500 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257175 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT "up-regulates activity" phosphorylation Ser487 GQPTSMLsPRHRMSP 9606 BTO:0000801 29170386 t "Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties." SIGNOR-256097 CSNK2A1 protein P68400 UNIPROT LIG1 protein P18858 UNIPROT "up-regulates activity" phosphorylation Ser66 KAARVLGsEGEEEDE 9606 BTO:0000567 12851383 t lperfetto "Moreover, these data confirmed the occurrence of Ser66 phosphorylation, which was previously studied with a specific monoclonal antibody (23)." SIGNOR-103258 STAT5A protein P42229 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 t "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" SIGNOR-261551 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by destabilization" 10090 17548510 f "Simone Vumbaca" "Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability" SIGNOR-255637 PRKCD protein Q05655 UNIPROT TBL1XR1 protein Q9BZK7 UNIPROT "up-regulates activity" phosphorylation Ser123 AAASQQGsAKNGENT 9606 18374649 t Manara "In addition, we describe that the functions and the specificity of these two highly- related exchange factors is tightly regulated by signal-induced phosphorylation events at the level of target gene promoters, as exemplified by the role of TBLR1 phosphorylation at Ser 123 by PKCδ upon retinoic acid or estrogen stimulation." SIGNOR-260903 Ub:E2 complex SIGNOR-C497 SIGNOR KCMF1 protein Q9P0J7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271242 WNK4 protein Q96J92 UNIPROT STK39 protein Q9UEW8 UNIPROT "up-regulates activity" phosphorylation Ser371 VRRVPGSsGHLHKTE 16990453 t lperfetto "Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1" SIGNOR-264641 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 f gcesareni "In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation." SIGNOR-178639 metaproterenol chemical CHEBI:6792 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" SIGNOR-257873 TRAF6 protein Q9Y4K3 UNIPROT MCL1 protein Q07820 UNIPROT "up-regulates activity" ubiquitination 9606 25340740 t miannu "TRAF6 likely directly ubiquitinates MCL-1 since purified TRAF6 promoted the ubiquitination of recombinant GST-MCL-1 and co-expression of Tax with TRAF6 further enhanced MCL-1 ubiquitination .|Therefore, TRAF6 mediated MCL-1 stabilization appears to be a common mechanism of cell survival usurped by both viral and non viral cancers." SIGNOR-278726 RPS6KB1 protein P23443 UNIPROT PIP5K1C protein O60331 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr553 QPRYRRRtQSSGQDG 27780861 t miannu "Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation." SIGNOR-277282 AKT1 protein P31749 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates phosphorylation Ser159 LLRERKSsAPSHSSQ 9606 11782427 t lperfetto "Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation." SIGNOR-252468 AKT proteinfamily SIGNOR-PF24 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0003324 25323588 t miannu "Earlier studies found that expression of active Akt increases mitochondrial HK activity and the anti-apoptotic effect of Akt required mitoHK" SIGNOR-267577 FBXW7 protein Q969H0 UNIPROT CCDC6 protein Q16204 UNIPROT down-regulates binding 9606 BTO:0000551 23108047 t miannu "Fbxw7 interacts with and targets ccdc6 for ubiquitin-mediated proteasomal degradation" SIGNOR-199279 Ub:E2 complex SIGNOR-C497 SIGNOR TRIML1 protein Q8N9V2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271200 EDN1 protein P05305 UNIPROT EDNRB protein P24530 UNIPROT up-regulates binding 9606 16597412 t gcesareni "Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors." SIGNOR-145762 QRICH1 protein Q2TAL8 UNIPROT FARS2 protein O95363 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269403 ARNTL protein O00327 UNIPROT MAGEL2 protein Q9UJ55 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 22208286 t miannu "Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization." SIGNOR-253517 RET protein P07949 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000944 15994200 t lperfetto "The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity" SIGNOR-252619 axitinib chemical CHEBI:66910 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150 21297102 t gcesareni "Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine." SIGNOR-171857 FLT3 protein P36888 UNIPROT XRCC5 protein P13010 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 21228325 f fcortellessa "We detected an approximately 5-fold decrease in Ku86 expression in early pro-B cells from FLT3/ITD mice compared with the wild-type controls. These data support the finding that FLT3/ITD mutations exert a suppressive role on Ku86 expression." SIGNOR-261684 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12857757 t gcesareni "We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch)." SIGNOR-103611 p38 proteinfamily SIGNOR-PF16 SIGNOR BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 10116 15486195 t miannu "Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination." SIGNOR-260443 DPYD protein Q12882 UNIPROT 5-fluorouracil chemical CHEBI:46345 ChEBI "down-regulates quantity" "chemical modification" 9606 10499634 t miannu "Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil." SIGNOR-253987 NEUROD1 protein Q13562 UNIPROT MGAT5B protein Q3V5L5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001976 21771782 f miannu "By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression." SIGNOR-253825 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT "up-regulates activity" phosphorylation Tyr692 HEELTVLySELKKTH -1 12051764 t miannu "Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2." SIGNOR-274007 PTGER1 protein P34995 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." SIGNOR-256811 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "up-regulates quantity" "precursor of" 9606 31422819 t miannu "This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-267512 DTNBP1 protein Q96EV8 UNIPROT ABI1 protein Q8IZP0 UNIPROT "up-regulates activity" binding 10116 BTO:0000601 20531346 t miannu "Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1." SIGNOR-265660 PRKCA protein P17252 UNIPROT MEP1B protein Q16820 UNIPROT "down-regulates quantity" phosphorylation Ser687 KKYRERMsSNRPNLT 9534 BTO:0001538 12941954 t miannu "These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate." SIGNOR-263172 ALDH1A1 protein P00352 UNIPROT D-glyceraldehyde smallmolecule CHEBI:17378 ChEBI "down-regulates quantity" "chemical modification" 9606 23444097 t miannu "Aldehyde dehydrogenases (ALDHs) couple the oxidation of aldehydes to the reduction of NAD(P)(+) . These enzymes have gained importance as they have been related to the detoxification of aldehydes generated in several diseases involving oxidative stress." SIGNOR-280249 CAD protein P27708 UNIPROT (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI "up-regulates quantity" "chemical modification" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267420 "AL/b2 integrin" complex SIGNOR-C169 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257712 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20584981 f fspada "Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program." SIGNOR-166426 RPS6KA5 protein O75582 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 12213813 t lperfetto "Phosphorylation of Bad at Ser112 in response to growth factors or cytokines is generally linked to cell survival. Knockdown of MSK1 suppressed Bad phosphorylation after calcium ionophore A23187 treatment in neuronal cells" SIGNOR-262990 SCN5A protein Q14524 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253401 DVL1 protein O14640 UNIPROT PLCB1 protein Q9NQ66 UNIPROT "up-regulates activity" 9606 19279717 t areggio "Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin" SIGNOR-258978 JAK1 protein P23458 UNIPROT STAT2 protein P52630 UNIPROT "up-regulates activity" phosphorylation 9606 9020188 t lperfetto "The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-?, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases." SIGNOR-88285 RNF8 protein O76064 UNIPROT H2AX protein P16104 UNIPROT up-regulates ubiquitination 9606 18001824 t gcesareni "Rnf8 can ubiquitylate histone h2a and h2ax," SIGNOR-159309 HOXC13 protein P31276 UNIPROT DSG4 protein Q86SJ6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000552 19683850 f miannu "we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle." SIGNOR-254184 PRKACA protein P17612 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Thr138 GGFIRRVtNDARENE 10116 BTO:0001009 12459461 t miannu "Thr138 as the exclusive site of SNAP-25 phosphorylation by protein kinase A in vivo. PMA or forskolin treatment alone resulted in dramatic phosphorylation of SNAP-25 Ser187 and/or Thr138 without appreciable neurotransmitter release." SIGNOR-250052 RAB1A protein P62820 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 27479033 t Giulio "Hemagglutinin (HA)-Rab1A is associated with mTOR and Raptor, not Rictor (Figure S2A), and is bound more with Myc-Raptor than Myc-mTOR (Figures S2B and S2C).|Rab1A Is an mTORC1 Activator and a Colorectal Oncogene" SIGNOR-261286 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM59 protein Q8IWR1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271123 PRKACA protein P17612 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation 10090 23644383 t milica "Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381." SIGNOR-236991 GAST protein P01350 UNIPROT EGR1 protein P18146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000269 22228178 f "Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation." SIGNOR-254252 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser539 GLITINSsQEHLTVQ 9606 22123827 t lperfetto "Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication." SIGNOR-177797 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr22 GVLPSHYyESFLEKK 9606 12540842 t lperfetto "To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src." SIGNOR-247333 TLN1 protein Q9Y490 UNIPROT ITGB7 protein P26010 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257633 AKT proteinfamily SIGNOR-PF24 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT "down-regulates activity" phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 BTO:0000759 17554339 t lperfetto "Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin." SIGNOR-155532 IL1B protein P01584 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32446778 f "doi: 10.1016/j.cytogfr.2020.05.003" miannu "Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α)" SIGNOR-260855 DGC complex SIGNOR-C217 SIGNOR NRXN1 protein P58400 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 11470830 t miannu "In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan." SIGNOR-265447 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR up-regulates 25901680 f lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262602 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr288 IDDNEYAyLKAIIFF 9606 22308320 t lperfetto "Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function." SIGNOR-195900 AURKA protein O14965 UNIPROT CETN2 protein P41208 UNIPROT up-regulates phosphorylation Ser170 LRIMKKTsLY 9606 BTO:0000150 21731694 t llicata "Our studies show that aurora a phosphorylates centrin at serine 170 in vitro and that the serine 170 phosphorylation affects the stability of centrin by regulating its interaction with apc/c. finally we demonstrated that phosphorylation of centrin serine 170 is an absolute requirement for aurora a-mediated centriole amplification." SIGNOR-174686 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 19282669 t lperfetto "Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway" SIGNOR-252961 CDK1 protein P06493 UNIPROT PPM1D protein O15297 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 t lperfetto "Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20)" SIGNOR-275489 APC-c complex SIGNOR-C150 SIGNOR CCNB1 protein P14635 UNIPROT "down-regulates quantity by destabilization" ubiquitination 21596315 t lperfetto "Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B." SIGNOR-265051 dactolisib chemical CHEBI:71952 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21803746 t "ATP-competitive inhibitor of PI3K and mTOR" gcesareni "While the pi3k inhibitors, ly294002 or wortmannin, in the presence of plx4032 were individually inactive against pprm cell lines (fig. S4), the dual pi3k and mtorc1/2 inhibitor bez235 was highly specific (vs. parental lines) and potent in growth-inhibiting pprm cell lines" SIGNOR-175709 CDK5RAP2 protein Q96SN8 UNIPROT TUBG1 protein P23258 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 17959831 t Giulio "Immunoprecipitation of CDK5RAP2 specifically coprecipitated _TuRC components, as detected on immunoblots of _-tubulin and GCP3 (Figure 3A).