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 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 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 Naltriben chemical CID:5486827 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-258424 Naltrindole chemical CHEBI:81528 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-258817 Naltrindole chemical CHEBI:81528 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-258816 NAMPT protein P43490 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 12555668 t gcesareni "Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesi" SIGNOR-238602 "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 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 NANOG protein Q9H9S0 UNIPROT CDX2 protein Q99626 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-254622 NANOG protein Q9H9S0 UNIPROT CGA protein P01215 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-254623 NANOG protein Q9H9S0 UNIPROT CGB protein P01233 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-254624 NANOG protein Q9H9S0 UNIPROT DNMT1 protein P26358 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003298 22795133 t lperfetto "Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation" SIGNOR-253157 NANOG protein Q9H9S0 UNIPROT FOXA2 protein Q9Y261 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-253166 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 NANOG protein Q9H9S0 UNIPROT GATA4 protein P43694 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-254626 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 NANOG protein Q9H9S0 UNIPROT GATA6 protein Q92908 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-254627 NANOG protein Q9H9S0 UNIPROT GATA6 protein Q92908 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-253160 NANOG protein Q9H9S0 UNIPROT LAMB1 protein P07942 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-254628 NANOG protein Q9H9S0 UNIPROT PAX6 protein P26367 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-253164 NANOG protein Q9H9S0 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 f flangone "Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes." SIGNOR-242076 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 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN1 protein Q92952 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-258026 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 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 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN4 protein O15554 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-258025 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 naratriptan chemical CHEBI:7478 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-258338 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 15758953 t gcesareni "Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm" SIGNOR-134508 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni "Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm" SIGNOR-181631 NBN protein O60934 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-251505 NBR1 protein Q14596 UNIPROT GABARAPL1 protein Q9H0R8 UNIPROT up-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" SIGNOR-184264 NBR1 protein Q14596 UNIPROT GABARAPL2 protein P60520 UNIPROT up-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." SIGNOR-184267 NBR1 protein Q14596 UNIPROT GABARAP protein O95166 UNIPROT up-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" SIGNOR-184261 NCBP1 protein Q09161 UNIPROT IRF8 protein Q02556 UNIPROT "up-regulates activity" binding 9606 BTO:0001413 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-222939 NCK1 protein P16333 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" binding 9606 11494134 t lperfetto "We also show that overexpression of nck could repress the phosphorylation of cbl by abl in vivo. Studies with nck mutants suggested that the nck sh2 domain is responsible for inhibiting the activity of abl toward both cbl and nck itself, most likely by competing with the abl sh2 for tyrosine-phosphorylated binding sites" SIGNOR-109672 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 10026169 t lperfetto "Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors." SIGNOR-236512 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9534 BTO:0004055 8824201 t lperfetto "We describe here a specific interaction of the Nck adapter molecule with PAK1 both in vitro and in vivo. Association of Nck with PAK1 may serve to link this important regulatory kinase to cell activation by growth factor receptors." SIGNOR-236324 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 BTO:0000782 11157752 t lperfetto "Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors." SIGNOR-235947 NCK1 protein P16333 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10029 BTO:0000246 7862111 t lperfetto "We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located." SIGNOR-236321 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 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 NCKAP1 protein Q9Y2A7 UNIPROT "WRC complex" complex SIGNOR-C191 SIGNOR "form complex" binding 9606 21107423 t miannu "WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems" SIGNOR-253569 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 NCL protein P19338 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity" "translation regulation" 9606 BTO:0002731 16508016 t Regulation miannu "Nucleolin binds human β-globin mRNA. A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo" SIGNOR-251844 NCL protein P19338 UNIPROT MYBL1 protein P10243 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 10660576 t miannu "We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity." SIGNOR-221233 NCL protein P19338 UNIPROT MYB protein P10242 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 10660576 t miannu "We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity." SIGNOR-221236 NCOA1 protein Q15788 UNIPROT ALDOB protein P05062 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255061 NCOA1 protein Q15788 UNIPROT APOA5 protein Q6Q788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255064 NCOA1 protein Q15788 UNIPROT APOC3 protein P02656 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255065 NCOA1 protein Q15788 UNIPROT ASXL1 protein Q8IXJ9 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 16606617 t irozzo "We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation.Therefore, both the ability to bind SRC-1 and the autonomous activation of ASXL1 are required for its coactivator function. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR." SIGNOR-255924 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 NCOA1 protein Q15788 UNIPROT OTC protein P00480 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255062 NCOA1 protein Q15788 UNIPROT PCK2 protein Q16822 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255066 NCOA1 protein Q15788 UNIPROT PGR protein P06401 UNIPROT up-regulates 9606 10449719 f miannu "Progesterone receptor (pr) functions as a transcription factor that modulates the transcription of target genes in response to progesterone and other signals. The transcriptional activity of pr requires the involvement of coactivators such as steroid receptor coactivator-1 (src-1)." SIGNOR-70149 NCOA1 protein Q15788 UNIPROT RARA protein P10276 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000567 16606617 f irozzo "We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR." SIGNOR-255932 NCOA1 protein Q15788 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 BTO:0000149 12954634 t miannu "Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain." SIGNOR-100258 NCOA1 protein Q15788 UNIPROT STAT5B protein P51692 UNIPROT up-regulates binding 9606 BTO:0000149 12954634 t miannu "Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain." SIGNOR-100261 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-251531 NCOA2 protein Q15596 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" binding 10090 BTO:0000801 29170386 t "Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator." SIGNOR-256095 NCOA2 protein Q15596 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18584035 t gcesareni "Collectively, our data provide the first evidence that erbeta-deficiency protects against diet-induced ir and glucose intolerance which involves an augmented ppargamma signaling in adipose tissue. Moreover, our data suggest that the coactivators src1 and tif2 are involved in this interaction." SIGNOR-179175 NCOA2 protein Q15596 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 12503607 t gcesareni "Transcriptional coactivator for steroid receptors and nuclear receptors.nteracts with casp8ap2 and ttll5/stamp. Interacts with esr1, rara and rxra." SIGNOR-96827 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 NCOA3 protein Q9Y6Q9 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 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 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 NCOR1 protein O75376 UNIPROT BCL6 protein P41182 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10898795 t miannu "The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT." SIGNOR-252239 NCOR1 protein O75376 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22395773 t FFerrentino "In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription." SIGNOR-253507 NCOR1 protein O75376 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000094 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 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 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 NCOR2 protein Q9Y618 UNIPROT PGR protein P06401 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-101289 NCOR2 protein Q9Y618 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22395773 t FFerrentino "In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription." SIGNOR-253508 NCOR2 protein Q9Y618 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t "Ncor2 is a Skip corepressor" gcesareni "Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt." SIGNOR-74227 NCOR2 protein Q9Y618 UNIPROT SPEN protein Q96T58 UNIPROT up-regulates binding 9606 11331609 t gcesareni "Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt" SIGNOR-107260 NCR2 protein O95944 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 BTO:0000914 22021614 f miannu "NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. In this study, we show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through NKp44/ITIM." SIGNOR-260044 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 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12471034 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-96250 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 NCSTN protein Q92542 UNIPROT g-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-209711 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12471034 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-96253 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 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000975 14572442 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-118852 NCSTN protein Q92542 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 10993067 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-81936 N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide chemical CHEBI:91407 ChEBI JAK1 protein P23458 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191244 NDEL1 protein Q9GZM8 UNIPROT DYNC1H1 protein Q14204 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 11163259 t miannu "LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex" SIGNOR-252159 NDFIP2 protein Q9NV92 UNIPROT NEDD4 protein P46934 UNIPROT "up-regulates activity" relocalization 9606 BTO:0002181 26363003 t SARA "Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2." SIGNOR-260996 NDN protein Q99608 UNIPROT BMI1 protein P35226 UNIPROT down-regulates 9606 BTO:0000007 24392140 f lperfetto "In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity," SIGNOR-253384 NDN protein Q99608 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates 9606 24392140 f lperfetto "In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity," SIGNOR-253383 NDN protein Q99608 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates activity" binding 10090 BTO:0000920 24392139 t lperfetto "Necdin interacts with E2F transcription factors and suppresses E2F1-dependent transcriptional activation of the cyclin-dependent kinase Cdk1 gene. Here we show that necdin serves as a suppressor of NPC proliferation in the embryonic neocortex." SIGNOR-253382 NDN protein Q99608 UNIPROT EID1 protein Q9Y6B2 UNIPROT "up-regulates activity" binding 10090 BTO:0000165 18557765 t llicata "The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation." SIGNOR-237614 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 NDN protein Q99608 UNIPROT PIAS1 protein O75925 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 24911587 f 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 NDN protein Q99608 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007;BTO:0000793 26971449 t lperfetto "Necdin binds and stabilizes PGC-1α|Necdin strongly stabilizes PGC-1α by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration." SIGNOR-253390 NDRG1 protein Q92597 UNIPROT RAB4A protein P20338 UNIPROT up-regulates binding 9606 BTO:0000150;BTO:0001130 17786215 t miannu "In this report evidence is provided that ndrg1 is a rab4a effector protein that localizes to perinuclear recycling/sorting vesicles in the trans golgi network by binding to phophatidylinositol 4-phosphate and is involved in recycling of e-cadherin. This is the first demonstration providing evidence that ndrg1 is a rab4a effector recruiting to recycling/sorting endosomes." SIGNOR-157697 NEB protein P20929 UNIPROT WASL protein O00401 UNIPROT up-regulates binding 9606 21798082 t gcesareni "Igf1-akt signaling, by inhibiting gsk3b, allows the interaction of n-wasp with the unphosphorylated nebulin;the consequent recruitment of n-wasp to the z-disk promotes actin nucleation and elongation of actin filaments." SIGNOR-175671 NECAP1 protein Q8NC96 UNIPROT "AP-2 complex" complex SIGNOR-C245 SIGNOR "up-regulates activity" binding 9606 24130457 t lperfetto "Knockdown and functional rescue studies demonstrate that through these interactions, NECAP 1 and AP-2 cooperate to increase the probability of clathrin-coated vesicle formation and to control the number, size, and cargo content of the vesicles." SIGNOR-260710 NECTIN2 protein Q92692 UNIPROT CD226 protein Q15762 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 15039383 t lperfetto "CD226 (DNAM-1) is an adhesion molecule involved in NK and T cell-mediated cytotoxicity against certain tumors. Here, we have identified the human poliovirus receptor-related (PRR) family members CD155 [poliovirus receptor (PVR)] and CD112 (nectin-2/PRR-2) as the ligands for human CD226." SIGNOR-261426 NEDD1 protein Q8NHV4 UNIPROT TUBG1 protein P23258 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19029337 t miannu "It has been reported that NEDD1 directly interacts with and recruits the γ-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly" SIGNOR-261422 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 NEDD4L protein Q96PU5 UNIPROT SCN11A protein Q9UI33 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-253462 NEDD4L protein Q96PU5 UNIPROT SCN1A protein P35498 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-253457 NEDD4L protein Q96PU5 UNIPROT SCN3A protein Q9NY46 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-253464 NEDD4L protein Q96PU5 UNIPROT SCN4A protein P35499 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-253460 NEDD4L protein Q96PU5 UNIPROT SCN5A protein Q14524 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-253456 NEDD4L protein Q96PU5 UNIPROT SCN8A protein Q9UQD0 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-253461 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 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 NEDD4L protein Q96PU5 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates ubiquitination 9606 19917253 t gcesareni "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-161710 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 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-232104 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 9606 19917253 t gcesareni "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-161713 NEDD4 protein P46934 UNIPROT KCNH2 protein Q12809 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0002181 26363003 t SARA "We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels." SIGNOR-260998 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 nefazodone chemical CHEBI:7494 ChEBI SLC6A4 protein P31645 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-259068 NEFH protein P12036 UNIPROT "Neurofilament bundle assembly" phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 BTO:0000938 8376466 f miannu "Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons." SIGNOR-252390 NEFH protein P12036 UNIPROT "Neurofilament L/H" complex SIGNOR-C208 SIGNOR "form complex" binding 9606 BTO:0000938 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-255273 NEFL protein P07196 UNIPROT "Neurofilament bundle assembly" phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 BTO:0000938 8376466 f miannu "Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons." SIGNOR-252392 NEFL protein P07196 UNIPROT "Neurofilament L/H" complex SIGNOR-C208 SIGNOR "form complex" binding 9606 BTO:0000938 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-255272 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 NEK11 protein Q8NG66 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser88 DSGFCLDsPGPLDSK 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-187871 NEK1 protein Q96PY6 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates phosphorylation Ser193 DGTEFGGsIYQKVNK 9606 20230784 t lperfetto "Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux." SIGNOR-164222 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 NEK2 protein P51955 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 24695856 t lperfetto "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-204837 NEK2 protein P51955 UNIPROT NDC80 protein O14777 UNIPROT up-regulates phosphorylation Ser165 LGYPFALsKSSMYTV 9606 12386167 t lperfetto "Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo." SIGNOR-94322 NEK2 protein P51955 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation 9606 15161910 t esanto "Nek2 directly phosphorylated nek11 in the c-terminal non-catalytic region and elevated nek11 kinase activity." SIGNOR-124944 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Ser241 RRIPYRYsDELNEII 9606 17197699 t gcesareni "Enzymatic activity, inhibited;" SIGNOR-151767 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Thr179 FAKTFVGtPYYMSPE 9606 17197699 t gcesareni "Enzymatic activity, inhibited;" SIGNOR-151771 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser171 RILNHDTsFAKTFVG 9606 17197699 t gcesareni "Enzymatic activity, induced;" SIGNOR-151755 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr170 ARILNHDtSFAKTFV 9606 17197699 t gcesareni "Thus, it appears that autophosphorylation of thr-170 and/or ser-171 in nek2 may fine-tune overall activity of nek2 in vivo. regardless, the importance of thr-175 suggested by its conservation in many other kinases is underlined by the t175a mutant that shows reduced kinase activity and a significant reduction in efficiency of cs." SIGNOR-151759 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr175 HDTSFAKtFVGTPYY 9606 17197699 t gcesareni "Enzymatic activity, induced;" SIGNOR-151763 NEK2 protein P51955 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates phosphorylation Thr307 EKKKPNAtRPVTPPR 9606 10880350 t miannu "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-78306 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 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser14 LKKSFQDsLEDIKKR 9606 17621308 t lperfetto "Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)" SIGNOR-156878 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser507 TDLCFLNsPIFKQKK 9606 17621308 t lperfetto "Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)" SIGNOR-156882 NEK3 protein P51956 UNIPROT NEK3 protein P51956 UNIPROT "down-regulates activity" phosphorylation T165 FACTYVGTPYYVPPE -1 27489110 t Manara "Autophosphorylation at Thr-165 is required for NEK3 kinase activity in vitro." SIGNOR-260919 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT "up-regulates activity" phosphorylation Ser377 PPFNPNVsGPNDLRH -1 12023960 t miannu "The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6." SIGNOR-250296 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 NEK9 protein Q8TD19 UNIPROT NEK6 protein Q9HC98 UNIPROT "up-regulates activity" phosphorylation Ser206 SETTAAHsLVGTPYY 9606 BTO:0000007 12840024 t lperfetto "Nercc1/nek9 activates the nek6 and nek7 kinases. Nercc1 catalyzes the direct phosphorylation of prokaryotic recombinant nek6 at ser206 in vitro concomitant with 20-25-fold activation of nek6 activity." SIGNOR-102996 NEK9 protein Q8TD19 UNIPROT NEK7 protein Q8TDX7 UNIPROT "up-regulates activity" phosphorylation Ser195 SKTTAAHsLVGTPYY 9606 BTO:0000007 12840024 t lperfetto "Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity" SIGNOR-103030 NEK9 protein Q8TD19 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates phosphorylation Ser944 GQQVGMHsKGTQTAK 9606 21454704 t lperfetto "We find that the interaction of lc8 with nek9 depends on a (k/r)xtqt motif adjacent to the nek9 c-terminal coiled coil motif, results in nek9 multimerization, and increases the rate of nek9 autoactivation. Lc8 binding to nek9 is regulated by nek9 activity through the autophosphorylation of ser(944), a residue immediately n-terminal to the (k/r)xtqt motif." SIGNOR-173026 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 neostigmine chemical CHEBI:7514 ChEBI ACHE protein P22303 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001239 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-257758 nepicastat chemical CHEBI:139334 ChEBI DBH protein P09172 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194625 neratinib chemical CHEBI:61397 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-258254 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000551 17311002 t gcesareni "However, the same cells were highly sensitive to the irreversible dual-specificity egfr/erbb2 kinase inhibitor hki-272, as were those overexpressing wild-type erbb2." SIGNOR-153318 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194628 neratinib chemical CHEBI:61397 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-258255 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 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194631 NET1 protein Q7Z628 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-260561 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 NEU1 protein Q99519 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0003554 32164705 f Giorgia "Taken together, these findings indicate that NEU1 overexpression reduces cell proliferation and enhances cell apoptosis through by downregulation of FN-integrin β1-mediated Akt signaling pathway." SIGNOR-260659 NEU1 protein Q99519 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0003554 32164705 f miannu "Our data showed that NEU1 inhibited cancer cell proliferation, induced apoptosis, and suppressed tumor formation both in vitro and in vivo, by disrupting interaction of FN and integrin β1 and inhibiting the Akt signaling pathway." SIGNOR-260657 NEU1 protein Q99519 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000182 19151752 f Giorgia "One of the major molecular