| Perturbing CDK5RAP2 function delocalized gamma-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in gammaTuRC attachment and therefore in the microtubule organizing function of the centrosome." SIGNOR-260310 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9534 7791754 t fspada "Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor." SIGNOR-33440 NUP62 protein P37198 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262079 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser44 PGTALVGsQKEPSEV 9606 10617144 t fspada "In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64" SIGNOR-73606 PFDN2 protein Q9UHV9 UNIPROT "URI1 prefoldin co-chaperone" complex SIGNOR-C514 SIGNOR "form complex" binding 9606 30484151 t miannu "In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR96" SIGNOR-270919 PRKCG protein P05129 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto "The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization." SIGNOR-202788 MASP2 protein O00187 UNIPROT C2 protein P06681 UNIPROT "up-regulates activity" cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 t lperfetto "The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase" SIGNOR-263416 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 15541388 t lperfetto "Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles." SIGNOR-216896 Zalospirone chemical CID:163925 PUBCHEM HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258864 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT "up-regulates activity" phosphorylation Ser51 GVVSESDsPVKRPGR 9606 BTO:0000567 12851383 t lperfetto "Thus, phosphorylation of serine 51 on hligi plays a critical role in regulating the interaction between hligi and rfc, which is required for efficient dna replication and repair." SIGNOR-103246 CSNK2A1 protein P68400 UNIPROT CERS4 protein Q9HA82 UNIPROT "up-regulates activity" phosphorylation Ser347 IRSDVEEsDSSEEAA 9606 BTO:0000007 26887952 t miannu "Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. " SIGNOR-273983 bortezomib chemical CHEBI:52717 ChEBI PSMB1 protein P20618 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000898 21504411 t miannu "Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma." SIGNOR-259306 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser362 AAAHRKGsSSNEPSS 16055710 t lperfetto "Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos" SIGNOR-262996 "ER stress" stimulus SIGNOR-ST9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates 9606 22492984 f gcesareni "Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins" SIGNOR-196941 PRKACA protein P17612 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates activity" phosphorylation Ser65 HSHSPRHsLRHSPGS 9606 30017192 t miannu "In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia." SIGNOR-256153 RPS3A protein P61247 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262420 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0000944 SIGNOR-C3 17510057 t lperfetto "mTORC1 catalyzes the phosphorylation of eIF4E binding protein-1 (4EBP1, also known as PHAS-I) and p70 S6 kinase 1 (S6K1)Phosphorylation of S6K1 at Thr-389" SIGNOR-235507 STAT5A protein P42229 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 23132946 f irozzo "We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells." SIGNOR-255885 KANSL1 protein Q7Z3B3 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu "Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation." SIGNOR-267172 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 23028682 t lperfetto "The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program." SIGNOR-217268 CYP26A1 protein O43174 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "down-regulates activity" "chemical inhibition" 9606 9716180 t Gianni "The RA-induced CYP26 was shown to be highly specific for the hydroxylation of all-trans-RA and did not recognize the 13-cis and 9-cis isomers. This substrate specificity is promising for finding retinoids that are not recognized by this enzyme and, therefore, could be more effective in growth inhibition of susceptible cancer cells." SIGNOR-266425 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT "up-regulates activity" phosphorylation Tyr398 HLGADGVyLDDLTDM 9606 BTO:0002181 33203880 t miannu "Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride." SIGNOR-277292 CGA protein P01215 UNIPROT TSH complex SIGNOR-C412 SIGNOR "form complex" binding 9606 BTO:0001379 8196184 t scontino "TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors." SIGNOR-267046 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-252865 PAK3 protein O75914 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser714 EGVRNIKsMWEKGNV 9606 BTO:0000887;BTO:0001260 20858431 t gcesareni "We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin." SIGNOR-167976 C7 protein P10643 UNIPROT "Membrane attack complex" complex SIGNOR-C313 SIGNOR "form complex" binding -1 30552328 t lperfetto "The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer" SIGNOR-263443 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser203 PRLQHSFsFAGFPSA 9606 18326031 t lperfetto "Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation." SIGNOR-161270 EFNA5 protein P52803 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9330863 t tpavlidou "Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor" SIGNOR-52476 HSPA1A protein P0DMV8 UNIPROT PACRG protein Q96M98 UNIPROT "up-regulates quantity by stabilization" binding -1 12150907 t miannu "Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo." SIGNOR-272890 UFL1 protein O94874 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000007 30886146 t lperfetto "UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage." SIGNOR-265073 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT "up-regulates activity" cleavage Thr663 IATVIVItLVMLKKK -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261793 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Pro) smallmolecule CHEBI:29177 ChEBI "up-regulates quantity" "chemical modification" 9606 27911719 t lperfetto "RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)" SIGNOR-269493 MIF protein P14174 UNIPROT CXCR4 protein P61073 UNIPROT "up-regulates activity" binding 10090 BTO:0000876 17435771 t gcesareni "We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis." SIGNOR-252062 PPARD protein Q03181 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001951 18048767 f miannu "Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs." SIGNOR-255053 NEDD4 protein P46934 UNIPROT SAG protein P10523 UNIPROT "down-regulates quantity" ubiquitination 9606 25216516 t miannu "These data collectively indicate that NEDD4-1 negatively regulates the SAG protein levels.