changes by NEU1 was decreased sialylation of integrin beta4, assessed by PNA- and MAL-II-lectin blotting of immunoprecipitates with anti-integrin beta4 antibody. The desialylation was accompanied by decreased phosphorylation of the integrin followed by attenuation of focal adhesion kinase and Erk1/2 pathway." SIGNOR-260656 NEU1 protein Q99519 UNIPROT ITGB4 protein P16144 UNIPROT "down-regulates activity" 9606 BTO:0000182 19151752 f Giorgia "In HT-29 cells cultured with 10% fetal bovine serum (FBS), the phosphorylation of integrin β4 was significantly decreased in NEU1-overexpressing cells and the level seemed to be inversely correlated with the sialidase activity. These results suggest that NEU1 is involved in the regulation of integrin β4 phosphorylation probably through desialylation in colon cancer cells." SIGNOR-260655 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 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 NEUROG3 protein Q9Y4Z2 UNIPROT INSM1 protein Q01101 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944 17300785 f miannu "The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32." SIGNOR-253814 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROD1 protein Q13562 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." SIGNOR-254630 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROD4 protein Q9HD90 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-254631 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROG1 protein Q92886 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." SIGNOR-254632 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROG2 protein Q9H2A3 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-254633 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 NEUROG3 protein Q9Y4Z2 UNIPROT VSX2 protein P58304 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-254635 "Neurokinin A" smallmolecule CHEBI:80311 ChEBI TACR2 protein P21452 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-257587 "Neurokinin B" smallmolecule CHEBI:80312 ChEBI TACR3 protein P29371 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-257588 "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 "neuropeptide FF receptor agonist" smallmolecule CHEBI:141000 ChEBI NPFFR1 protein Q9GZQ6 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-257549 "neuropeptide FF receptor agonist" smallmolecule CHEBI:141000 ChEBI NPFFR2 protein Q9Y5X5 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-257550 "Neuropeptide W-30" smallmolecule CHEBI:80256 ChEBI NPBWR1 protein P48145 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-257548 NF1 protein P21359 UNIPROT ADCY3 protein O60266 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-204034 NF1 protein P21359 UNIPROT ADCY4 protein Q8NFM4 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-204091 NF1 protein P21359 UNIPROT ADCY5 protein O95622 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-204140 NF1 protein P21359 UNIPROT ADCY6 protein O43306 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-204195 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 NF1 protein P21359 UNIPROT ADCY8 protein P40145 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-204289 NF1 protein P21359 UNIPROT ADCY9 protein O60503 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-204354 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 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000938 24431436 t miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204357 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 NF2 protein P35240 UNIPROT LATS2 protein Q9NRM7 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 Mst1/2" 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-202607 NFATC1 protein O95644 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-251730 NFATC1 protein O95644 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-251956 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 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 NFATC1 protein O95644 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR "up-regulates activity" 10358178 f "The transcription factor NF-ATc that controls gene expression in T lymphocytes and embryonic cardiac cells is expressed in three prominent isoforms." SIGNOR-252344 NFATC2 protein Q13469 UNIPROT FST protein P19883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15130492 t lperfetto "MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA" SIGNOR-251729 NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 11956291 f "IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production" SIGNOR-254502 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 NFATC2 protein Q13469 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 9606 11796223 t lperfetto "Upon dephosphorylation by calcineurin, nfatc2, also referred to as nfatp/nfat1, translocates to the nucleus where it directly associates with mef2a and -d. Nfatc2 stimulates mef2-dependent transcription by facilitating recruitment of the p300 coactivator to mef2-response elements." SIGNOR-117586 NFATC2 protein Q13469 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11796223 t lperfetto "Upon dephosphorylation by calcineurin, nfatc2, also referred to as nfatp/nfat1, translocates to the nucleus where it directly associates with mef2a and -d. Nfatc2 stimulates mef2-dependent transcription by facilitating recruitment of the p300 coactivator to mef2-response elements." SIGNOR-117589 NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 23612709 f miannu "Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin" SIGNOR-255465 NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates "transcriptional regulation" 9606 23612709 f "Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin" SIGNOR-255461 NFATC2 protein Q13469 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18676376 f gcesareni "€ provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis." SIGNOR-235006 NFATC3 protein Q12968 UNIPROT CTSD protein P07339 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16219765 f miannu "Overexpression of NFAT3 enhanced both ERalpha and ERbeta transcriptional activities in a ligand-independent manner and up-regulated downstream estrogen-responsive genes including pS2 and cathepsin D. Reduction of endogenous NFAT3 with NFAT3 small interfering RNA or overexpression of NFAT3 deletion mutants that lack the ER-binding sites reduced the NFAT3 coactivation of ERalpha and ERbeta." SIGNOR-254640 NFATC3 protein Q12968 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-251732 NFE2L1 protein Q14494 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000599 8962164 f irozzo "These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2." SIGNOR-256280 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 NFE2L2 protein Q16236 UNIPROT CAT protein P04040 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22493435 f miannu "BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2" SIGNOR-254651 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 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22459801 f miannu "Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed." SIGNOR-254643 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 24024136 f 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 NFE2L2 protein Q16236 UNIPROT GSTA1 protein P08263 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22459801 f miannu "Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed." SIGNOR-254644 NFE2L2 protein Q16236 UNIPROT GSTA1 protein P08263 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 24024136 f 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-256278 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22459801 f miannu "Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed." SIGNOR-254641 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 24024136 f 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 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 31257023 t "Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme." SIGNOR-259334 NFE2L2 protein Q16236 UNIPROT KRT16 protein P08779 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000552 18629308 f miannu "When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression." SIGNOR-254645 NFE2L2 protein Q16236 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-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-259285 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22459801 f miannu "Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed." SIGNOR-254642 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 24024136 f 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-256275 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000599 8962164 f irozzo "These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2." SIGNOR-256279 NFE2L2 protein Q16236 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-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-256262 NFE2L2 protein Q16236 UNIPROT TXN protein P10599 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000552 18629308 f miannu "When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression." SIGNOR-254646 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 NFE2 protein Q16621 UNIPROT HBD protein P02042 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-251843 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 NFE2 protein Q16621 UNIPROT HBG1 protein P69891 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-251841 NFE2 protein Q16621 UNIPROT HBG2 protein P69892 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-251840 NFIB protein O00712 UNIPROT NFIB protein O00712 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 9099724 t 2 miannu "Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function." SIGNOR-240883 NFIB protein O00712 UNIPROT NFIC protein P08651 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 9099724 t 2 miannu "Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function." SIGNOR-240880 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 9099724 t 2 miannu "Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function." SIGNOR-240915 NFIL3 protein Q16649 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003104 10082541 f lperfetto "NFIL3 inhibits apoptosis without affecting Bcl-xL expression." SIGNOR-256618 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 NFIL3 protein Q16649 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 10090 BTO:0003104 10082541 f lperfetto "the effect of NFIL3 on cytokine-mediated cell survival was independent of an effect on cell proliferation." SIGNOR-242760 NFIX protein Q14938 UNIPROT PKCtheta/Nfix complex SIGNOR-C121 SIGNOR "form complex" binding 10090 BTO:0000165 20178747 t llicata "In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A." SIGNOR-238016 NFKB1 protein P19838 UNIPROT BIRC2 protein Q13490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f gcesareni "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59948 NFKB1 protein P19838 UNIPROT BIRC3 protein Q13489 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f gcesareni "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59951 NFKB1 protein P19838 UNIPROT CD80 protein P33681 UNIPROT "up-regulates quantity by expression" "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-253934 NFKB1 protein P19838 UNIPROT CTCF protein P49711 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004298 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 NFKB1 protein P19838 UNIPROT IEX-1L protein O75353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9703517 f gcesareni "Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here. Its transcription induced by tnf was decreased in cells with defective nf-kappab activation, rendering them sensitive to tnf-induced apoptosis, which was abolished by transfection with iex-1l." SIGNOR-59539 NFKB1 protein P19838 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321 11909978 t "NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer." SIGNOR-253668 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 NFKB1 protein P19838 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-55375 NFKB1 protein P19838 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-253648 NFKB1 protein P19838 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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 NFKB1 protein P19838 UNIPROT THBD protein P07204 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004602 17211835 f miannu "Blocking the transcriptional activation of NF-kappaB prevented the TNFalpha-induced downregulation of TM." SIGNOR-254811 NFKB1 protein P19838 UNIPROT TRAF1 protein Q13077 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f gcesareni "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59954 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 NFKBIA protein P25963 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates activity" binding 9606 SIGNOR-C13 1340770 t lperfetto "Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b" SIGNOR-17688 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" binding 9606 1340770 t lperfetto "Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b" SIGNOR-217394 NFKBIA protein P25963 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C13 1340770 t lperfetto "Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b." SIGNOR-17691 NFKBIA protein P25963 UNIPROT S100A6 protein P06703 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 12859951 f miannu "Transient expression of NF-kappaB (p65) increased S100A6 promoter activity and expression of inhibitor of NF-kappaB (IkappaBalpha) decreased TNFalpha-induced S100A6 promoter activity. " SIGNOR-254804 NFKBIE protein O00221 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates binding 9606 BTO:0001271 SIGNOR-C13 12835716 t gcesareni "Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe" SIGNOR-102774 NFKBIE protein O00221 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 BTO:0001271 12835716 t lperfetto "Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe" SIGNOR-217361 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19763573 f miannu "PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB." SIGNOR-254654 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 22021368 f apalma "Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB." SIGNOR-255693 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR B2M protein P61769 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12480693 f miannu "The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m." SIGNOR-254658 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BHMT protein Q93088 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16953798 f miannu "SAM and MTA down-regulate BHMT expression in HepG2 cells in part by inducing NF-kappaB, which acts as a repressor for the human BHMT gene. While SAM's mechanism is NF-kappaB-dependent, MTA has both NF-kappaB-dependent and -independent mechanisms." SIGNOR-254659 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC2 protein Q13490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9916987 f gcesareni "The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop." SIGNOR-64100 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC3 protein Q13489 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9916987 f gcesareni "The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop." SIGNOR-64103 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL11 protein P51671 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16604092 f miannu "Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling." SIGNOR-254661 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 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-254509 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001103 20219869 t apalma "Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation." SIGNOR-255358 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 10409765 f lperfetto "Nf-kappab regulation of cyclin d1 occurs at the transcriptional level and is mediated by direct binding of nf-kappab to multiple sites in the cyclin d1 promoter." SIGNOR-235648 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCR3 protein P51677 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16604092 f miannu "Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling." SIGNOR-254660 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD40 protein P25942 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19164127 f miannu "We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40." SIGNOR-254785 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD80 protein P33681 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12860928 f miannu "Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor." SIGNOR-254783 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD83 protein Q01151 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19164127 f miannu "We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40." SIGNOR-254781 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CFI protein P05156 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10630630 f miannu "The production of CFI by Hep G2 cells was enhanced in a dose- and time-dependent fashion by 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), a potent PKC activator. The enhancement of the activity of transfected chimeric CAT constructs by TPA was abrogated by calphostin C and by pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB and AP-1 transactivation). These results indicate that TPA regulation of CFI gene requires PKC signalling and is mediated by via a TPA response element (TRE) in the CFI promoter region located at -136/-130 and involves the transactivation of AP-1 and NF-kappaB transcription factors" SIGNOR-254786 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EGR1 protein P18146 UNIPROT up-regulates binding 9606 10671503 t lperfetto "The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo" SIGNOR-216328 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EPCAM protein P16422 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11505407 f miannu "The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects." SIGNOR-254790 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR F3 protein P13726 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001949 12744731 f miannu "In conclusion, NF-kappaB could be activated promptly after HUVEC incubated with TNF-alpha, then it was bound to TF promotor to start the TF transcription, TF mRNA expression was upregulated, that leaded to the increase of TF expression on the HUVEC surface and activated the coagulation cascade." SIGNOR-254810 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Fibrosis phenotype SIGNOR-PH90 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-260446 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR FTH1 protein P02794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003212 19258503 f miannu "We show that inhibition of constitutively active NF-kappaB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS." SIGNOR-254792 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HES1 protein Q14469 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001938 24300895 f "These data indicate that basal NFκB activity at the conserved +26/+34 site of the HES1 gene promotes its expression, and that glucocorticoids can silence HES1 by inhibiting this activity." SIGNOR-253063 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HSD11B2 protein P80365 UNIPROT "up-regulates quantity by expression" "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-253877 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 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-255355 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001412 8021507 t "In these studies, we show that NF-kappa B induces transcription from the human pro-IL-1 beta (IL-1 beta) gene." SIGNOR-255938 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL4 protein P05112 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 15048722 f "We demonstrate that NF-kappa B binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappa B nuclear translocation in living cells blocked binding of NF-kappa B to the IL-4 promoter. The data provide first evidence that NF-kappa B is directly involved in IL-4 transcription" SIGNOR-254497 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto "The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response." SIGNOR-216319 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni "The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules." SIGNOR-245039 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 25309941 f "Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6)." SIGNOR-255489 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto "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-216322 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0002572 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR JUN protein P05412 UNIPROT up-regulates binding 9606 18174238 t lperfetto "Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment" SIGNOR-216337 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321 11909978 t "NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer." SIGNOR-253667 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR LCN2 protein P80188 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-254796 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR LTC4S protein Q16873 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001433 12574384 f miannu "activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism." SIGNOR-254799 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 BTO:0000801 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 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 20921405 f gcesareni "Nf-kb activation following t-cell receptor engagement induces the expression of mdm2 through interaction with nf-kb sites in its p1 promoter" SIGNOR-168296 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR miR-155 mirna MI0000681 miRBase "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004479 25092144 f miannu "We showed a strong induction of miR-155 promoter activity by p65. We demonstrate that NF-κB (p65) directly binds to the miR-155 promoter in FLT3-ITD-associated MV4;11 cells." SIGNOR-255816 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR miR-155 mirna MI0000681 miRBase "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000011 21986534 f "We revealed that TNFα treatment results in the up-regulation of miR-155 through the NFκB pathway in 3T3-L1 cells." SIGNOR-255935 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003858 12734180 f miannu "The suppressive effect of IGF-1 and OP-1 on MMP-13 expression was due in part to down-regulation of the expression of pro-inflammatory cytokines and the activity of their intermediate molecules, including NF-kappaB and AP-1 factors." SIGNOR-254800 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP9 protein P14780 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-254798 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001103 20219869 t apalma "Furthermore, NF-kB activation can cause destabilization of MyoD mRNA and degradation of MyoD protein (35, 49), which would further impede muscle differentiation" SIGNOR-255352 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NOS2 protein P35228 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-255353 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR 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-254805 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19643666 t lperfetto "Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways." SIGNOR-249566 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21357467 