|Third, NEDD4-1 promotes SAG poly-ubiquitylation and degradation, as demonstrated by both in vitro and in vivo ubiquitylation assays." SIGNOR-278610 CDH3 protein P22223 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265865 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248515 NMUR2 protein Q9GZQ4 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257010 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT "up-regulates activity" binding 9606 27629041 t miannu "Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival" SIGNOR-260174 FOXJ1 protein Q92949 UNIPROT SPAG6 protein O75602 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000939 23822649 t miannu "FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1)." SIGNOR-266935 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor" SIGNOR-198747 DCAF11 protein Q8TEB1 UNIPROT GEN1 protein Q17RS7 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 31409866 t miannu "(WDR23) isoforms differentially ubiquitinate (GEN1). In the presence of the necessary components for a successful ubiquitination reaction (CUL4A-DDB1-WDR23 complex, UBE1, UBE2D1, ubiquitin, and ATP) GEN1 receives the addition of ubiquitin in a time dependent manner." SIGNOR-272258 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8702662 t lperfetto "A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function" SIGNOR-42968 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257968 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii" SIGNOR-203544 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0000567 10806207 t llicata "Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity." SIGNOR-77204 MYOD1 protein P15172 UNIPROT SMARCA4 protein P51532 UNIPROT up-regulates binding 9606 SIGNOR-C92 17194702 t miannu "Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes" SIGNOR-151685 PIM1 protein P11309 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation 9606 25280219 t "FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells" SIGNOR-261557 BAG3 protein O95817 UNIPROT HSPA8 protein P11142 UNIPROT "up-regulates activity" binding -1 27474740 t lperfetto "Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70." SIGNOR-254116 QRICH1 protein Q2TAL8 UNIPROT FARSB protein Q9NSD9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269404 GSK3A protein P49840 UNIPROT PKD2 protein Q13563 UNIPROT unknown phosphorylation Ser76 AGAAASPsPPLSSCS 9606 BTO:0000007 BTO:0000671 16551655 t llicata "We report the identification of a new phosphorylation site for pc2 within its n-terminal domain (ser(76)) and demonstrate that this residue is phosphorylated by glycogen synthase kinase 3 (gsk3)." SIGNOR-145306 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" phosphorylation Ser327 DPEMEEDsYDSFGEP -1 9558331 t llicata "In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites." SIGNOR-250800 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Thr178 NHNHRIRtNPAIVKT 10090 BTO:0001103 17609368 t gcesareni "AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter" SIGNOR-228642 ETF1 protein P62495 UNIPROT "Translation release factor ERF1-ERF3" complex SIGNOR-C494 SIGNOR "form complex" binding 9606 29735640 t miannu "Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex." SIGNOR-270813 CSNK1D protein P48730 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Ser159 GIPVRCYsAEVVTLW -1 10500146 t llicata "We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro." SIGNOR-250798 ARF6 protein P62330 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 14973189 f lperfetto "ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface" SIGNOR-272154 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 t lperfetto "Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation." SIGNOR-235709 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT "up-regulates activity" phosphorylation Ser464 DKEGLSEsVRSSCTL 9606 20643644 t Manara "We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase." SIGNOR-260796 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM71 protein Q2Q1W2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271014 BDKRB2 protein P30411 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256974 FGF4 protein P08620 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni "Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides." SIGNOR-18567 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-252815 "vinorelbine L-tartrate" chemical CHEBI:32296 ChEBI TUBB protein P07437 UNIPROT "down-regulates activity" "chemical inhibition" 9606 7740336 t miannu "Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) and paclitaxel (Taxol; Bristol-Myers Oncology, Princeton, NJ) as single-agent therapy exhibit good activity in breast and lung cancers. Because these agents bind to distinct sites on tubulin and affect microtubules in opposite ways, a pilot study was conducted of the combination of vinorelbine and paclitaxel in patients with metastatic breast cancer or lung cancer who were refractory to first-line chemotherapy." SIGNOR-259348 STAT6 protein P42226 UNIPROT RETN protein Q9HD89 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 20508200 f lperfetto "Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation." SIGNOR-249536 AURKA protein O14965 UNIPROT PIN1 protein Q13526 UNIPROT "down-regulates activity" phosphorylation Ser16 PGWEKRMsRSSGRVY 9606 23970419 t llicata "Here, we found that aurora a can interact with and phosphorylate pin1 at ser16, which suppresses the g2/m function of pin1 by disrupting its binding ability and mitotic entry." SIGNOR-202487 atomoxetine chemical CHEBI:127342 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2." SIGNOR-259067 MCHR2 protein Q969V1 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257334 naltrexone chemical CHEBI:7465 ChEBI OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258936 FOXO1 protein Q12778 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 18391974 f "Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism." SIGNOR-253010 MCU protein Q8NE86 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270874 SRC protein P12931 UNIPROT DAPP1 protein Q9UN19 UNIPROT "up-regulates activity" phosphorylation Tyr139 KVEEPSIyESVRVHT 9606 BTO:0000776 10880360 t lperfetto "Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell linesyrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins." SIGNOR-247119 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Ser281 NRRQLAFsTVGTPDY 9606 12493777 t lperfetto "We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo" SIGNOR-96679 SOX9 protein P48436 UNIPROT OTX2 protein P32243 UNIPROT "up-regulates activity" binding 10090 20530484 t miannu "BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles." SIGNOR-255184 TUT7 protein Q5VYS8 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 f lperfetto "Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails." SIGNOR-268345 PIK3R1 protein P27986 UNIPROT PIK3CG protein P48736 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 14665640 t lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242646 SNCA protein P37840 UNIPROT VAMP2 protein P63027 UNIPROT "down-regulates quantity" binding 9606 BTO:0000938 31110017 t miannu "The normal function of the small presynaptic protein α-synuclein (α-syn) is of exceptional interest, not only in the context of neurodegeneration, but also as a cytosolic regulator of neurotransmission. we show that α-syn-VAMP2 interactions are necessary for α-syn-induced synaptic attenuation. Our data connect divergent views and suggest a unified model of α-syn function. the data indicate that α-syn–VAMP2 binding is essential for α-syn function and advocate an “interlocking model” where α-syn multimers on the SV surface interact with VAMP2 on adjacent SVs, helping to maintain physiologic SV clustering." SIGNOR-264104 Enolase proteinfamily SIGNOR-PF74 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9534 BTO:0000318 2005901 t "inferred from family member" Luana "This result suggests that MBP-1 in vivo acts as a sequence-specific repressor." SIGNOR-270308 HCRTR1 protein O43613 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257128 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159476 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10980595 t llicata "We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway" SIGNOR-81460 MC4R protein P32245 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257336 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr720 IPKEPSNyDFVYDCN 9606 15952790 t llicata "We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts." SIGNOR-138158 ACTL6A protein O96019 UNIPROT "Muscle cell-specific SWI/SNF ARID1B variant" complex SIGNOR-C482 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270712 FGR protein P09769 UNIPROT FGR protein P09769 UNIPROT "up-regulates activity" phosphorylation Tyr412 RLIKDDEyNPCQGSK -1 8612628 t "Autophosphorylation of c-Fgr under basal conditions involves Tyr-400 (homologous of c-Src Tyr-416) but not, to any appreciable extent, Tyr-511. Both Tyr-511 and Tyr-400, however, incorporate phosphate if autophosphorylation is performed in the presence of polycationic peptides, such as polylysine, histones H1 and protamines. Such a double phosphorylation induced by polylysine gives rise to an upshifted form of c-Fgr on SDS-PAGE and correlates with a stimulation of catalytic activity instead of a down-regulation" SIGNOR-251143 IC-87114 chemical CHEBI:90686 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206187 PARVA protein Q9NVD7 UNIPROT "IPP complex" complex SIGNOR-C380 SIGNOR "form complex" binding 16493410 t lperfetto "Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton." SIGNOR-265761 TGFB1 protein P01137 UNIPROT TAGLN protein Q01995 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20846954 f Regulation miannu "We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes." SIGNOR-251924 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120012 SLBP protein Q14493 UNIPROT H2AC18 protein Q6FI13 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265396 PPP2CA protein P67775 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation Thr202 HDHTGFLtEYVATRW 9606 phosphorylation:Thr202 HDHTGFLtEYVATRW 16456541 t gcesareni "B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk" SIGNOR-144322 PRKCA protein P17252 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation Ser657 QSDFEGFsYVNPQFV 9606 15277524 t lperfetto "Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function" SIGNOR-127253 KLF10 protein Q13118 UNIPROT SIN3A protein Q96ST3 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 11438660 t miannu "detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A." SIGNOR-222394 etoposide chemical CHEBI:4911 ChEBI TOP2B protein Q02880 UNIPROT "down-regulates activity" "chemical inhibition" 9606 16101488 t miannu "Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II." SIGNOR-259326 "pyridoxal 5'-phosphate(2-)" smallmolecule CHEBI:597326 ChEBI PSAT1 protein Q9Y617 UNIPROT "up-regulates activity" "chemical activation" 3702 30034403 t lperfetto "Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction." SIGNOR-268561 GLI2 protein P10070 UNIPROT GLI1 protein P08151 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209629 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates phosphorylation 9606 18596912 t lbriganti "The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform" SIGNOR-210182 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 9606 23817177 t irozzo "RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity." SIGNOR-255708 SOSTDC1 protein Q6X4U4 UNIPROT WNT3 protein P56703 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242730 WNT8A protein Q9H1J5 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131987 EEF2K protein O00418 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser445 SGDSGYPsEKRGELD 9606 22669845 t gcesareni "The combination of eef2k autophosphorylation (targeting ser445) and a yet to be identified kinase (targeting ser441) would be needed to generate the eef2k phosphodegron specifically in response to dna damage." SIGNOR-197725 NSMCE1 protein Q8WV22 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR "form complex" binding -1 27427983 t miannu "The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks" SIGNOR-265483 GATA3 protein P23771 UNIPROT CD8A protein P01732 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8413295 f miannu "Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity." SIGNOR-254079 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr525 ALRADENyYKAQTHG 9606 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246617 ATG9A protein Q7Z3C6 UNIPROT YWHAE protein P62258 UNIPROT "up-regulates activity" binding 9606 25266655 t miannu "Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK." SIGNOR-266368 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257925 MARCHF9 protein Q86YJ5 UNIPROT PTPRJ protein Q12913 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001522 19457934 t miannu "MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. " SIGNOR-271535 sapropterin smallmolecule CHEBI:59560 ChEBI GCHFR protein P30047 UNIPROT "up-regulates activity" "chemical activation" 9606 11361142 t miannu "The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine" SIGNOR-252204 STAT1 protein P42224 UNIPROT "ISGF3 complex" complex SIGNOR-C124 SIGNOR "form complex" binding -1 8943351 t 2 miannu "The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3" SIGNOR-240606 SHANK2 protein Q9UPX8 UNIPROT ACTN1 protein P12814 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264584 SMURF1 protein Q9HCE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 t "Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes" gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps" SIGNOR-195660 nintedanib chemical CHEBI:85164 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257802 CDK2 protein P24941 UNIPROT UHRF1 protein Q96T88 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser675 KTKVEPYsLTAQQSS -1 26727879 t miannu "UHRF1 is phosphorylated by CDK2/cyclin A. In vitro kinase assay was performed with CDK2/cyclin A using recombinant wild-type UHRF1 or UHRF1-S674A mutant " SIGNOR-277192 PLEKHG3 protein A1L390 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260585 GSDMD protein P57764 UNIPROT Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates cleavage:Asp275 CLHNFLTdGVPAEGA 26375003 f lperfetto "These results establish that proteolytic cleavage at Asp275 in GSDMDis sufficient to instructmammalian cells to undergo pyroptosis" SIGNOR-256416 CHUK protein O15111 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "form complex" binding 9606 20300203 t gcesareni "The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta." SIGNOR-164506 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM JAK3 protein P52333 UNIPROT "down-regulates activity" "chemical inhibition" -1 24556163 t miannu "This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine" SIGNOR-262234 RXRA protein P19793 UNIPROT PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR "up-regulates activity" binding 10090 17613434 t irozzo "RXR Binding Increases the DNA-Binding Affinity of PML/RARA. Here, we demonstrate that the presence of the RARA heterodimeric partner RXR in the PML/RARA complex is required for leukemogenesis in transgenic mice. RXR greatly facilitates the binding of PML/RARA to DNA, but titration of RXR by PML/RARA could also contribute to transformation." SIGNOR-255804 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15769897 t "The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5. Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD." SIGNOR-261543 CDK5 protein Q00535 UNIPROT TLN1 protein Q9Y490 UNIPROT up-regulates phosphorylation Ser425 TMLEDSVsPKKSTVL 9606 19363486 t lperfetto "Cdk5 phosphorylated talin head at ser 425, inhibiting its binding to smurf1, thus preventing talin head ubiquitylation and degradation." SIGNOR-185210 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT "up-regulates activity" phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 BTO:0000452 8702790 t lperfetto "These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation." SIGNOR-43088 IL17A protein Q16552 UNIPROT KLF15 protein Q9UIH9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23332504 f fspada "Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic." SIGNOR-192474 SRC protein P12931 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000763 14978237 t lperfetto "The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation." SIGNOR-235696 PLK1 protein P53350 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19473992 f lperfetto "Plk1-mediated phosphorylation of topors regulates p53 stability. Herein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation." SIGNOR-185841 AURKB protein Q96GD4 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates phosphorylation Ser109 KETNRRKsLHPIHQG 9606 20471944 t lperfetto "To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant)." SIGNOR-165550 "SKA complex" complex SIGNOR-C364 SIGNOR "Ndc80 complex" complex SIGNOR-C361 SIGNOR "up-regulates activity" relocalization -1 22483620 t lperfetto "The Ska complex is an essential mitotic component required for accurate cell division in human cells. It is composed of three subunits that function together to establish stable kinetochore-microtubule interactions in concert with the Ndc80 network. |We discuss how this symmetric architecture might complement and stabilize the Ndc80-microtubule attachments" SIGNOR-265225 GNB5 protein O14775 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "down-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC" SIGNOR-267850 CDK2 protein P24941 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser286 TSGGVSEsPSGFSKH 9606 21765472 t lperfetto "Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency" SIGNOR-175079 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT "down-regulates activity" phosphorylation Ser2070 DEYNVTPsPPGTVLT 9606 BTO:0000007 12794074 t "Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes." SIGNOR-251254 TNFAIP1 protein Q13829 UNIPROT RHOA protein P61586 UNIPROT "down-regulates quantity" binding 9606 19782033 t miannu "BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex." SIGNOR-264235 CDK1 protein P06493 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr92 EVPDVTAtPARLLFF 9606 SIGNOR-C17 20526282 t gcesareni "Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons." SIGNOR-165867 MAPK1 protein P28482 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 t lperfetto "Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity" SIGNOR-161851 EEF1A1P5 protein Q5VTE0 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269552 CRP protein P02741 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates activity" 9606 BTO:0004602 17942113 f miannu "The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP-mediated pathway. In the present study, CRP-mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues." SIGNOR-252215 S1PR5 protein Q9H228 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256676 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18854138 f lperfetto "Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts." SIGNOR-181624 MRPL47 protein Q9HD33 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262349 CREB1 protein P16220 UNIPROT GDA protein Q9Y2T3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0000938 BTO:0000142 21715638 t lperfetto "In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches." SIGNOR-268968 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates phosphorylation Tyr321 LGQRIYQyIQSRFYR 9606 10910078 t lperfetto "Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site" SIGNOR-79764 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 10090 14585074 t lperfetto "Tradd mediates recruitment of the traf2 adaptor protein" SIGNOR-118770 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000150 12167717 f lperfetto "PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473," SIGNOR-252710 NTNG2 protein Q96CW9 UNIPROT LRRC4 protein Q9HBW1 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 19467332 t miannu "The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively." SIGNOR-264048 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 t gcesareni "The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation." SIGNOR-70603 EGFR protein P00533 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Tyr228 YPGGSDNyGSLSRVT 9606 BTO:0000017 14996911 t llicata "In A431 cells, epidermal growth factor induced striking p120 phosphorylation at Y228. Y228-phosphorylated p120 localized to adherens junctions and lamellipodia, and was significantly enhanced in cells around the colony periphery." SIGNOR-251092 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 12438563 t gcesareni "Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (4345) is required for signal transduction" SIGNOR-95626 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser588 QTLSDSLsGSSLYST -1 17711846 t done miannu "Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626)." SIGNOR-274096 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT "up-regulates activity" deacetylation Lys63 TGGMANVkAAPKIID 9606 BTO:0002806 30327428 t miannu "SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR" SIGNOR-262293 AKAP12 protein Q02952 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" relocalization 