f gcesareni "The nfkb p65/p50 heterodimer increases sod2, and p50/p50 suppresses it nf-kb p65/p50 binds to the enhancer and is important for cytokine-induced sod2" SIGNOR-172392 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SP1 protein P08047 UNIPROT up-regulates binding 9606 10671503 t lperfetto "Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1." SIGNOR-216334 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 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 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR TP53 protein P04637 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 15044535 f gcesareni "These results indicate that nf-kb actions occur upstream of p53 to regulate both p53 levels and activity." SIGNOR-123602 N-formyl-L-methionyl-L-leucyl-L-phenylalanine smallmolecule CHEBI:53490 ChEBI FPR1 protein P21462 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-257492 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 NFX1 protein Q12986 UNIPROT SIN3A protein Q96ST3 UNIPROT "up-regulates activity" binding 9606 BTO:0004117 18505829 t miannu "we investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression." SIGNOR-226360 NFX1 protein Q12986 UNIPROT TERT protein O14746 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000007 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 NFX1 protein Q12986 UNIPROT TERT protein O14746 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004117 17267499 f miannu "NFX1-123 augments the activation of hTERT expression through interactions with PABPCs" SIGNOR-226015 NFYA protein P23511 UNIPROT CBS protein P35520 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12427542 f 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-254815 NFYA protein P23511 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15496512 f miannu "Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter." SIGNOR-252232 NFYA protein P23511 UNIPROT OGG1 protein O15527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14688259 f miannu "these results demonstrate that MMS can up-regulate hOGG1 expression through the induction of the transcription factor, NF-YA, and increased transcription level of the hOGG1 gene correlates with an increase in enzyme activity providing functional protection from MMS." SIGNOR-254817 NFYA protein P23511 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-254818 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 NFYB protein P25208 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15496512 f miannu "Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter." SIGNOR-252233 NFYB protein P25208 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-254431 NFYB protein P25208 UNIPROT NFY complex SIGNOR-C1 SIGNOR "form complex" binding 9606 BTO:0000801;BTO:0000876 9885213 t lperfetto "Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding." SIGNOR-63016 NFYB protein P25208 UNIPROT PHGDH protein O43175 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18378410 f miannu "Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y." SIGNOR-255210 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 NFY complex SIGNOR-C1 SIGNOR CCNB1 protein P14635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 BTO:0000887;BTO:0001103 10362252 f lperfetto "In conclusion, our data demonstrate that nf-y is required for cyclin b1 promoter activity." SIGNOR-235834 NFY complex SIGNOR-C1 SIGNOR CCNB2 protein O95067 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10086339 f gcesareni "In this study, we analysed the mechanisms leading to activation of the cyclin b2 ccaat boxes: a combination of (i) genomic footprinting, (ii) transfections with single, double and triple mutants, (iii) emsas with nuclear extracts, antibodies and nf-y recombinant proteins and (iv) transfections with an nf-ya dominant negative mutant established the positive role of the three ccaat sequences and proved that nf-y plays a crucial role in their activation." SIGNOR-65638 NFY complex SIGNOR-C1 SIGNOR ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000972 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 NFY complex SIGNOR-C1 SIGNOR TOP2A protein P11388 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25328138 t lperfetto "The expression of human TOP2A is controlled by its promoter region that contains two GC boxes and five CCAAT boxes. NF-Y recognizes and binds to the ICBs. This binding of NF-Y to the TOP2A promoter can be promoted by HMGB1/2 and inhibited by pRb." SIGNOR-242526 NFY complex SIGNOR-C1 SIGNOR ZDHHC5 protein Q9C0B5 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000526 28775165 t "Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y" SIGNOR-261151 NFYC protein Q13952 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15496512 f miannu "Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter." SIGNOR-252234 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 NFYC protein Q13952 UNIPROT NFY complex SIGNOR-C1 SIGNOR "form complex" binding 9606 BTO:0000801;BTO:0000876 9885213 t lperfetto "Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding." SIGNOR-63019 NGEF protein Q8N5V2 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-260562 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 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 BTO:0000007 10764727 t gcesareni "The low affinity neurotrophin receptor p75ntr can mediate cell survival as well as cell death of neural cells by ngf and other neurotrophins." SIGNOR-76832 NGF protein P01138 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 t gcesareni "Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb." SIGNOR-85114 NGF protein P01138 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003306 24493753 f miannu "Long-term (more than 24 h) treatment with nerve growth factor (NGF) upregulated Nav1.7 functional expression in the strongly metastatic MAT-LyLu rat PCa cell line; acute application had no effect" SIGNOR-253495 NGFR protein P08138 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14699954 f amattioni "Neurotrophin binding to p75ntrhas also been shown to induce apoptosis" SIGNOR-120558 NGFR protein P08138 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14699954 f amattioni "Neurotrophin binding to p75ntr has also been shown to induce apoptosis" SIGNOR-256655 NGFR protein P08138 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 14699954 f amattioni "Jnk3 is expressed exclusively in the nervous system and recent evidence indicates that this jnk isoform may be required for p75ntr-mediated cell death" SIGNOR-120561 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 NHLH2 protein Q02577 UNIPROT ASCL1 protein P50553 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21573214 f miannu "Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1." SIGNOR-254823 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 NHLH2 protein Q02577 UNIPROT MAOA protein P21397 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000142 22169038 f 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-254829 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 NHS protein Q6T4R5 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 20332100 f miannu "We demonstrate that NHS is essential for maintaining cell morphology through the regulation of actin cytoskeletal dynamics and suggest that an important mechanism of remodelling of the actin cytoskeleton during development would therefore be lost in patients with NHS." SIGNOR-253565 NHS protein Q6T4R5 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" relocalization 9606 20332100 t miannu "NHS knockdown also resulted in the mislocalization of the Arp2/3 complex and disruption of the actin cytoskeleton. in the absence of NHS, Arp2/3 localization and F-actin distribution are disrupted, suggesting that Arp2/3 actin-nucleation activity is mediated, in part, by NHS providing an additional functional link between NHS and actin." SIGNOR-253566 NHS protein Q6T4R5 UNIPROT "WRC complex" complex SIGNOR-C191 SIGNOR "up-regulates activity" relocalization 9606 20332100 t miannu "Excessive cell spreading and lamellipod extension as a result of NHS knockdown is likely to be a result of loss of WAVE complex regulation, leading to overactive WAVE activity or a dysregulation of nascent focal adhesions in lamellipodia.WAVE and NHS protein partners Abi1 and HSPC300, and the p34 subunit of the Arp2/3 complex, consistently localized at the edges of cells treated with NHS siRNA, independent of EGF stimulation and WAVE complex activation. These data show that localization of Abi1 and HSPC300 was altered in the absence of NHS." SIGNOR-253577 N-hydroxy-1-[(4-methoxyphenyl)methyl]-6-indolecarboxamide chemical CHEBI:94192 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189684 N-hydroxy-2-[4-[[(1-methyl-3-indolyl)methylamino]methyl]-1-piperidinyl]-5-pyrimidinecarboxamide chemical CHEBI:94771 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193513 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 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 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257924 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257982 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257930 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257986 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257987 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 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-257926 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 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257927 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257980 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 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-257928 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 "Niflumic acid" chemical CHEBI:34888 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-258062 nilotinib chemical CHEBI:52172 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-258256 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "down-regulates activity" "chemical inhibition" 9606 19108785 t irozzo "Nilotinib is an oral second-generation bcr-abl TKI indicated for the treatment of imatinib resistant or -intolerant Ph+ CML-CP and -AP in adults. Nilotinib binds to inactive configuration of the abl kinase, thus preventing the tyrosine phosphorylation of proteins involved in bcr-abl signal transduction. Nilotinib binds to the inactive (unphosphorylated) configuration of the abl TK, with the P-Ioop folding over, disrupting the ATP binding site and catalytic activity of the enzyme." SIGNOR-255818 nilotinib chemical CHEBI:52172 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-259269 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 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 nilotinib chemical CHEBI:52172 ChEBI PDGFRB protein P09619 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-258259 nilutamide chemical CHEBI:7573 ChEBI AR protein P10275 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194649 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 NIN protein Q8N4C6 UNIPROT JAK2 protein O60674 UNIPROT down-regulates binding 9606 25332239 t miannu "We showed that jak2 directly phosphorylates the n-terminus ofnineinwhile the c-terminus ofnineininhibits jak2 kinase activity in vitro." SIGNOR-205581 nintedanib chemical CHEBI:85164 ChEBI FGFR1 protein P11362 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-257804 nintedanib chemical CHEBI:85164 ChEBI FGFR2 protein P21802 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-257806 nintedanib chemical CHEBI:85164 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190299 nintedanib chemical CHEBI:85164 ChEBI FLT4 protein P35916 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-257801 nintedanib chemical CHEBI:85164 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190302 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 nintedanib chemical CHEBI:85164 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190305 nintedanib chemical CHEBI:85164 ChEBI PDGFRA protein P16234 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-257805 nintedanib chemical CHEBI:85164 ChEBI PDGFRB protein P09619 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-257799 nisoxetine chemical CHEBI:73410 ChEBI SLC6A2 protein P23975 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-257797 nitrendipine chemical CHEBI:7582 ChEBI KCNN4 protein O15554 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9730970 t miannu "IK was blocked by the classical inhibitors of the Gardos channel charybdotoxin (IC50 28 nM) and clotrimazole (IC50 153 nM) as well as by nitrendipine (IC50 27 nM), Stichodactyla toxin (IC50 291 nM), margatoxin (IC50 459 nM), miconazole (IC50 785 nM), econazole (IC50 2.4 microM), and cetiedil (IC50 79 microM). Finally, 1-ethyl-2-benzimidazolinone, an opener of the T84 cell IK channel, activated hIK with an EC50 of 74 microM." SIGNOR-258831 Nitrendipine chemical CID:4507 PUBCHEM 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-257767 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A2-B2 complex SIGNOR-C137 SIGNOR "up-regulates activity" binding 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 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A2-B3 complex SIGNOR-C138 SIGNOR "up-regulates activity" binding 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 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A3-B2 complex SIGNOR-C139 SIGNOR "up-regulates activity" binding 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 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A3-B3 complex SIGNOR-C140 SIGNOR "up-regulates activity" binding 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-243967 "nitric oxide" smallmolecule CHEBI:16480 ChEBI M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates BTO:0000801 BTO:0001103 24669294 f apalma "While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines" SIGNOR-255556 "nitric oxide" smallmolecule CHEBI:16480 ChEBI NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 BTO:0001103 20219869 t apalma "Similarly, exposure of cells to oxidative stress, in particular, nitric oxide (NO) or peroxynitrite (ONOO), can activate NF-kB and cause its translocation." SIGNOR-255350 nivolumab antibody DB09035 DRUGBANK PDCD1 protein Q15116 UNIPROT "down-regulates activity" binding 9606 BTO:0001023 26351349 t miannu "Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer." SIGNOR-259895 NKD1 protein Q969G9 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 20858476 t gcesareni "Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation" SIGNOR-167984 NKX2-1 protein P43699 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-254172 NKX2-5 protein P52952 UNIPROT ANKRD1 protein Q15327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003265 9043061 f "Finally, a carp promoter-lacZ transgene, which displays cardiac-specific expression in wild-type and Nkx2-5(+/-) background, was also significantly reduced in Nkx2-5(-/-) embryos, indicating that Nkx2-5 either directly or indirectly regulates carp promoter activity during in vivo cardiogenesis as well as in cultured cardiac myocytes" SIGNOR-253646 NKX2-5 protein P52952 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003265 19479054 f "Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5." SIGNOR-253653 NKX2-5 protein P52952 UNIPROT GATA4 protein P43694 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003265 19479054 f "Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5." SIGNOR-253654 NKX2-5 protein P52952 UNIPROT LYL1 protein P12980 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9060 BTO:0001106 19608273 f "Sequence analysis of the LYL1 promoter region revealed potential binding sites for transcription factors HOXA10, LMO2 and NKX2-5. Overexpression analysis, reporter gene assays and chromatin immuno-precipitation confirmed their activating impact on LYL1 expression. In conclusion, we identified multiple mechanisms which activate LYL1 in leukemic cells, including structural genomic alterations, namely microdeletion or amplification, together with the involvement of prominent oncogenic transcription factors." SIGNOR-253655 NKX2-5 protein P52952 UNIPROT MYL2 protein P10916 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003265 9043061 f "The mammalian homolog of the Drosophila tinman homeobox gene, Nkx2-5, is specifi- cally required for ventricular chamber-specific myosin light chain-2 (MLC-2v) expression and looping morphogenesis during mammalian heart development." SIGNOR-253645 NKX2-5 protein P52952 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-253649 NKX2-5 protein P52952 UNIPROT TBX5 protein Q99593 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 15095414 f "Mutation at the potential TBE-B and -C sites, and at the GC box and NKX2.5 sites significantly decreased luciferase activity, suggesting that the GC box and the potential TBE-B, -C, and NKX2.5 sites are functionally important for the activation of the promoter function." SIGNOR-253650 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 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 NKX3-1 protein Q99801 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16697957 t miannu "Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events." SIGNOR-251547 NKX3-1 protein Q99801 UNIPROT HDAC1 protein Q13547 UNIPROT "down-regulates activity" binding 9606 16697957 t miannu "NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity." SIGNOR-251549 NKX3-1 protein Q99801 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-82087 NKX3-1 protein Q99801 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" 9606 16697957 f miannu "NKX3.1 stabilizes p53.NKX3.1 can physically associate with HDAC1 and promotes p53 acetylation by recruiting HDAC1 from p53-MDM2-HDAC1 complex" SIGNOR-251548 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 NLK protein Q9UBE8 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 20118921 t gcesareni "Nlk-phosphorylated notch1icd is impaired in its ability to form a transcriptionally_ active_ ternary_ complex." SIGNOR-163697 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 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 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates phosphorylation Thr201 PHHVHPLtPLITYSN 9606 12556497 t llicata "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-97819 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates phosphorylation Thr212 TYSNEHFtPGNPPPH 9606 12556497 t llicata "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-97873 "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 NLRC4 protein Q9NPP4 UNIPROT "NLRC4 inflammasome" complex SIGNOR-C223 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-256404 "NLRP1 inflammasome" complex SIGNOR-C224 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-256380 "NLRP1 inflammasome" complex SIGNOR-C224 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-260355 NLRP1 protein Q9C000 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-256407 "NLRP3 inflammasome" complex SIGNOR-C225 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-256381 "NLRP3 inflammasome" complex SIGNOR-C225 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32133002 f miannu "Both the NLRP3 inflammasome activation and the subsequent inflammation play significant roles in defending against viral infections. However, aberrant NLRP3 inflammasome activation or chronic inflammation can also lead to severe pathological injury. Accordingly, activation of the NLRP3 inflammasome and its associated inflammation is a double-edged sword for host to defense viral infection. Modulating the NLRP3 inflammasome activity can prove to be a promising strategy for the intervention of viral diseases." SIGNOR-260346 "NLRP3 inflammasome" complex SIGNOR-C225 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-260356 NLRP3 protein Q96P20 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-256410 NLRX1 protein Q86UT6 UNIPROT MAVS protein Q7Z434 UNIPROT "down-regulates activity" binding 9606 "BTO:0000567; BTO:0002181" 18200010 t Giorgia "Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Co-immunoprecipitation studies demonstrate that HA–NLRX1 interacts with MAVS but not with other known mitochondrial outer membrane proteins (BCL2 and BCL2L1), indicating specificity of the NLRX1–MAVS interaction. Finally, endogenous NLRX1 associates strongly with endogenous MAVS after immunoprecipitation with two different MAVS antibodies" SIGNOR-260357 NLRX1 protein Q86UT6 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 21703539 t Giorgia "Immunoprecipitation experiments showed that NLRX1 interacted with TRAF6 and TRAF3, but not with TRAF2 or TRAF5. These results further suggest that NLRX1 specifically inhibits TLR-induced TRAF6-dependent NF-kB signaling through targeting TRAF6." SIGNOR-260364 NMB protein P08949 UNIPROT NMBR protein P28336 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." SIGNOR-107022 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 NMBR protein P28336 UNIPROT GNA13 protein Q14344 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-107028 NMBR protein P28336 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-257422 NMBR protein P28336 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-257047 NMBR protein P28336 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-257160 NMBR protein P28336 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-256918 NMBR protein P28336 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-257373 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 NMBR protein P28336 UNIPROT GNAS protein Q5JWF2 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-256775 NMBR protein P28336 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-257315 NME1 protein P15531 UNIPROT CCN2 protein P29279 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-255160 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 NME1 protein P15531 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates phosphorylation Ser406 TRLRRTEsVPSDINN 9606 BTO:0000007 12105213 t gcesareni "Autophosphorylated recombinant nm23-h1 phosphorylated ksr in vitro. Using site-directed mutagenesis, we found that nm23-h1 phosphorylated ksr serine 392, a 14-3-3-binding site, consistent with the recent identification of c-tak1 as a kinase for this site." SIGNOR-90390 NME1 protein P15531 UNIPROT KSR1 protein Q8IVT5 UNIPROT unknown phosphorylation Ser406 TRLRRTEsVPSDINN -1 12105213 t miannu "Mutation of Ser392 to alanine consistently reduced Nm23-H1 phosphorylation, confirming it as a site of Nm23-H1 kinase activity The unique phosphorylation pattern of KSR by Nm23-H1 will be the subject of further investigation to determine its effects on KSR protein binding, subcellular localization, response to various signals, etc." SIGNOR-250299 NME1 protein P15531 UNIPROT L1CAM protein P32004 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-255161 NME1 protein P15531 UNIPROT LPAR1 protein Q92633 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-255163 NME1 protein P15531 UNIPROT MET protein P08581 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-255164 NME1 protein P15531 UNIPROT MMP2 protein P08253 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-255165 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser125 HGSDSVEsAEKEIGL -1 8810265 t miannu "For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown." SIGNOR-250198 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 21316371 t gcesareni "In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)" SIGNOR-171907 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 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT up-regulates phosphorylation His118 QVGRNIIhGSDSVES 9606 BTO:0000763 22869372 t llicata "Ndpk catalytic function requires autophosphorylation at the catalytic his-118 residue. the simplest interpretation of these data is that ampk does not directly phosphorylate ndpk-a at ser-120 or ser-122 (or at any other site) but rather enhances ndpk-a autophosphorylation at his-118." SIGNOR-198667 NME1 protein P15531 UNIPROT PTN protein P21246 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-255167 NME1 protein P15531 UNIPROT SMO protein Q99835 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-255168 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 BTO:0000782 17157250 t lperfetto "Ndpk-b directly binds and activates kca3.1 by phosphorylating histidine 358 in the carboxyl terminus of kca3.1" SIGNOR-151130 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 BTO:0000782 18796614 t gcesareni "We previously showed that nucleoside diphosphate kinase beta (ndpk-b), a mammalian histidine kinase, is required for kca3.1 channel activation in human cd4 t lymphocytes." SIGNOR-181083 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 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT "up-regulates activity" phosphorylation Ser44 AMKFLRAsEEHLKQH 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-250201 N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide chemical CHEBI:91370 ChEBI PTK2B protein Q14289 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206070 N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide chemical CHEBI:91370 ChEBI PTK2 protein Q05397 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206067 NMI protein Q13287 UNIPROT SOX10 protein P56693 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 16214168 t miannu "we identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific." SIGNOR-225602 NMI protein Q13287 UNIPROT SOX10 protein P56693 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16214168 t miannu "we identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific." SIGNOR-225599 NMS protein Q5H8A3 UNIPROT NMUR1 protein Q9HB89 UNIPROT up-regulates binding 9606 BTO:0000142 15635449 t gcesareni "Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus." SIGNOR-133074 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 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 NMUR2 protein Q9GZQ4 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-257402 NMUR2 protein Q9GZQ4 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-257292 NMUR2 protein Q9GZQ4 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-257352 NMUR2 protein Q9GZQ4 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-256731 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 NMUR2 protein Q9GZQ4 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-257126 NOC3L protein Q8WTT2 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 15564382 f "Fad24, a mammalian homolog of Noc3p, is a positive regulator in adipocyte differentiation" SIGNOR-253060 nociceptin smallmolecule CHEBI:80266 ChEBI OPRL1 protein P41146 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-257553 nocodazole chemical CHEBI:34892 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194838 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 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 NOD1 protein Q9Y239 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18079694 f miannu "Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase." SIGNOR-252411 NOD2 protein Q9HC29 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-252405 NOD2 protein Q9HC29 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-252403 NOD2 protein Q9HC29 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18079694 f miannu "Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase." SIGNOR-252412 NOD2 protein Q9HC29 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 17355968 t miannu "The function of NOD2 could be to recruit RICK at the plasma membrane to form an active complex able to activate part of the NF-κB pathway. NOD2 induces a membrane recruitment of RICK that is dependent on a CARD-CARD interaction." SIGNOR-252402 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 NODAL protein Q96S42 UNIPROT ACVR1C protein Q8NER5 UNIPROT "up-regulates activity" binding 9606 BTO:0004094 15531507 t "Indirect_regulation of expression" miannu "Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation." SIGNOR-251936 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 NODAL protein Q96S42 UNIPROT Cell_death phenotype SIGNOR-PH109 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-256656 NODAL protein Q96S42 UNIPROT LIF protein P15018 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20383200 f Regulation miannu "Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway." SIGNOR-251941 NODAL protein Q96S42 UNIPROT MMP2 protein P08253 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20383200 f Regulation miannu "Ectopic expression of Nodal or activation of Nodal signaling by addition of rNodal increased MMP-2 protein level and cell invasion. the expression level of Nodal correlates well with MMP-2 expression and cell invasion." SIGNOR-251940 NODAL protein Q96S42 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-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-251935 NODAL protein Q96S42 UNIPROT TDGF1 protein P13385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20383200 f Regulation miannu "Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway." SIGNOR-251942 NOG protein Q13253 UNIPROT BMP2 protein P12643 UNIPROT down-regulates binding 9606 12700180 t lperfetto "Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides" SIGNOR-100657 NOG protein Q13253 UNIPROT BMP4 protein P12644 UNIPROT down-regulates binding 9606 12700180 t lperfetto "Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides" SIGNOR-100660 NOG protein Q13253 UNIPROT BMP7 protein P18075 UNIPROT "down-regulates activity" binding -1 12478285 t "We report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors." SIGNOR-256484 NOG protein Q13253 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR down-regulates binding 9606 22298955 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.Noggin Inhibits bmpby blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors" SIGNOR-217529 NOG protein Q13253 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR down-regulates binding 9606 BTO:0000142 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.Noggin Inhibits bmpby blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors" SIGNOR-217541 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT "down-regulates activity" binding 9031 BTO:0000140 12478285 t 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-219221 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT "down-regulates activity" binding 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto "Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptorsNoggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285)" SIGNOR-192799 NOG protein Q13253 UNIPROT BMPR1B protein O00238 UNIPROT "down-regulates activity" binding 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto "Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285)" SIGNOR-192802 NOG protein Q13253 UNIPROT BMPR2 protein Q13873 UNIPROT "down-regulates activity" binding 9031 BTO:0000140 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 NOG protein Q13253 UNIPROT BMPR2 protein Q13873 UNIPROT "down-regulates activity" binding 9606 BTO:0001593 BTO:0000140 SIGNOR-C29 22298955 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.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285)" SIGNOR-195612 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT "down-regulates activity" binding 9606 19956691 t Regulation miannu "We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity." SIGNOR-251865 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 "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 "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 "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR PPARG protein P37231 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-252251 "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 NONO protein Q15233 UNIPROT TOP1 protein P11387 UNIPROT up-regulates binding 9606 BTO:0000017 9756848 t miannu "We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i" SIGNOR-60557 "Non-structural protein 10" protein P0C6X7_PRO_0000037317 UNIPROT C11orf74 protein Q86VG3 UNIPROT unknown binding 4932 18433331 t lperfetto "In our previous work, we isolated a gene from a cDNA library of human embryo lung tissue, which en- coded a novel protein that specifically interacted with nsp-10 of SARS-CoV in a yeast trap experiment.|Since nsp- 10 of SARS-CoV is involved in viral genomic replica- tion and was observed to interact with ATF5, the cellular initiation factor of the RNA pol II complex (13), we in- ferred that HEPIS may also be involved in cellular gene transcription. Therefore, the significance of HEPIS ex- pression in cells needed to be further investigated. The work we describe here suggests that HEPIS represses cel- lular transcription initiation through interaction with a component of the RNA pol II complex" SIGNOR-260251 "Non-structural protein 10" protein P0C6X7_PRO_0000037317 UNIPROT MT-CO2 protein P00403 UNIPROT "down-regulates activity" binding 9606 BTO:0000764 16157265 t lperfetto "This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication." SIGNOR-260254 "Non-structural protein 10" protein P0C6X7_PRO_0000037317 UNIPROT MT-ND4L protein P03901 UNIPROT "down-regulates activity" binding 9606 BTO:0000764 16157265 t lperfetto "This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication." SIGNOR-260253 Norbinaltorphimine chemical CHEBI:81529 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-258820 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 Norbinaltorphimine chemical CHEBI:81529 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-258821 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 Normorphine chemical CHEBI:7633 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-258822 Normorphine chemical CHEBI:7633 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-258823 Norzotepine chemical CID:10041551 PUBCHEM SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 20223878 t Luana "These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity." SIGNOR-257831 Norzotepine chemical CID:10041551 PUBCHEM SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 20223878 t Luana "These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity." SIGNOR-257830 NOS1 protein P29475 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-255996 NOS1 protein P29475 UNIPROT HDAC2 protein Q92769 UNIPROT "down-regulates activity" s-nitrosylation 10090 BTO:0001103 19047631 t gcesareni "we found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation" SIGNOR-236919 NOS1 protein P29475 UNIPROT "nitric oxide" smallmolecule CHEBI:16480 ChEBI "up-regulates quantity" "small molecule catalysis" 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 NOS2 protein P35228 UNIPROT L-citrulline smallmolecule CID:9750 PUBCHEM up-regulates 9606 BTO:0000801 7537672 f apalma "Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline" SIGNOR-255382 NOS2 protein P35228 UNIPROT "nitric oxide" smallmolecule CHEBI:16480 ChEBI up-regulates 9606 BTO:0000801 7537672 f apalma "Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline" SIGNOR-255381 NOS3 protein P29474 UNIPROT "nitric oxide" smallmolecule CHEBI:16480 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0001853 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 NOTCH1 protein P46531 UNIPROT ADAM19 protein Q9H013 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782;BTO:0001454 10933396 f gcesareni "Deltex, meltrin beta, ifi-202, and ifi-204 were also upregulated by notchic in the 2b4.11 t cell hybridoma, whereas ifi-d3 was expressed constitutively at relatively high levels and slightly upregulated by notchic, and pre-talfa was not expressed. Deltex, meltrin beta, pre-talfa, ifi-202, and ifi-204 were upregulated by notchic expression in the akr1 dp thymoma cell line, whereas ifi-d3 was not expressed" SIGNOR-80330 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 NOTCH1 protein P46531 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f gcesareni "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-149730 NOTCH1 protein P46531 UNIPROT 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-114592 NOTCH1 protein P46531 UNIPROT CD44 protein P16070 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-80333 NOTCH1 protein P46531 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 18342499 f flangone "Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages" SIGNOR-241998 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 NOTCH1 protein P46531 UNIPROT FABP7 protein O15540 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 16554461 f gcesareni "Here we demonstrate that neuronal induction of radial glia formation is the result of sequential signaling through notch1 and erbb receptors. First, notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes." SIGNOR-145365 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 NOTCH1 protein P46531 UNIPROT HEY1 protein Q9Y5J3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0001593 15207708 f lperfetto "Previously, we have shown that commitment of the C2C12 cells to the osteoblastic lineage occurs around 24h after BMP treatment, when the osteoblast specific transcription factor Cbfa1 and the novel osteoblast related genes Tcf7 and Hey1 become regulated" SIGNOR-235397 NOTCH1 protein P46531 UNIPROT HEYL protein Q9NQ87 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 11044625 f gcesareni "These data confirm heyl as a notch1 target gene that is likely involved in somite formation and patterning." SIGNOR-83399 NOTCH1 protein P46531 UNIPROT HIF1A protein Q16665 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 16256737 t lperfetto "The notch intracellular domain interacts with hif-1alpha and hif-1alpha is recruited to notch-responsive promoters upon notch activation under hypoxic conditions." SIGNOR-141315 NOTCH1 protein P46531 UNIPROT HOXA5 protein P20719 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f 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-149770 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 NOTCH1 protein P46531 UNIPROT IL7R protein P16871 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-197452 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15207708 f gcesareni "Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta." SIGNOR-236845 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f gcesareni "Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta." SIGNOR-195621 NOTCH1 protein P46531 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11591772 f lperfetto "Nf-kappab activity is regulated by notch-1 via transcriptional control of nf-kappab." SIGNOR-110963 NOTCH1 protein P46531 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9528780 f gcesareni "In transient-transfection assays we show that truncated notch-1 strongly induces nf-kappab2 promoter activity." SIGNOR-56097 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 NOTCH1 protein P46531 UNIPROT PAX7 protein P23759 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto "Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells" SIGNOR-219374 NOTCH1 protein P46531 UNIPROT PIN1 protein Q13526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 19151708 f gcesareni "Notch1 directly induces transcription of pin1" SIGNOR-183458 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 NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding 9606 7566092 t "Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter." SIGNOR-254381 NOTCH1 protein P46531 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 19165418 t 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-183510 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 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 960 BTO:0000165;BTO:0000567 10713164 t gcesareni "SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function." SIGNOR-75782 NOTCH1 protein P46531 UNIPROT TCF12 protein Q99081 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-197514 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 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 NOTCH2 protein Q04721 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 BTO:0000776 9528794 t gcesareni "In an effort to identify processes that regulate e47, and potentially b-cell development, we found that activated notch1 and notch2 effectively inhibit e47 activity." SIGNOR-56222 NOTCH3 protein Q9UM47 UNIPROT HES1 protein Q14469 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-174750 NOTCH3 protein Q9UM47 UNIPROT HEYL protein Q9NQ87 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 11044625 f gcesareni "In the latter, heyl is coexpressed with notch3, so far the only notch pathway gene detected in vascular smooth muscles (fig. 2h,i;joutel et al., 2000). Both genes are also coexpressed during late thymus development and our own promoter studies further suggest a potential regulation of heyl transcription by notch3." SIGNOR-83402 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 NOTCH4 protein Q99466 UNIPROT HEY2 protein Q9UBP5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12548545 f gcesareni "Herp1 appears to be important particularly in the development of vascular tissue, and herp1might be regulated by vascular-specific isoforms of ligands and receptors such as dll4 and notch4" SIGNOR-97630 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 NOTCH4 protein Q99466 UNIPROT MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 12370315 t gcesareni "Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo" SIGNOR-94109 NOTCH proteinfamily SIGNOR-PF30 SIGNOR ADAM19 protein Q9H013 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782;BTO:0001454 10933396 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-254340 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f gcesareni "Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression." SIGNOR-254344 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 NOTCH proteinfamily SIGNOR-PF30 SIGNOR CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11486031 f gcesareni "Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo" SIGNOR-254349 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 32195003 f "Notch signaling is initiated by the interaction of Notch ligands and receptors on adjacent cells, which further triggers two proteolytic cleavage events. The first cleavage releases a functional extracellular domain (NECD); the second cleavage, mediated by γ-secretase, releases the intracellular domain (NICD) into the cytoplasm. The NICD then translocates to the nucleus, binds to the transcription factor CBF/Su (H)/LAG-2 (CSL), and recruits Mastermind-like protein 1 and p300/CBP to induce transcription of Notch target genes, including Hes1, p21, Akt, cyclin D1, and mTOR" SIGNOR-261534 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEY1 protein Q9Y5J3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0001593 15207708 f gcesareni "Deltex, meltrin beta, ifi-202, and ifi-204 were also upregulated by notchic in the 2b4.11 t cell hybridoma, whereas ifi-d3 was expressed constitutively at relatively high levels and slightly upregulated by notchic, and pre-talfa was not expressed. Deltex, meltrin beta, pre-talfa, ifi-202, and ifi-204 were upregulated by notchic expression in the akr1 dp thymoma cell line, whereas ifi-d3 was not expressed" SIGNOR-254341 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEY2 protein Q9UBP5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12548545 f gcesareni "SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function." SIGNOR-254338 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 NOTCH proteinfamily SIGNOR-PF30 SIGNOR IL7R protein P16871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f lperfetto "Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells" SIGNOR-254345 NOTCH proteinfamily SIGNOR-PF30 SIGNOR JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20953350 f 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-254348 NOTCH proteinfamily SIGNOR-PF30 SIGNOR LFNG protein Q8NES3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f gcesareni "Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta." SIGNOR-254336 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 NOTCH proteinfamily SIGNOR-PF30 SIGNOR MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 12370315 t flangone "Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages" SIGNOR-254346 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PAX7 protein P23759 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001103;BTO:0002314 22493066 f 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-254343 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PIN1 protein Q13526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 19151708 f lperfetto "Previously, we have shown that commitment of the C2C12 cells to the osteoblastic lineage occurs around 24h after BMP treatment, when the osteoblast specific transcription factor Cbfa1 and the novel osteoblast related genes Tcf7 and Hey1 become regulated" SIGNOR-254342 NOTCH proteinfamily SIGNOR-PF30 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates BTO:0001103 12361602 f apalma "Taken together, these results show that Notch-1 activity promotes myogenic cell proliferation and that attenuation of Notch-1 activity by its antagonist Numb causes cells to exit from the cell cycle, express MRFs, and undergo myogenic differentiation." SIGNOR-255376 NOTCH proteinfamily SIGNOR-PF30 SIGNOR 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-255377 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 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding BTO:0001103 7566092 t svumbaca "Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter." SIGNOR-255363 NOTCH proteinfamily SIGNOR-PF30 SIGNOR SNW1 protein Q13573 UNIPROT up-regulates binding 960 BTO:0000165;BTO:0000567 10713164 t gcesareni "Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta." SIGNOR-254337 NOXA1 protein Q86UR1 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" 9606 19879762 t lperfetto "BH3-only proteins containing only a single BH domain and including Puma, Noxa, Bid and Bad as well as other factors are particularly important for such neutralisation, binding and regulating the anti-apoptotic Bcl-2 proteins to promote apoptosis" SIGNOR-209684 NPAS1 protein Q99742 UNIPROT TH protein P07101 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003945 17457889 t lperfetto "Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter." SIGNOR-253702 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 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 NPC2 protein P61916 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000452 21084287 f Giorgia "Here we show that NPC2 deficiency in human fibroblasts confers their activation. The activation phenomenon was not limited to fibroblasts as it was also observed in aortic smooth muscle cells upon silencing NPC2 gene by siRNA. The molecular mechanism responsible for activation of NPC2-null cells was shown to be a sustained phosphorylation of ERK 1/2 mitogen-activated protein kinase (MAPK), which fulfills both the sufficient and necessary fibroblast activation criteria. All of these findings highlight a novel mechanism where NPC2 by negatively regulating ERK 1/2 MAPK phosphorylation may efficiently suppress development of maladaptive tissue remodeling and inflammation." SIGNOR-260660 NPC complex SIGNOR-C263 SIGNOR Nuclear_pore_function phenotype SIGNOR-PH130 SIGNOR