14657015 t lperfetto "A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor." SIGNOR-271835 SCN3A protein Q9NY46 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu "The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons." SIGNOR-253455 "AP-3/clathrin vescicle" complex SIGNOR-C250 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI "up-regulates quantity" relocalization 9606 25720354 t scontino "APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place." SIGNOR-267862 ING2 protein Q9H160 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001913 19437536 f miannu "ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression." SIGNOR-254491 GSK3B protein P49841 UNIPROT DPYSL5 protein Q9BPU6 UNIPROT "up-regulates activity" phosphorylation Thr516 TPLADTPtRPVTRHG 9606 BTO:0000938 25040932 t lperfetto "The T516 phosphorylation was achieved by the glycogen synthase kinase-3beta (GSK-3beta), which can phosphorylate the wildtype protein but not the non-phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin-binding property of CRMP5. Therefore, CRMP5-induced growth inhibition is dependent on T516 phosphorylation through the GSK-3beta pathway." SIGNOR-264835 IL22 protein Q9GZX6 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 17208301 t gcesareni "See table 2" SIGNOR-151880 CFAP53 protein Q96M91 UNIPROT DNAH11 protein Q96DT5 UNIPROT "up-regulates activity" binding 10090 BTO:0000379 33347437 t miannu "CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B)." SIGNOR-265545 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser408 GPLPRAPsISTVEPK 26843621 t "Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation." SIGNOR-253540 ITK protein Q08881 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 t lperfetto "These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2" SIGNOR-112475 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203588 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248628 MRGPRX1 protein Q96LB2 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257433 FRG1 protein Q14331 UNIPROT KMT5B protein Q4FZB7 UNIPROT "down-regulates activity" binding 10090 BTO:0000165 23720823 t miannu "Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis." SIGNOR-266639 RXRB protein P28702 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16683 PCSK5 protein Q92824 UNIPROT "Neurophysin 1" protein P01178-PRO_0000020496 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0001073 11690596 t miannu "Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension." SIGNOR-270336 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "up-regulates activity" binding 9606 10976919 t "inferred from family member" gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr" SIGNOR-267805 MC3R protein P41968 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257298 CXCL8 protein P10145 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252288 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 t milica "The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3)." SIGNOR-204841 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA7 protein Q9Y5G6 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265687 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t gcesareni "The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c." SIGNOR-84050 VEGFD protein O43915 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252278 MET protein P08581 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 22128289 t irozzo "For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS." SIGNOR-256261 PRKCB protein P05771 UNIPROT protein Q5T7P8 UNIPROT "up-regulates activity" phosphorylation Thr417 RRLKKKKtTIKKNTL 9606 BTO:0001277 16111671 t miannu "We have previously reported that synaptotagmin VI is present in human sperm cells and that a recombinant protein containing the C2A and C2B domains abrogates acrosomal exocytosis in permeabilized spermatozoa, an effect that was regulated by phosphorylation. We found by site-directed mutagenesis that Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain--a key region for the function of synaptotagmins--are the PKC target that regulates its inhibitory effect on acrosomal exocytosis. Similarly, we showed that Thr284 in the polybasic region of C2A (KCKLQTR) is the target for PKC-mediated phosphorylation in this domain." SIGNOR-273564 DUSP9 protein Q99956 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 21908610 t gcesareni "Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein." SIGNOR-176583 CSNK1E protein P49674 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 11524435 t gcesareni "Tcf3 is a substrate for both glycogen synthase kinase (gsk) 3 and casein kinase (ck) 1epsilon, and phosphorylation of tcf3 by ckiepsilon stimulates its binding to beta-catenin, an effect reversed by gsk3." SIGNOR-110056 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation 10029 BTO:0000246 15379552 t "inferred from 70% family members" lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-270060 GAB2 protein Q9UQC2 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12819203 t gcesareni "Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2we propose that gab1 and gab2 in cooperation with other adapter molecules might regulate the cellular localization of gc-gap under specific stimuli." SIGNOR-102628 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR VEPH1 protein Q14D04 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000938 22055343 f "In the neuronal differentiation" lperfetto "Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9" SIGNOR-269959 MAPK14 protein Q16539 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Thr311 NSLALSLtADQMVSA 9606 12138194 t gcesareni "P38 mitogen-activated protein kinase was involved in estrogen receptor activation by estrogens and mekk1. Here, we report estrogen receptor-dependent p38 activation by estrogens in endometrial adenocarcinoma cells and in vitro and in vivo phosphorylation of the estrogen receptor alpha mediated through p38. The phosphorylation site was identified as threonine-311 (thr(311)), located in helix 1 of the hormone-binding domain." SIGNOR-90823 PTPRG protein P23470 UNIPROT PTPRG protein P23470 UNIPROT "down-regulates activity" binding 9606 25624455 t miannu "The main regulatory mechanism of RPTP activity consists of the reversible transition from a homodimeric inactive form to a monomeric active form. PTPRG is constitutively expressed on monocyte plasma membrane as a homodimer with the WD involved in catalytic domain blockade." SIGNOR-254737 CAMK2A protein Q9UQM7 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT "down-regulates activity" phosphorylation Thr591 LKQGYNKtLLRLRLR -1 37193065 t miannu "CaM inhibits the function of TRPP3 through promoting CaMK2's phosphorylation towards T591 on TRPP3." SIGNOR-277798 