up-regulates 9606 BTO:0000007 9660920 f 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-261395 NPC complex SIGNOR-C263 SIGNOR XPOT protein O43592 UNIPROT "up-regulates quantity" relocalization 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-261394 NPFF protein O15130 UNIPROT NPFFR1 protein Q9GZQ6 UNIPROT up-regulates binding 9606 11024015 t gcesareni "Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems" SIGNOR-82916 NPFF protein O15130 UNIPROT NPFFR2 protein Q9Y5X5 UNIPROT up-regulates binding 9606 11024015 t gcesareni "Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems" SIGNOR-82961 NPFFR1 protein Q9GZQ6 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-256708 NPFFR1 protein Q9GZQ6 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-256851 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 NPFFR1 protein Q9GZQ6 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-257103 NPFFR2 protein Q9Y5X5 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-256709 NPFFR2 protein Q9Y5X5 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-256852 NPFFR2 protein Q9Y5X5 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-256988 NPFFR2 protein Q9Y5X5 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-257104 NPLOC4 protein Q8TAT6 UNIPROT UFD1 protein Q92890 UNIPROT "up-regulates activity" binding 9606 20442859 t miannu "These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes." SIGNOR-252422 NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT "up-regulates activity" binding 10090 16199867 t gcesareni "The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division" SIGNOR-245073 NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT "up-regulates quantity" binding 10090 BTO:0002572 18625840 t gcesareni "We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7" SIGNOR-245084 NPM1 protein P06748 UNIPROT HEXIM1 protein O94992 UNIPROT "down-regulates activity" binding 9606 BTO:0001545 18371977 t miannu "We identified NPM as a novel HEXIM1-binding protein. NPM functioned as a negative regulator of HEXIM1. cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction." SIGNOR-260134 NPM1 protein P06748 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001545 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 NPNT protein Q6UXI9 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 10090 22613833 t lperfetto "The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome." SIGNOR-253344 NPNT protein Q6UXI9 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 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-255458 NPPA protein P01160 UNIPROT NPR1 protein P16066 UNIPROT up-regulates binding 9606 15911069 t gcesareni "Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp)" SIGNOR-137600 NPRL2 protein Q8WTW4 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR "form complex" binding 9606 23723238 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-255281 NPRL3 protein Q12980 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR "form complex" binding 9606 23723238 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-255282 N protein P0DTC9 UNIPROT G3BP1 protein Q13283 UNIPROT "down-regulates activity" binding 9606 32353859 t miannu "N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms" SIGNOR-260749 N protein P59595 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001950 14623261 t Luana "Taken together, we have shown that the coronavirus N protein can activate AP-1 signal transduction pathway." SIGNOR-260725 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 N protein P59595 UNIPROT ATF2 protein P15336 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-260727 N protein P59595 UNIPROT CREB1 protein P16220 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-260729 N protein P59595 UNIPROT EEF1A2 protein Q05639 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 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 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 N protein P59595 UNIPROT FOS protein P01100 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-260726 N protein P59595 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "down-regulates quantity" "transcriptional repression" 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 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 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 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 N protein P59595 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" 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-260434 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 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 NPTX1 protein Q15818 UNIPROT BAD protein Q92934 UNIPROT "up-regulates quantity" 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto "We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control" SIGNOR-260410 NPTX1 protein Q15818 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" relocalization 10090 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-261439 NPTX1 protein Q15818 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity" 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto "We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control" SIGNOR-260411 linifanib chemical CHEBI:91435 ChEBI PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193666 NPTX1 protein Q15818 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates quantity" 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto "We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control" SIGNOR-260412 NPTX1 protein Q15818 UNIPROT GRIA1 protein P42261 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 15115814 t 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-261430 NPTX1 protein Q15818 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity" 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto "We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control" SIGNOR-260413 NPY protein P01303 UNIPROT NPY1R protein P25929 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-56522 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 NPY protein P01303 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 7592911 t gcesareni "Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid." SIGNOR-29633 NQO1 protein P15559 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000849 20226854 f irozzo "More importantly, our results also indicate that NF-kappaB p50 correlates with the expression of NQO1 and mediates its role in the proliferation of melanoma cells." SIGNOR-256264 NQO1 protein P15559 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003934 28599455 f irozzo "The results demonstrated that NQO1 siRNA-mediated knockdown effectively impaired colony formation capacity, induced cell cycle arrest at the G1 phase and suppressed migration of KKU-100 cells." SIGNOR-256265 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 NR0B2 protein Q15466 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates activity" binding 9606 17094771 t miannu "SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription." SIGNOR-254831 NR0B2 protein Q15466 UNIPROT ESR1 protein P03372 UNIPROT down-regulates binding 9606 BTO:0000975 11861507 t gcesareni "Our results identify shp as an inhibitor of 4-oht agonist activity in rl95-2 human endometrial carcinoma cells that express endogenous er?. We conclude that shp does not decrease er expression, but rather it is the direct interaction of shp with er that inhibits er transcriptional activity." SIGNOR-115033 NR0B2 protein Q15466 UNIPROT ESR2 protein Q92731 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10648597 f gcesareni "These novel insights provide a mechanistic explanation for the inhibitory role of shp in nuclear receptor signaling, and they may explain how shp functions as a negative coregulator or corepressor for ligand-activated receptors, a novel and unique function for an orphan nuclear receptor." SIGNOR-74291 NR0B2 protein Q15466 UNIPROT ESRRG protein P62508 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000671 11705994 f gcesareni "The current study also demonstrates that shp inhibits err_ transactivation." SIGNOR-111620 NR0B2 protein Q15466 UNIPROT G6PC protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17909097 f gcesareni "As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells" SIGNOR-158065 NR0B2 protein Q15466 UNIPROT HNF4A protein P41235 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10594021 f gcesareni "Here we show that shp inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (hnf-4) and the retinoid x receptor (rxr) by at least two mechanisms shp also competes with coactivators for binding to ligand-activated rxr, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of shp-mediated repression." SIGNOR-73032 NR0B2 protein Q15466 UNIPROT NR1H2 protein P55055 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000195 12198243 f gcesareni "Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (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. T" SIGNOR-91901 NR0B2 protein Q15466 UNIPROT NR1H3 protein Q13133 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000195 12198243 f gcesareni "Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (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. T" SIGNOR-91996 NR0B2 protein Q15466 UNIPROT NR1I2 protein O75469 UNIPROT down-regulates binding 9606 12805410 t gcesareni "Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments." SIGNOR-101924 NR0B2 protein Q15466 UNIPROT NR1I3 protein Q14994 UNIPROT down-regulates binding 9606 15000748 t gcesareni "The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition." SIGNOR-123154 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 BTO:0000150 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 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 BTO:0000195 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 NR0B2 protein Q15466 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17909097 f gcesareni "As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells" SIGNOR-158068 NR0B2 protein Q15466 UNIPROT PCK2 protein Q16822 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17094771 f miannu "SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription." SIGNOR-254832 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 NR0B2 protein Q15466 UNIPROT THRA protein P10827 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11368516 f 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-108248 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001103 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 NR1D1 protein P20393 UNIPROT NR2E3 protein Q9Y5X4 UNIPROT up-regulates 9606 15190009 f gcesareni "Our results show that nr1d1 (rev-erb?) Also functions as a transcriptional activator of rod genes in the presence of nr2e3" SIGNOR-125658 NR1H2 protein P55055 UNIPROT BHLHE40 protein O14503 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000575 19032342 f lperfetto "LXRα and LXRβ are potent positive regulators for hepatic Dec1" SIGNOR-253690 NR1H3 protein Q13133 UNIPROT BHLHE40 protein O14503 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000575 19032342 f lperfetto "LXRα and LXRβ are potent positive regulators for hepatic Dec1" SIGNOR-253691 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 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 NR1I2 protein O75469 UNIPROT CYP3A4 protein P08684 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-254835 NR1I2 protein O75469 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11706036 t gcesareni "The constitutive androstane receptor (car, nr1i4), like fxr and pxr, binds dna as a heterodimer with rxr?" SIGNOR-111624 NR1I2 protein O75469 UNIPROT UGT1A1 protein P22309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18172616 f miannu "This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities." SIGNOR-254440 NR1I3 protein Q14994 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-253875 NR1I3 protein Q14994 UNIPROT CYP2B6 protein P20813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19702527 f miannu "Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding." SIGNOR-254863 NR1I3 protein Q14994 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 12896978 t gcesareni "Therefore, both car-rxr heterodimers and car monomers can contribute to the gene activating function of pbrems in car target genes." SIGNOR-104441 NR1I3 protein Q14994 UNIPROT UGT1A1 protein P22309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18172616 f miannu "This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities." SIGNOR-254438 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 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 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 NR2F2 protein P24468 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14739255 f gcesareni "Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors." SIGNOR-121419 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 NR3C1 protein P04150 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 9162033 f gcesareni "Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity." SIGNOR-48516 NR3C1 protein P04150 UNIPROT ATP1B1 protein P05026 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000318 9694812 f 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 NR3C1 protein P04150 UNIPROT CAV1 protein Q03135 UNIPROT up-regulates binding 9606 23339905 t gcesareni "He mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay." SIGNOR-251683 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 11279134 f lperfetto "The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin" SIGNOR-235346 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 t "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα" SIGNOR-256116 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates activity" binding 10090 BTO:0000011 11279134 t lperfetto "The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin" SIGNOR-250566 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates activity" binding 10116 9428795 t "We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU)" SIGNOR-251655 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 f "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα." SIGNOR-256117 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000011 10649448 t gcesareni "We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPδ; C/EBPδ then binds to PPARγ2 promoter and transactivates PPARγ2 gene expression." SIGNOR-253061 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000011 1840554 t "The expression levels of both C/EBPB and C/EBPD are increased dramatically during the time of hormonal stimulation (see Fig. 8). Furthermore, the C/EBPB- and C/EBPD encoding genes are activated directly by adipogenic hormones" SIGNOR-251648 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 NR3C1 protein P04150 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000759 22848740 t miannu "We show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress." SIGNOR-255759 NR3C1 protein P04150 UNIPROT G6PC protein P35575 UNIPROT "up-regulates quantity" "transcriptional regulation" 9600 BTO:0000567 26652733 t "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-256104 NR3C1 protein P04150 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 10116 BTO:0004428 BTO:0000759 18762022 t "The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene" SIGNOR-253057 NR3C1 protein P04150 UNIPROT HNF4A protein P41235 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17978169 t gcesareni "Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4alpha to the HNF4-RE and that an interaction of GR and HNF4alpha occurred at this site." SIGNOR-251684 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 25910399 f "Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged." SIGNOR-257599 NR3C1 protein P04150 UNIPROT IRAK3 protein Q9Y616 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 25585690 t "We show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter" SIGNOR-259287 NR3C1 protein P04150 UNIPROT JUN protein P05412 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-251679 NR3C1 protein P04150 UNIPROT KLF15 protein Q9UIH9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 20956975 f lperfetto "We identified glucocorticoid response element sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation" SIGNOR-236212 NR3C1 protein P04150 UNIPROT KLF5 protein Q13887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 t "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα" SIGNOR-256118 NR3C1 protein P04150 UNIPROT KLF9 protein Q13886 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 t "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα" SIGNOR-256119 NR3C1 protein P04150 UNIPROT LCK protein P06239 UNIPROT up-regulates binding 9606 16888650 t gcesareni "The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation." SIGNOR-251685 NR3C1 protein P04150 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 11742987 f gcesareni "The MAP kinase p38 is also a target for negative regulation by glucocorticoids" SIGNOR-251675 NR3C1 protein P04150 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" 10090 BTO:0000944 11742987 f 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-251678 NR3C1 protein P04150 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" 10090 BTO:0000944 11742987 f gcesareni "Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation." SIGNOR-251677 NR3C1 protein P04150 UNIPROT MAPK8 protein P45983 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 11742987 f gcesareni "GR-mediated inhibition of c-Jun N-terminal kinase (JNK) activity" SIGNOR-251676 NR3C1 protein P04150 UNIPROT NCOA1 protein Q15788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9590696 t gcesareni "Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP." SIGNOR-251682 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 NR3C1 protein P04150 UNIPROT NFKBIA protein P25963 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7569975 f "andrea cerquone perpetuini" "Here it is shown that the synthetic glucocorticoid dexamethasone induces the transcription of the IKBc gene, which results in an increased rate of IKBa protein synthesis" SIGNOR-255688 NR3C1 protein P04150 UNIPROT NR2F2 protein P24468 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14739255 f gcesareni "Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors." SIGNOR-121422 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 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 NR3C1 protein P04150 UNIPROT NR4A1 protein P22736 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15591535 f gcesareni "Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b." SIGNOR-132251 NR3C1 protein P04150 UNIPROT NR4A2 protein P43354 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15591535 f gcesareni "We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors." SIGNOR-132254 NR3C1 protein P04150 UNIPROT NR4A3 protein Q92570 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15591535 f gcesareni "We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors." SIGNOR-132309 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 BTO:0004428 11069927 t "In the liver, glucocorticoids induce a 10-15-fold increase in the rate of transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene, which encodes a key gluconeogenic enzyme" SIGNOR-253056 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity" "transcriptional regulation" 9600 BTO:0000567 26652733 t "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 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 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 11279134 f lperfetto "The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin" SIGNOR-250561 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 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 NR3C1 protein P04150 UNIPROT RXRA protein P19793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12573484 f gcesareni "Physiological concentrations of glucocorticoids increase cellular cyp2c9 (and cyp3a5) but also car, rxr and pxr levels via a gr-mediated mechanism" SIGNOR-98102 NR3C1 protein P04150 UNIPROT SGK1 protein O00141 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 BTO:0000632 15793248 f "We show here that dexamethasone upregulates transcription and expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in insulin-secreting cells, an effect reversed by mifepristone (RU486), an antagonist of the nuclear glucocorticoid receptor." SIGNOR-255926 NR3C1 protein P04150 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 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-44376 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 NR3C1 protein P04150 UNIPROT TSC22D3 protein Q99576 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001372 9430225 f "In thymocytes and peripheral T cells, GILZ gene expression is induced by DEX" SIGNOR-253295 NR3C1 protein P04150 UNIPROT UGT1A1 protein P22309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18172616 f miannu "This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities." SIGNOR-254439 NR3C1/STAT5A complex SIGNOR-C84 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 12540601 f fspada "We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner." SIGNOR-97562 NR3C2 protein P08235 UNIPROT ATP1B1 protein P05026 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000318 9694812 f 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-254865 NR4A1 protein P22736 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005761 15666793 f miannu "Herein we discuss the evidence that suggests a role for NURR1 (NR4A2) in the expression of CYP11B2 in the glomerulosa as well as in the dysregulation of CYP11B2 gene expression as is seen in aldosterone-producing adenoma (APA), a major cause of endocrine hypertension. NURR1 appears to be important for CYP11B2 transcription and is found at higher levels in glomerulosa and in APA." SIGNOR-254866 NR4A1 protein P22736 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15591535 f gcesareni "Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b." SIGNOR-132312 NR4A3 protein Q92570 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 30455429 f 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-259398 NR4A3 protein Q92570 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000150;BTO:0000551 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 NR4A3 protein Q92570 UNIPROT BBC3 protein Q9BXH1 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000150;BTO:0000551 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-259396 NR4A3 protein Q92570 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 30455429 t miannu "NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis." SIGNOR-259399 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 NR5A1 protein Q13285 UNIPROT CYP11B2 protein P19099 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002588 21169726 f miannu "Inhibitory SF-1 was found to decrease the sensitivity of CYP11B2 and aldosterone to Ang II stimulation, whereas a down-regulation of SF-1 enhanced basal CYP11B2 expression and aldosterone production in H295R cells." SIGNOR-254867 NR5A1 protein Q13285 UNIPROT CYP19A1 protein P11511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f 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-254871 NR5A1 protein Q13285 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f 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-254868 NR5A1 protein Q13285 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f 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-254869 NR5A2 protein O00482 UNIPROT CYP11B1 protein P15538 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002588 11564608 f miannu "The ability