PTH1R protein Q03431 UNIPROT SLC34A3 protein Q8N130 UNIPROT "down-regulates quantity" 28363951 f lperfetto "PTH inhibits reabsorption of phosphate from the glomerular filtrate in RPT by decreasing the abundance of sodium-phosphate co-transporters NPT2a and NPT2c on the apical membrane, thus enhancing renal phosphate excretion" SIGNOR-270557 SRC protein P12931 UNIPROT ARHGEF4 protein Q9NR80 UNIPROT up-regulates phosphorylation Tyr165 VGSEEDLyDDLHSSS 9606 BTO:0000017 18653540 t llicata "This observation strongly argues for the positive role of tyr94 phosphorylation in egf-induced asef activation following the activation of rac1." SIGNOR-179601 SEMA3C protein Q99985 UNIPROT PLXNA2 protein O75051 UNIPROT "up-regulates activity" binding 19666519 t lperfetto "Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes." SIGNOR-253151 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2G1 protein P62253 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271315 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr141 EDEAKFPtMNRRGAI 9606 19366211 t llicata "This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. a t141d substitution markedly increases basal lipid-independent pkcdelta activity;" SIGNOR-185279 bromocriptine chemical CHEBI:3181 ChEBI DRD3 protein P35462 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258722 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 9545235 t lperfetto "IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspasesThese findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis" SIGNOR-56484 NFYC protein Q13952 UNIPROT GFI1B protein Q5VTD9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19965638 f miannu "HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter." SIGNOR-254433 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR G3BP1 protein Q13283 UNIPROT "up-regulates activity" binding 30804210 t SARA "The RGG domain of G3BP1 could mediate the direct binding of HCV-dsRNA and poly(IC)" SIGNOR-260979 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259015 FYN protein P06241 UNIPROT PTPRF protein P10586 UNIPROT "up-regulates activity" phosphorylation 9534 12496362 t "LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. we confirmed that LAR dephosphorylated the phosphorylated tyrosine residues of Lck and Fyn, and tyrosine residue(s) in LAR PTPase D2 was phosphorylated by Fyn to supply Fyn SH2 binding site." SIGNOR-251180 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 t llicata "In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. " SIGNOR-250803 NARS1 protein O43776 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270457 PPARG protein P37231 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 32991581 t brain lperfetto "NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog," SIGNOR-263984 LTN1 protein O94822 UNIPROT "RQC complex" complex SIGNOR-C559 SIGNOR "form complex" binding 28528489 t lperfetto "The ribosome-bound quality control (RQC) complex is a multi-protein complex conserved throughout eukaryotes and composed of the E3 ubiquitin ligase Ltn1/Listerin, the ATPase Cdc48/p97 with its co-factors Ufd1/UFD1L and Npl4/NPLOC4, as well as the factors Rqc1/TCF25 and Rqc2/NEMF (Fig. 1)." SIGNOR-277694 MAPK14 protein Q16539 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation 9606 7479834 t gcesareni "Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression." SIGNOR-26511 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT "up-regulates activity" phosphorylation Tyr139 EKLRVLGyNQNGEWS -1 34144039 t miannu " PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2." SIGNOR-277302 AIRE protein O43918 UNIPROT ICA1 protein Q05084 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 22447927 t lperfetto "Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression." SIGNOR-268973 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 31257023 f "Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme." SIGNOR-259334 Ast-487 chemical CID:11409972 PUBCHEM FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259693 PGK1 protein P00558 UNIPROT "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI "down-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266502 GCSAM protein Q8N6F7 UNIPROT GRB2 protein P62993 UNIPROT "down-regulates activity" binding 9606 31362927 t miannu "Herein, we demonstrate that the adaptor protein HGAL, specifically expressed in GC lymphocytes and GC-derived lymphomas, directly binds to Grb2 upon BCR activation and negates the inhibitory effects of Grb2 on the BCR-induced biochemical signaling cascade. " SIGNOR-273608 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Thr292 PQLQAHStPHPDDFA 9606 12734188 t lperfetto "Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9." SIGNOR-101055 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258782 DCTN2 protein Q13561 UNIPROT Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR "up-regulates activity" relocalization 25364732 t lperfetto "ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores" SIGNOR-265018 FOXA1 protein P55317 UNIPROT SFTPB protein P07988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004299 18003659 f miannu "TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription." SIGNOR-254171 MARCHF5 protein Q9NX47 UNIPROT MFN1 protein Q8IWA4 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 20103533 t lperfetto "MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate." SIGNOR-272981 ROCK1 protein Q13464 UNIPROT RDX protein P35241 UNIPROT "up-regulates activity" phosphorylation Thr564 AGRDKYKtLRQIRQG 10090 BTO:0005065 9456324 t lperfetto " A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad. | In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active." SIGNOR-248994 MED10 protein Q9BTT4 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266656 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys22 GPRDGLKkERLLDDR 9606 7479976 t gcesareni "Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha." SIGNOR-26577 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 10197981 t llicata "Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain." SIGNOR-66746 PLK1 protein P53350 UNIPROT TP53BP1 protein Q12888 UNIPROT "down-regulates activity" phosphorylation Ser1618 LTKAADIsLDNLVEG -1 24703952 t lperfetto "Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Addition of the inhibitors for PLK1 and the p38 MAPK leads to a complete loss of pT1609/pS1618 signal within 3 hr in mitotic cells" SIGNOR-264413 CEP72 protein Q9P209 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 26297806 t lperfetto "By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically." SIGNOR-271720 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr106 EDPVTVEyITRYIAS 9606 25620702 t Manara "PSMA7 degradation is suppressed by c-Abl-mediated tyrosine phosphorylation at Y106" SIGNOR-260937