of LRH-1 to enhance transcription of the gene encoding human 11 beta- hydroxylase (hCYP11B1) was then examined using the H295R adrenal cell line. LRH-1 co-transfection with hCYP11B1 luciferase promoter constructs caused a 25-fold induction of luciferase activity. Furthermore, co-transfection of a hCYP11B1 reporter construct containing a mutation in the SF-1 binding cis-element abolished the stimulatory effect of both SF-1 and LRH-1. Electrophoretic mobility shift assay (EMSA) demonstrated that LRH-1 could bind to the SF-1 response element. Taken together, our data suggested that LRH-1 is expressed in the adrenal, and can substitute for SF-1 to enhance transcription of genes encoding certain of the steroid-metabolizing enzymes." SIGNOR-254880 NR5A2 protein O00482 UNIPROT CYP19A1 protein P11511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f 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-254872 NR5A2 protein O00482 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f 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-254873 NR5A2 protein O00482 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f 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-254870 NRARP protein Q7Z6K4 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates binding 8355 11485984 t lperfetto "Overexpression of nrarp in embryos blocks notch signaling and inhibits the activation of notch target genes by icd. We show that nrarp forms a ternary complex with the icd of xnotch1 and the csl protein xsu(h) and that in embryos nrarp promotes the loss of icd." SIGNOR-219228 NRAS protein P01111 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 t gcesareni "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-175216 NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" 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-175219 NRAS protein P01111 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 f gcesareni "Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu)" SIGNOR-157773 NRAS protein P01111 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 21779497 t lperfetto "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-252700 NRAS protein P01111 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9606 21779497 t lperfetto "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-175222 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 NRAS protein P01111 UNIPROT PIK3CG protein P48736 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.llysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-175228 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 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-261451 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 NRF1 protein Q16656 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-254881 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 NRF1 protein Q16656 UNIPROT RETREG3 protein Q86VR2 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000934 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 NRF1 protein Q16656 UNIPROT SLC46A1 protein Q96NT5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20724482 f miannu "Overexpression of NRF-1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression." SIGNOR-254884 NRF1 protein Q16656 UNIPROT SPAST protein Q9UBP0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22574173 f miannu "we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11." SIGNOR-254885 NRG1 protein Q02297 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 t gcesareni "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-26875 NRG1 protein Q02297 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 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-26878 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 NRG1 protein Q02297 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-122053 NRG2 protein O14511 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 t gcesareni "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.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-26881 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 NRG2 protein O14511 UNIPROT ERBB4 protein Q15303 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." SIGNOR-26211 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 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 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." SIGNOR-26251 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 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 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-122062 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 NRL protein P54845 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-253818 NRL protein P54845 UNIPROT RHO protein P08100 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-253819 NRP1 protein O14786 UNIPROT PHACTR1 protein Q9C0D0 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001949 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 NRP2 protein O60462 UNIPROT VEGFC protein P49767 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t gcesareni "By in vitro binding studies we found that both vegf-c and vegf-d interact with np2, vegf-c in a heparin-independent and vegf-d in a heparin-dependent manner." SIGNOR-147530 NRTN protein Q99748 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-49119 NRTN protein Q99748 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-49122 NSD1 protein Q96L73 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates methylation 9606 20080798 t lperfetto "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-217388 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys218 EIFLLCDkVQKEDIE 9606 SIGNOR-C13 20080798 t miannu "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-163454 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 t miannu "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-163458 NSD2 protein O96028 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19481544 t miannu "In this study, we discovered that nsd2 specifically interacts with the dna-binding domain of androgen receptor (ar) via its hmg domain, and the nuclear translocation of both nsd2 and ar is enhanced in the presence of ligand / the histone methyltransferase, nsd2, enhances androgen receptor-mediated transcription." SIGNOR-186045 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 NSD3 protein Q9BZ95 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" 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-259200 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 N-tert-butyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-phenylpropanamide chemical CHEBI:104131 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-258896 N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide chemical CHEBI:91408 ChEBI JAK2 protein O60674 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-258301 N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide chemical CHEBI:91408 ChEBI JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207239 NTN1 protein O95631 UNIPROT UNC5C protein O95185 UNIPROT up-regulates binding 9606 10399920 t gcesareni "We provide evidence that netrin-1 triggers the formation of a receptor complex of dcc and unc5 proteins and simultaneously derepresses the interaction between their cytoplasmic domains, thereby converting dcc-mediated attraction to unc5/dcc-mediated repulsion." SIGNOR-69047 NTN4 protein Q9HB63 UNIPROT UNC5A protein Q6ZN44 UNIPROT up-regulates binding 9606 12598531 t gcesareni "The unc5hs are axon guidance receptors that mediate netrin-1-dependent chemorepulsion, and dependence receptors that mediate netrin-1-independent apoptosis." SIGNOR-98483 NTRK1 protein P04629 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 BTO:0000938 BTO:0000142 12446789 t gcesareni "Grit translocation was regulated by receptor stimulation" SIGNOR-95809 NTRK1 protein P04629 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 BTO:0000938 10092678 t gcesareni "The signaling adapter frs-2 competes with shc for binding to the nerve growth factor receptor trka:a model for discriminating proliferation and differentiation" SIGNOR-65955 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr496 HIIENPQyFSDACVH 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47167 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr676 FGMSRDIySTDYYRV 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47171 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr680 RDIYSTDyYRVGGRT 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47175 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr681 DIYSTDYyRVGGRTM 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47179 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr791 LAQAPPVyLDVLG 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47183 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 t esanto "Autophosphorylated trka binds directly to plc?, Abl, and shc." SIGNOR-75405 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 NTRK1 protein P04629 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates binding 9606 BTO:0000938 15082760 t lperfetto "The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons." SIGNOR-124198 NTRK1 protein P04629 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9856458 t lperfetto "Two substrates of trk kinases, raps and sh2-b. raps and sh2-b mediate trk signaling in developing neurons" SIGNOR-62619 NTRK1 protein P04629 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 t esanto "Autophosphorylated trka binds directly to plc?, Abl, and shc." SIGNOR-75408 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT "up-regulates activity" phosphorylation Tyr417 EPPRQLNyIQVELKG 9606 BTO:0000007 11432792 t miannu "The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type" SIGNOR-250202 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT "up-regulates activity" phosphorylation Tyr455 PARSSDSyAVIDLKK 9606 BTO:0000007 11432792 t miannu "The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type" SIGNOR-250203 NTRK2 protein Q16620 UNIPROT FYN protein P06241 UNIPROT up-regulates binding 9606 BTO:0000938 9648856 t gcesareni "All these data suggest the involvement of fyn in the neurotrophin signal transduction pathways downstream of trkb. We investigated whether fyn is involved in the trk-dependent signal transduction pathways of neurotrophin. The fyn-src homology domain 2 (sh2) was observed to associate in vitro with the intracellular domain of trkb (icd-trkb)." SIGNOR-58424 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr161 PSFDAILyYYQSGGR 9606 BTO:0000938 BTO:0000671 19166614 t gcesareni "Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein." SIGNOR-183515 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr162 SFDAILYyYQSGGRI 9606 BTO:0000938 BTO:0000671 19166614 t gcesareni "Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein." SIGNOR-183519 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr163 FDAILYYyQSGGRIR 9606 BTO:0000938 BTO:0000671 19166614 t gcesareni "Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein." SIGNOR-183523 NTRK2 protein Q16620 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 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 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 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT unknown phosphorylation Tyr707 DVYSTDYyRVGGHTM 10090 BTO:0000944 10533983 t miannu "TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785." SIGNOR-250207 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT "up-regulates activity" phosphorylation Tyr516 PVIENPQyFGITNSQ 10090 BTO:0000944 10533983 t miannu "TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc" SIGNOR-250204 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT "up-regulates activity" phosphorylation Tyr702 FGMSRDVySTDYYRV 10090 BTO:0000944 10533983 t miannu "TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc" SIGNOR-250205 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT "up-regulates activity" phosphorylation Tyr817 LAKASPVyLDILG 10090 BTO:0000944 10533983 t miannu "TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. the Y785F mutation abolish the BDNF-inducible tyrosine phosphorylation of PLCy, but receptors containing this mutation are also defective in the ability to induce the tyrosine phosphorylation of the c-cbl proto-oncogene product." SIGNOR-250312 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 NTRK3 protein Q16288 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000938 10235685 t gcesareni "Unglycosylated trka core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules shc and plc-gamma." SIGNOR-67404 NTRK3 protein Q16288 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000938 10092678 t gcesareni "We demonstrate that the phosphotyrosine binding domain of frs-2 directly binds the trk receptors at the same phosphotyrosine residue that binds the signaling adapter shc, suggesting a model in which competitive binding between frs-2 and shc regulates differentiation versus proliferation." SIGNOR-65958 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 NTS protein P30990 UNIPROT NTSR2 protein O95665 UNIPROT down-regulates binding 9606 BTO:0000975 9851594 t gcesareni "Neurotensin binding to recombinant neurotensin nt2 receptor expressed in cho cells does not elicit a biological response as determined by second messenger measurements." SIGNOR-62519 NUAK1 protein O60285 UNIPROT CASP6 protein P55212 UNIPROT "down-regulates activity" phosphorylation Ser257 TLVNRKVsQRRVDFC -1 15273717 t miannu "ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system." SIGNOR-250209 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 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser445 LGLRKTGsYGALAEI 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-164747 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser472 AGVTRSAsSPRLSSS 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-164751 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 NUAK1 protein O60285 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 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-172008 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 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 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 NUDT3 protein O95989 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-81759 NUMA1 protein Q14980 UNIPROT TUBA1A protein Q71U36 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116640 NUMA1 protein Q14980 UNIPROT TUBA1B protein P68363 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116472 NUMA1 protein Q14980 UNIPROT TUBA1C protein Q9BQE3 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116677 NUMA1 protein Q14980 UNIPROT TUBA3C protein Q13748 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116717 NUMA1 protein Q14980 UNIPROT TUBA3E protein Q6PEY2 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116738 NUMA1 protein Q14980 UNIPROT TUBA4A protein P68366 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116788 NUMA1 protein Q14980 UNIPROT TUBA8 protein Q9NY65 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116826 NUMA1 protein Q14980 UNIPROT TUBB2A protein Q13885 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116936 NUMA1 protein Q14980 UNIPROT TUBB3 protein Q13509 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116979 NUMA1 protein Q14980 UNIPROT TUBB4A protein P04350 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-117025 NUMA1 protein Q14980 UNIPROT TUBB4B protein P68371 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-117078 NUMA1 protein Q14980 UNIPROT TUBB6 protein Q9BUF5 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-117109 NUMA1 protein Q14980 UNIPROT TUBB protein P07437 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-116900 NUMA1 protein Q14980 UNIPROT TUBD1 protein Q9UJT1 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-117159 NUMA1 protein Q14980 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-117203 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 NUMB protein P49757 UNIPROT GLI1 protein P08151 UNIPROT down-regulates binding 9606 20818436 t gcesareni "The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation." SIGNOR-167841 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 NUMB protein P49757 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates binding 9606 20940030 t gcesareni "Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53" SIGNOR-168454 NUMB protein P49757 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 12682059 t lperfetto "Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain" SIGNOR-99762 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 t apalma "Numb is an inhibitor of Notch signaling that interacts with the intracellular portion of Notch and antagonizes its activity by preventing nuclear translocation" SIGNOR-255374 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 t apalma "Therefore, these genetic data further support the hypothesis that activation of Notch-1 promotes a less committed myogenic phenotype and that the attenuation of Notch-1 activity by Numb promotes progression along the myogenic lineage toward a myoblast cell fate." SIGNOR-255375 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 20940030 f gcesareni "Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53." SIGNOR-168457 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000150 18492217 t gcesareni "Numb can actually interact in vivo with endogenous mdm2 and p53, resulting in a trimeric complex between the three proteins [10]. This interaction appears to regulate the stability of p53, as reduction of numb levels by rna interference (rnai) causes a decrease in the half-life of p53 and consequently a reduction in steady-state levels of the protein. Consistent with this observation, overexpression of numb increases the level of p53 in both unstressed and stressed cells." SIGNOR-178668 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 NUP214 protein P35658 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "up-regulates activity" relocalization 9606 12917407 t lperfetto "We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import." SIGNOR-217719 NUP214 protein P35658 UNIPROT SMAD4 protein Q13485 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-117647 NUP54 protein Q7Z3B4 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR "form complex" binding 10116 BTO:0000154 2050741 t Simone "Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function." SIGNOR-261259 NUP58 protein Q9BVL2 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR "form complex" binding 10116 BTO:0000154 2050741 t Simone "Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function." SIGNOR-261260 NUP62 protein P37198 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR "form complex" binding 10116 BTO:0000154 2050741 t Simone "Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function." SIGNOR-261258 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 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 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 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR HDAC1 protein Q13547 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-261498 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR PBX3 protein P40426 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0004054 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. PBX3, a member of the PBX family of TALE homeobox genes, is upregulated in both NUP98‐HOXA9–transduced adult and cord blood CD34+ cells (Table 3)." SIGNOR-261504 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR PECAM1 protein P16284 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0004054 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 platelet endothelial cell adhesion molecule PECAM1 is also downregulated by NUP98‐HOXA9." SIGNOR-261500 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR RBPMS protein Q93062 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0004054 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 gene for the RNA‐binding protein with multiple splicing (RBPMS) was upregulated in NUP98‐HOXA9–transduced cord blood CD34+ cells and also in the transcriptosomes of normal CD34+ and CD133+ cells." SIGNOR-261503 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR RUNX1 protein Q01196 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0004054 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 NUP98 protein P52948 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 20498086 f miannu "The export of mRNAs is a multistep process, involving the packaging of mRNAs into messenger ribonucleoprotein particles (mRNPs), their transport through nuclear pore complexes, and mRNP remodeling events prior to translation. Ribonucleic acid export 1 (Rae1) and Nup98 are evolutionarily conserved mRNA export factors that are targeted by the vesicular stomatitis virus matrix protein to inhibit host cell nuclear export. these data suggest that the Rae1*Nup98 complex directly binds to the mRNP at several stages of the mRNA export pathway." SIGNOR-260872 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 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 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP53 protein P04637 UNIPROT up-regulates 9606 17700533 t miannu "Nutlin, a class of small molecule antagonist of HDM2, binds to the p53-binding pocket of HDM2, preventing p53 from binding to HDM2 and thus, resulting in stabilization and activation of p53" SIGNOR-255471 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 NVP-AEW541 chemical CID:11476171 PUBCHEM INSR protein P06213 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194895 NVP-BEP800 chemical CID:25210273 PUBCHEM HSP90AB1 protein P08238 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194904 "NVP-BSK805 dihydrochloride" chemical CID:57339395 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194934 NVP-BVU972 chemical CID:44206063 PUBCHEM MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194943 NXF1 protein Q9UBU9 UNIPROT RBM15/NXF1 complex SIGNOR-C67 SIGNOR "form complex" binding 9606 17001072 t miannu "Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression." SIGNOR-149880 NXPH1 protein P58417 UNIPROT NRXN1 protein P58400 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-62699 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 NXPH1 protein P58417 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 t gcesareni "We show that neurexophilins 1 and 3 but not 4 (neurexophilin 2 is not expressed in rodents) bind to a single individual lns domain, the second overall lns domain in all three alpha-neurexins." SIGNOR-60643 NYYJKMXNVNFOFQ-MHZLTWQESA-N chemical CID:9829836 PUBCHEM ADRB3 protein P13945 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "There were several β3-selective compounds (e.g. AZ 40140d, L 755507, L 748337 and TAK 677)" SIGNOR-257856 OAT protein P04181 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 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 OAT protein P04181 UNIPROT L-proline smallmolecule CHEBI:17203 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 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-256033 Obatoclax chemical CID:16681698 PUBCHEM 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-200478 "Obatoclax mesylate" chemical CID:46930996 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194952 obinutuzumab antibody DB08935 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0001546;BTO:0004656 28584136 t miannu "Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL)." SIGNOR-259896 ODC1 protein P11926 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 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 ODC1 protein P11926 UNIPROT putrescine smallmolecule CHEBI:17148 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 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-256034 ODC1 protein P11926 UNIPROT spermidine smallmolecule CHEBI:16610 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 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 ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 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-256035 ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 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-256036 ofatumumab antibody DB06650 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0001546 28580841 t miannu "Ofatumumab is a human IgG1κ monoclonal antibody that binds to a membrane-proximal epitope of CD20 molecule expressed on the surface of B lymphocytes. Ofatumumab, the second-generation anti-CD20 antibody, induces cell lysis through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity. Ofatumumab is approved as monotherapy and in combination with chlorambucil for the treatment of fludarabine- and alemtuzumab-refractory CLL patients and previously untreated CLL patients, respectively." SIGNOR-259897 OFD1 protein O75665 UNIPROT IFT88 protein Q13099 UNIPROT "up-regulates activity" binding 9606 BTO:0001086 20230748 t "Regulation of binding" miannu "Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length." SIGNOR-251973 OGT protein O15294 UNIPROT TET1 protein Q8NFU7 UNIPROT "up-regulates activity" glycosylation 9606 BTO:0002181 23729667 t irozzo "The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt." SIGNOR-259184 olanzapine chemical CHEBI:7735 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-258511 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 olanzapine chemical CHEBI:7735 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000601 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-258509 olanzapine chemical CHEBI:7735 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-258507 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 olanzapine chemical CHEBI:7735 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-258508 olanzapine chemical CHEBI:7735 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-258512 olanzapine chemical CHEBI:7735 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-258506 olaparib chemical CHEBI:83766 ChEBI PARP3 protein Q9Y6F1 UNIPROT "down-regulates activity" "chemical inhibition" 9606 25981132 t miannu "The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT." SIGNOR-259320 OLIG1 protein Q8TAK6 UNIPROT OLIG2 protein Q13516 UNIPROT up-regulates 9606 BTO:0000938 25206819 f miannu "During central nervous system development, olig1 assists olig2 in formation of the motor neuron progenitor domain (pmn), the area responsible for generation of motor neurons and oligodendrocytes" SIGNOR-205304 olodaterol chemical CHEBI:82700 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" -1 20371707 t Luana "In vitro, olodaterol showed a potent, nearly full agonistic response at the hbeta(2)-AR (EC(50) = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (241- and 2299-fold [corrected] against the hbeta(1)- and hbeta(3)-ARs, respectively). " SIGNOR-257834 Olopatadine chemical CHEBI:7769 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-257782 OMG protein P23515 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-133640 O-phosphoethanolamine smallmolecule CHEBI:17553 ChEBI GABARAP protein O95166 UNIPROT up-regulates binding 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 OPRD1 protein P41143 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-256962 OPRD1 protein P41143 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-256683 OPRD1 protein P41143 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-256826 OPRK1 protein P41145 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-256710 OPRK1 protein P41145 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-256853 OPRK1 protein P41145 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-256989 OPRK1 protein P41145 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-257105 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 OPRL1 protein P41146 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-256722 OPRL1 protein P41146 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-256865 OPRL1 protein P41146 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-257001 OPRL1 protein P41146 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-257117 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 OPRM1 protein P35372 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-256854 OPRM1 protein P35372 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-256990 OPRM1 protein P35372 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-257106 OPTN protein Q96CV9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-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-259876 OPTN protein Q96CV9 UNIPROT BDNF protein P23560 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-259878 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 OPTN protein Q96CV9 UNIPROT NEFL protein P07196 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-259881 OPTN protein Q96CV9 UNIPROT NTF3 protein P20783 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-259879 OPTN protein Q96CV9 UNIPROT SNAP25 protein P60880 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-259880 orantinib chemical CHEBI:91088 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207438 "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 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 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 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 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 OSI-420 chemical CID:18924996 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195248 OSM protein P13725 UNIPROT AHR protein P35869 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24127753 f gcesareni "The il-6-type cytokine oncostatin m induces ahr expression in a stat3-ependent manner in human hepg2 hepatoma cells." SIGNOR-202963 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 OSM protein P13725 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0001271 1536831 t gcesareni "Oncostatin m binds the high-affinity leukemia inhibitory factor receptor" SIGNOR-19873 OSM protein P13725 UNIPROT OSMR protein Q99650 UNIPROT up-regulates binding 9606 16286453 t gcesareni "The oncostatin m receptor (osmr) is part of receptor complexes for oncostatin m and interleukin-31." SIGNOR-141588 OSU-03012 chemical CHEBI:131196 ChEBI PDPK1 protein O15530 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-197715 OTUB1 protein Q96FW1 UNIPROT UBE2N protein P61088 UNIPROT down-regulates binding 9606 21763684 t gcesareni "The deubiquitinating enzyme otub1 suppresses rnf168 dependent ubiquitination by direct the e2 ligase ubc13" SIGNOR-175050 OTX1 protein P32242 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 18849347 f miannu "Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity." SIGNOR-254887 OTX2 protein P32243 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 20530484 f 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-255186 OTX2 protein P32243 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 18849347 f miannu "Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity." SIGNOR-254888 OTX2 protein P32243 UNIPROT RBP3 protein P10745 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10354480 f miannu "OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments." SIGNOR-254889 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 oxaprozin chemical CHEBI:7822 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132;BTO:0003652 9650852 t miannu "We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively." SIGNOR-258929 oxaprozin chemical CHEBI:7822 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132;BTO:0003652 9650852 t miannu "We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively." SIGNOR-258930 Oxatomide chemical CHEBI:31943 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-257791 OXGR1 protein Q96P68 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-257417 OXGR1 protein Q96P68 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-257042 OXGR1 protein Q96P68 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-257155 OXGR1 protein Q96P68 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-256913 OXGR1 protein Q96P68 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-257243 OXGR1 protein Q96P68 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-257368 OXGR1 protein Q96P68 UNIPROT GNAS protein Q5JWF2 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-256770 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 Oxotremorine chemical CHEBI:7851 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-258651 Oxotremorine chemical CHEBI:7851 ChEBI CHRM2 protein P08172 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-258653 Oxotremorine chemical CHEBI:7851 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-258652 Oxotremorine chemical CHEBI:7851 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-258650 "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 "oxotremorine M" chemical CHEBI:38322 ChEBI CHRM2 protein P08172 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-258654 "oxotremorine M" chemical CHEBI:38322 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-258655 "oxotremorine M" chemical CHEBI:38322 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-258657 OXSR1 protein O95747 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" phosphorylation Thr84 LPSDFEHtIHVGFDA 9606 BTO:0000567 14707132 t miannu "OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. phosphorylation of PAK1 by OSR1 desensitizes PAK1 to activation by small G proteins, providing a modulatory input to PAK1 activity." SIGNOR-250210 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 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr203 HQHYYYDtHTNTYYL 9606 BTO:0000007 16669787 t miannu "We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1" SIGNOR-146513 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr207 YYDTHTNtYYLRTFG 9606 BTO:0000007 16669787 t miannu "We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1" SIGNOR-146517 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 BTO:0000007 16669787 t miannu "We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1" SIGNOR-146521 OXSR1 protein O95747 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates phosphorylation Thr60 MRTFGYNtIDVVPTY 9606 BTO:0000007 BTO:0000671 18270262 t miannu "We demonstrate that the spak and osr1 kinases that are activated by wnk1 phosphorylate human ncc at three conserved residues (thr46, thr55 and thr60) / our results also indicate that phosphorylation of thr60 plays the most crucial role in triggering the activation of ncc in hek293 cells and its mutation also inhibits phosphorylation of the adjacent thr46 and thr55 sites." SIGNOR-160833 OXT protein P01178 UNIPROT OXTR protein P30559 UNIPROT up-regulates binding 9606 1313946 t gcesareni "The oxytocin receptor, expressed in xenopus oocytes, specifically responds to oxytocin and induces an inward membrane current" SIGNOR-16758 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 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 OXTR protein P30559 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-257178 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 OXTR protein P30559 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-257266 EREG protein O14944 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 22891299 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4" SIGNOR-191785 OXTR protein P30559 UNIPROT GNAS protein Q5JWF2 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-256793 oxybutynin chemical CHEBI:7856 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 22243489 t Luana " Interestingly, unlike the methiodide 5, the tertiary amine 17 and to a lesser extent its (S)-eutomer preferentially block the M3 receptor subtype with respect to the M2, with an M3/M2 selectivity ratio slightly higher than those of oxybutynin and the conventional M3selective antagonist 4-DAMP. " SIGNOR-258327 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 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 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 oxymetazoline chemical CHEBI:7862 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-258917 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2B protein P18089 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-258916 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 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 oxymetazoline chemical CHEBI:7862 ChEBI HTR1D protein P28221 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-258927 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 P2RY10 protein O00398 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-257287 P2RY10 protein O00398 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-257348 P2RY10 protein O00398 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-257213 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 P2RY10 protein O00398 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-256869 P2RY10 protein O00398 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-257005 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 P2RY11 protein Q96G91 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-257435 P2RY11 protein Q96G91 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-257060 P2RY11 protein Q96G91 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-257173 P2RY11 protein Q96G91 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-256931 P2RY11 protein Q96G91 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-257261 P2RY11 protein Q96G91 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-257386 P2RY11 protein Q96G91 UNIPROT GNAS protein Q5JWF2 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-256788 P2RY11 protein Q96G91 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-257328 P2RY12 protein Q9H244 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-256712 P2RY12 protein Q9H244 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-256855 P2RY12 protein Q9H244 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-256991 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 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 P2RY13 protein Q9BPV8 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-257299 P2RY13 protein Q9BPV8 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-257027 P2RY13 protein Q9BPV8 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-257143 P2RY13 protein Q9BPV8 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-256749 P2RY13 protein Q9BPV8 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-256892 P2RY14 protein Q15391 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-257210 P2RY14 protein Q15391 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-256723 P2RY14 protein Q15391 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-256866 P2RY14 protein Q15391 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-257002 P2RY14 protein Q15391 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-257118 P2RY1 protein P47900 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-257394 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 P2RY1 protein P47900 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-257339 P2RY1 protein P47900 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-257072 P2RY1 protein P47900 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-256943 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 P2RY1 protein P47900 UNIPROT GNAS protein Q5JWF2 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-256800 P2RY1 protein P47900 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-257273 P2RY2 protein P41231 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-257145 P2RY2 protein P41231 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-257233 P2RY2 protein P41231 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-257031 P2RY2 protein P41231 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-256902 P2RY2 protein P41231 UNIPROT GNAS protein Q5JWF2 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-256759 P2RY4 protein P51582 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-257288 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 P2RY4 protein P51582 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-257214 P2RY4 protein P51582 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-256727 P2RY4 protein P51582 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-256870 P2RY4 protein P51582 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-257006 P2RY4 protein P51582 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-257122 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 P2RY6 protein Q15077 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-257398 P2RY6 protein Q15077 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-257277 P2RY6 protein Q15077 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-256947 P2RY6 protein Q15077 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-257076 P2RY6 protein Q15077 UNIPROT GNAS protein Q5JWF2 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-256804 P2RY6 protein Q15077 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-257189 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD2 protein Q15796 UNIPROT "up-regulates activity" acetylation Lys19 VKRLLGWkKSAGGSG 9606 17074756 t lperfetto "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. Smad2(FL) and Smad2(_E3) were also acetylated by P/CAF in vivo and the acetylation of both proteins was lost following mutation of Lys19 (Fig. 2D), suggesting that Lys19 in Smad2 is also targeted by P/CAF." SIGNOR-217607 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 BTO:0000150 15009097 t lperfetto "Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo." SIGNOR-217230 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates binding 9606 BTO:0000150 15009097 t lperfetto "Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo." SIGNOR-217233 p38 proteinfamily SIGNOR-PF16 SIGNOR Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 11591790 f "The p21 G protein Rho and its targets, Rho-associated coiled-coil forming protein kinases (p160ROCK/ROCK I/ROKβ and Rho kinase/ROCK II/ROKα), play a crucial role in actin cytoskeleton reorganization" SIGNOR-254360 p38 proteinfamily SIGNOR-PF16 SIGNOR BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser69 GPLAPPAsPGPFATR 10116 BTO:0001009 16818494 t Gianni "P38 MAP Kinase Mediates Apoptosis Through Phosphorylation of BimEL at Ser-65" SIGNOR-260443 p38 proteinfamily SIGNOR-PF16 SIGNOR BCL2 protein P10415 UNIPROT down-regulates phosphorylation Ser87 AAAGPALsPVPPVVH 9606 19336399 t Luana "The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38mapk" SIGNOR-260450 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 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT "down-regulates activity" phosphorylation Ser375 ARVLRSKsLCHDEIE 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-107416 p38 proteinfamily SIGNOR-PF16 SIGNOR HNF4A protein P41235 UNIPROT up-regulates phosphorylation Ser167 VLSRQITsPVSGING 9606 16351573 t lperfetto "Our results indicate that p38 kinase-mediated ser158 phosphorylation is essential for augmentation of the dna binding and transactivation potential of hnf4alpha" SIGNOR-143046 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 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser168 QGGGAFFsPSPGSSS 9606 11997522 t lperfetto "Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity." SIGNOR-87393 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser170 GGAFFSPsPGSSSLS 9606 11997522 t lperfetto "Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity." SIGNOR-87397 p62_complex complex SIGNOR-C259 SIGNOR Nuclear_pore_function phenotype SIGNOR-PH130 SIGNOR up-regulates 10116 2050741 f miannu "Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function." SIGNOR-261261 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 PABPC1 protein P11940 UNIPROT EIF4E protein P06730 UNIPROT "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-260968 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 PABPC1 protein P11940 UNIPROT NFX1 protein Q12986 UNIPROT "up-regulates activity" binding 9606 BTO:0000009 17267499 t Simone "We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123." SIGNOR-261052 PABPC4 protein Q13310 UNIPROT NFX1 protein Q12986 UNIPROT "up-regulates activity" binding 9606 BTO:0000008 17267499 t Simone "We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123." SIGNOR-261051 PAC-1 chemical CID:6851947 PUBCHEM CASP3 protein P42574 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-198535 paclitaxel chemical CHEBI:45863 ChEBI TUBA4A protein P68366 UNIPROT "down-regulates activity" binding 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-259346 paclitaxel chemical CHEBI:45863 ChEBI TUBB1 protein Q9H4B7 UNIPROT "down-regulates activity" binding 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-259347 paclitaxel chemical CHEBI:45863 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" binding 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 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 PAFAH1B1 protein P43034 UNIPROT CLIP1 protein P30622 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 11940666 t miannu "Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif." SIGNOR-252166 PAFAH1B1 protein P43034 UNIPROT DYNC1H1 protein Q14204 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 11163259 t miannu "We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex" SIGNOR-252158 PAFAH1B1 protein P43034 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 11163259 t miannu "We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 is required for the proper distribution of NUDEL and cellular components regulated by CDHC function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex" SIGNOR-252157 PAFAH1B1 protein P43034 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 20133715 f miannu "The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration." SIGNOR-252169 PAFAH1B2 protein P68402 UNIPROT APP protein P05067 UNIPROT up-regulates 9606 23238734 f miannu "We provide evidence that the loss of pafah1b2 potently reduces a_ by promoting the degradation of its immediate precursor, the _ctf." SIGNOR-200188 PAK1 protein Q13153 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Ser299 KNLGYRDsGYYWEVP 9606 BTO:0000848 15710605 t lperfetto "Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism." SIGNOR-236342 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser101 LESFKKQsFVLKEGV 9606 BTO:0000142 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-126650 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 BTO:0000142 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 PAK1 protein Q13153 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 19667072 t gcesareni "We identify gef-h1 as a binding target and substrate for p21-activated kinase 1 (pak1), we show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules." SIGNOR-187573 PAK1 protein Q13153 UNIPROT ARPC1B protein O15143 UNIPROT up-regulates phosphorylation Thr21 HAWNKDRtQIAICPN 9606 14749719 t lperfetto "The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21" SIGNOR-121642 PAK1 protein Q13153 UNIPROT AURKA protein O14965 UNIPROT up-regulates phosphorylation Thr288 APSSRRTtLCGTLDY 9606 24867643 t lperfetto "The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability" SIGNOR-205110 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser74 VEIRSRHsSYPAGTE 9606 BTO:0000007 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 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10611223 t lperfetto "Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau." SIGNOR-73529 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10611223 t lperfetto "Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau." SIGNOR-73533 PAK1 protein Q13153 UNIPROT BCL6 protein P41182 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000182 22723377 f "The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase-activated protein kinase PAK1." SIGNOR-253930 PAK1 protein Q13153 UNIPROT CTBP1 protein Q13363 UNIPROT "down-regulates activity" phosphorylation Ser158 REGTRVQsVEQIREV 9606 12872159 t lperfetto "Pak1 phosphorylates ctbp selectively on ser158 within a putative regulatory loop, triggering ctbp cellular redistribution and blocking ctbp ak1 superphosphorylates ctbp and inhibits ctbp dehydrogenase activitycorepressor functions." SIGNOR-103943 PAK1 protein Q13153 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 21822311 t lperfetto "Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin" SIGNOR-175944 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 t gcesareni "Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis." SIGNOR-165216 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 21079800 t gcesareni "Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis." SIGNOR-169690 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 20444238 t gcesareni "Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis." SIGNOR-165220 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 21079800 t gcesareni "Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis." SIGNOR-169694 PAK1 protein Q13153 UNIPROT DYNLL1 protein P63167 UNIPROT down-regulates phosphorylation Ser88 VAILLFKsG 9606 BTO:0000149 18084006 t lperfetto "Dlc1 phosphorylation on ser(88) by p21-activated kinase 1 (pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with bim and the stability of bim. Here we discovered that phosphorylation of ser(88), which juxtapose each other at the interface of the dlc dimer, disrupts dlc1 dimer formation and consequently impairs its interaction with bim" SIGNOR-159995 PAK1 protein Q13153 UNIPROT ELF3 protein P78545 UNIPROT up-regulates phosphorylation Ser207 GTGASRSsHSSDSGG 9606 BTO:0000150 17491012 t lperfetto "Phosphorylation-dependent regulation of stability and transforming potential of ets transcriptional factor ese-1 by p21-activated kinase 1. Pak1 selectively phosphorylates ese-1 at ser(207). Intriguingly, pak1 phosphorylation inactive mutant ese1-s207a is more unstable" SIGNOR-154743 PAK1 protein Q13153 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser305 IKRSKKNsLALSLTA 9606 BTO:0000149 12374744 t lperfetto "Pak1 directly phosphorylated the activation function-2 domain of the er at the n-terminal residue ser305, and its mutation to ala (s305a) abolished the pak1-mediated phosphorylation and transactivation functions of the er" SIGNOR-94206 PAK1 protein Q13153 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 12198493 t gcesareni "In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152." SIGNOR-92065 PAK1 protein Q13153 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 t gcesareni "Phosphorylation of either ser(16) by pak1 or ser(27) by pkc decreased the affinity of galpha(z) for gbetagamma;phosphorylation of both residues by pkc caused no further effect. Pak1 thus regulates galpha(z) function by attenuating the inhibitory effects of both gaps and gbetagamma." SIGNOR-48673 PAK1 protein Q13153 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000150 12151336 t gcesareni "Histone h3 is a substrate of pak1 both in vitro and in vivo, and it specifically interacted with pak1 but not pak2 or pak3. Site-directed mutagenesis indicated that pak1 phosphorylates histone h3 on ser10." SIGNOR-91050 PAK1 protein Q13153 UNIPROT HACE1 protein Q8IYU2 UNIPROT "down-regulates activity" phosphorylation Ser385 LMKNKRDsTEITSIL 9606 BTO:0004980 29362425 t "Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases […] We have established in vitro that HACE1 is a direct target of PAK1 kinase activity." SIGNOR-255537 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 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Thr173 DTFWKGTtRTRPRNG 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-154307 PAK1 protein Q13153 UNIPROT ITGB3BP protein Q13352 UNIPROT up-regulates phosphorylation Ser28 SKITRKKsVITYSPT 9606 BTO:0000150 18521086 t lperfetto "Serine 28 phosphorylation of nrif3 confers its co-activator function for estrogen receptor-alpha transactivation. p21-activated protein kinase 1 (pak1) phosphorylates eralpha at ser305 and this modification is important in eralpha transactivation function." SIGNOR-178795 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 PAK1 protein Q13153 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser192 VNSVRRKsCLVKEVE 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-199084 PAK1 protein Q13153 UNIPROT LIMK1 protein P53667 UNIPROT "up-regulates activity" phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 10559936 t lperfetto "Activation of lim-kinase by pak1 couplesp21-activated kinase (pak1) phosphorylates lim-kinase at threonine residue 508 within lim-kinase's activation loop" SIGNOR-72142 PAK1 protein Q13153 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser298 RTPGRPLsSYGMDSR 9606 BTO:0001955 12876277 t lperfetto "We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation." SIGNOR-236002 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 PAK1 protein Q13153 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0001955 12876277 t lperfetto "We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation." SIGNOR-244924 PAK1 protein Q13153 UNIPROT MYLK protein Q15746 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000567 10092231 t miannu "P21-activated kinase 1 (PAK1) phosphorylates MLCK, resulting in decreased MLCK activity. " SIGNOR-250317 PAK1 protein Q13153 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 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-159764 PAK1 protein Q13153 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Thr261 QYGLKMKtSRAFFSE 9606 BTO:0000150 18283314 t llicata "We found that pak1 phosphorylated ebp1 in vitro and mapped the phosphorylation site to threonine 261. these studies demonstrate for the first time that ebp1 is a substrate of pak1 and the importance of the pak1 phosphorylation site for the functional activity of ebp1 in breast cancer cells." SIGNOR-160963 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 11804587 t lperfetto "We show that pak1 forms homodimers in vivo and that its dimerization is regulated by the intracellular level of gtp-cdc42 or gtp-rac1. The dimerized pak1 adopts a trans-inhibited conformation." SIGNOR-236338 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" phosphorylation Ser199 PRPEHTKsVYTRSVI 9534 BTO:0000298 9032240 t miannu "Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation." SIGNOR-250216 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" phosphorylation Ser57 KKDRFYRsILPGDKT 9534 BTO:0000298 9032240 t miannu "Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation." SIGNOR-250219 PAK1 protein Q13153 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser118 QVKIWRRsYDVPPPP 9606 BTO:0000130 12189148 t "Activated pak1" gcesareni "Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity." SIGNOR-91594 PAK1 protein Q13153 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser23 WNLENRFsGWYDADL 9606 BTO:0000130 12189148 t "Activated pak1" gcesareni "Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity." SIGNOR-91598 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 PAK1 protein Q13153 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser49 EVLVDPRsRRRYVRG 9606 BTO:0000567 18427546 t llicata "We show here that pak1 is required for cell proliferation, mitotic progression and plk1 activity in hela cells. phosphorylation of plk1 on ser 49 is important for metaphase-associated events." SIGNOR-178353 PAK1 protein Q13153 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 16717130 t llicata "We show that p21-activated kinase (pak)-induced phosphorylation of serine 273 in paxillin is a critical regulator of this turnover." SIGNOR-146842 PAK1 protein Q13153 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 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-180808 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 PAK1 protein Q13153 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser246 QACARTFsRMSLLHK 9606 BTO:0000150 15833848 t lperfetto "Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions." SIGNOR-135605 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 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 10913145 t gcesareni "We find that, in vitro, pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays." SIGNOR-79955 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 19162178 t gcesareni "The hgf-induced wave2 transport, lamellipodia formation, stathmin/op18 phosphorylation at ser38 and binding to kinesin-wave2 complex, but not stathmin/op18 phosphorylation at ser25 and microtubule growth, were abrogated by pak1 inhibitor ipa-3" SIGNOR-183503 PAK1 protein Q13153 UNIPROT TBCB protein Q99426 UNIPROT up-regulates phosphorylation Ser128 VRSFLKRsKLGRYNE 9606 BTO:0000150 15831477 t lperfetto "P21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor b. Pak1 directly phosphorylated tcob in vitro and in vivo on serines 65 and 128 and colocalized with tcob on newly polymerized microtubules and on centrosomes. Pak1 phosphorylation is necessary for normal tcob function" SIGNOR-135460 PAK1 protein Q13153 UNIPROT TBCB protein Q99426 UNIPROT up-regulates phosphorylation Ser65 GVDDKFYsKLDQEDA 9606 BTO:0000150 15831477 t lperfetto "P21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor b. Pak1 directly phosphorylated tcob in vitro and in vivo on serines 65 and 128 and colocalized with tcob on newly polymerized microtubules and on centrosomes. Pak1 phosphorylation is necessary for normal tcob function" SIGNOR-135464 PAK1 protein Q13153 UNIPROT VIM protein P08670 UNIPROT unknown phosphorylation Ser56 SRSLYASsPGGVYAT 9606 BTO:0000887;BTO:0001260 15766329 t llicata "In the present study, pak1 was able to phosphorylate vimentin on ser-56 in vitro." SIGNOR-134520 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 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 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser619 PTPPKRSsSFREMDG 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-160219 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Ser239 WRSPGRGsWFVQALC 9606 BTO:0000150 21555521 t gcesareni "Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis." SIGNOR-173655 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Ser30 DAKPDRSsFVPSLFS 9606 BTO:0000150 21555521 t gcesareni "Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis." SIGNOR-173659 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Thr173 FRGDRCKtLLEKPKL 9606 BTO:0000150 21555521 t gcesareni "Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis." SIGNOR-173663 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 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr2 tAKMETTF 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-170760 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 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr8 MTAKMETtFYDDALN 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-170768 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr93 GHITTTPtPTQFLCP 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-170776 PAK2 protein Q13177 UNIPROT MKNK1 protein Q9BUB5 UNIPROT "down-regulates activity" phosphorylation Ser39 RRGRATDsLPGKFED 9606 BTO:0000007 15234964 t miannu "Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. When 293T cells are subjected to apoptotic induction by hydrogen peroxide, Mnk1 is phosphorylated at both Thr(22) and Ser(27). These results indicate a role for Pak2 in the down-regulation of translation initiation in apoptosis by phosphorylation of Mnk1." SIGNOR-250221 PAK2 protein Q13177 UNIPROT MYLK protein Q15746 UNIPROT "down-regulates activity" phosphorylation Ser1208 MKSRRPKsSLPPVLG -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-250222 PAK2 protein Q13177 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 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-159768 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser141 TVKQKYLsFTPPEKD -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. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197." SIGNOR-250228 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser192 PRPDHTKsIYTRSVI -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-250225 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser197 TKSIYTRsVIDPVPA -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-250226 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 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser20 APPVRMSsTIFSTGG -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. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197." SIGNOR-250227 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser55 KPRHKIIsIFSGTEK -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. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197." SIGNOR-250229 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Thr402 PEQSKRStMVGTPYW -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-250230 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 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 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser235 IAKRRRLsSLRASTS -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-250231 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 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser240 RLSSLRAsTSKSESS -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-250233 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser242 SSLRASTsKSESSQK -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-250234 PAK2 protein Q13177 UNIPROT SYN1 protein P17600 UNIPROT "up-regulates activity" phosphorylation Ser9 NYLRRRLsDSNFMAN 10116 BTO:0001009 12237306 t miannu "Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues. neurotransmitter release may require phosphorylation of site 1 (Ser9) in the N terminus of synapsins" SIGNOR-250236 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser26 GTASRPSsSRSYVTT -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-250237 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser39 TTSTRTYsLGSALRP -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-250239 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 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 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 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 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 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 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 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 PAK3 protein O75914 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser150 TLRRVRIsADAMMQA 9606 BTO:0000887 12242269 t llicata "Importantly, cardiac troponin i was found to be phosphorylated at serine 149 of human cardiac troponin i, representing a novel phosphorylation site. These findings suggest a novel mechanism of modulating the calcium sensitivity of cardiac muscle contraction." SIGNOR-92990 PAK4 protein O96013 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 22173096 t lperfetto "Pak4 interacts with and phosphorylates _-catenin on ser675, which promotes the tcf/lef transcriptional activity and stabilizes _-catenin through inhibition of its degradation." SIGNOR-191557 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser759 REFAKFQsERSRARY 9606 20507994 t llicata "Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration." SIGNOR-165702 PAK4 protein O96013 UNIPROT PAK4 protein O96013 UNIPROT "up-regulates activity" phosphorylation Ser474 KEVPRRKsLVGTPYW 10090 BTO:0000944 11668177 t lperfetto "Here we demonstrate that PAK4 is frequently overexpressed in human tumor cell lines of various tissue origins. We also have identified serine (Ser-474) as the likely autophosphorylation site in the kinase domain of PAK4 in vivo. Mutation of this serine to glutamic acid (S474E) results in constitutive activation of the kinase." SIGNOR-235867 PAK4 protein O96013 UNIPROT PAK4 protein O96013 UNIPROT up-regulates phosphorylation Ser474 KEVPRRKsLVGTPYW 9606 20926745 t gcesareni "Intracellular localization;enzymatic activity, induced;cell growth, altered;" SIGNOR-168301 PAK4 protein O96013 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 BTO:0001130 20406887 t llicata "We find that pak4 is localised at focal adhesions, is immunoprecipitated with paxillin and phosphorylates paxillin on serine 272." SIGNOR-164889 PAK4 protein O96013 UNIPROT RAN protein P62826 UNIPROT unknown phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 20805321 t llicata "We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis. our study suggests that pak4-mediated phosphorylation of gdp- or gtp-bound ran regulates the assembly of ran-dependent complexes on the mitotic spindle" SIGNOR-167671 PAK4 protein O96013 UNIPROT RAN protein P62826 UNIPROT up-regulates phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 20805321 t lperfetto "We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis.Altogether, our findings strongly suggest that pak4-mediated phosphorylation of gdp- or gtp-bound ran modulates the assembly of complexes that are required at specific subcellular localizations for ran to carry out its functions during mitotic progression." SIGNOR-167667 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 PAK5 protein Q9P286 UNIPROT PAK5 protein Q9P286 UNIPROT "up-regulates activity" phosphorylation His19 SGPSNFEhRVHTGFD -1 12860998 t miannu "Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation." SIGNOR-250248 PAK5 protein Q9P286 UNIPROT PAK5 protein Q9P286 UNIPROT "up-regulates activity" phosphorylation His22 SNFEHRVhTGFDPQE -1 12860998 t miannu "Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation." SIGNOR-250249 PAK proteinfamily SIGNOR-PF13 SIGNOR MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser298 RTPGRPLsSYGMDSR 9606 BTO:0000567 16129686 t gcesareni "Inhibition of pak kinase activity dramatically decreased phosphorylation of mek1 at ser(298) in response to either pdgf or egf." SIGNOR-140039 PAK proteinfamily SIGNOR-PF13 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 16129686 t lperfetto "Inhibition of pak kinase activity dramatically decreased phosphorylation of mek1 at ser(298) in response to either pdgf or egf." SIGNOR-244920 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 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 PALB2 protein Q86YC2 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-204541 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 palbociclib chemical CHEBI:85993 ChEBI CCND2 protein P30279 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205701 palbociclib chemical CHEBI:85993 ChEBI CDK4 protein P11802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205704 palbociclib chemical CHEBI:85993 ChEBI CDK6 protein Q00534 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205707 paliperidone chemical CHEBI:82978 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-258563 paliperidone chemical CHEBI:82978 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000601 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-258565 paliperidone chemical CHEBI:82978 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-258560 paliperidone chemical CHEBI:82978 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-258562 paliperidone chemical CHEBI:82978 ChEBI HTR1E protein P28566 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-258561 paliperidone chemical CHEBI:82978 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-258564 "AMG 900" chemical CID:24856041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189492 PAMPs stimulus SIGNOR-ST11 SIGNOR AIM2 protein O14862 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-256423 PAMPs stimulus SIGNOR-ST11 SIGNOR MEFV protein O15553 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-256426 PAMPs stimulus SIGNOR-ST11 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-256424 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRP1 protein Q9C000 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-256425 PAMPs stimulus SIGNOR-ST11 SIGNOR SLC11A1 protein P49279 UNIPROT up-regulates 9606 BTO:0000801 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-254039 PAMPs stimulus SIGNOR-ST11 SIGNOR TLR4 protein O00206 UNIPROT "up-regulates activity" 9606 BTO:0000801 19946286 f lperfetto "The lipopolysaccharide (LPS) of Gram negative bacteria is a wellknown inducer of the innate immune response1. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules." SIGNOR-249516 PAMPs stimulus SIGNOR-ST11 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR up-regulates 9606 20404851 f lperfetto "the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs)" SIGNOR-216295 panitumumab antibody DB01269 DRUGBANK EGFR protein P00533 UNIPROT "down-regulates activity" binding 9606 BTO:0000176 11255078 t miannu "ABX-EGF binds EGFr with high affinity (5x10(-11) M), blocks the binding of both EGF and transforming growth factor-alpha (TGF-alpha) to various EGFr-expressing human carcinoma cell lines, and inhibits EGF-dependent tumor cell activation, including EGFr tyrosine phosphorylation, increased extracellular acidification rate, and cell proliferation. Being a fully human antibody, ABX-EGF is anticipated to exhibit a long serum half-life and minimal immunogenicity with repeated administration, even in immunocompetent patients. These results demonstrate the potent anti-tumor activity of ABX-EGF and its therapeutic potential for the treatment of multiple human solid tumors that overexpress EGFr." SIGNOR-259898 panobinostat chemical CHEBI:85990 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-257754 panobinostat chemical CHEBI:85990 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-257756 panobinostat chemical CHEBI:85990 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-257749 panobinostat chemical CHEBI:85990 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-257755 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 panobinostat chemical CHEBI:85990 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-257752 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 panobinostat chemical CHEBI:85990 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-257750 "Papain-like proteinase" protein P0C6X7_PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" binding 9606 17761676 t lperfetto "PLpro interacts with IRF-3, and inhibits the phosphorylation and nuclear translocation of IRF-3, thereby disrupting the activation of type I IFN responses through either Toll-like receptor 3 or retinoic acid inducible gene I/melanoma differentiation-associated gene 5 pathways." SIGNOR-260276 "Papain-like proteinase" protein P0C6X7_PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" deubiquitination 9606 25481026 t miannu "Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response." SIGNOR-260249 "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 "Papain-like proteinase" protein P0C6X7_PRO_0000037311 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates activity" deubiquitination 9606 31226023 t miannu "Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-β and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3" SIGNOR-260246 "Papain-like proteinase" protein P0C6X7_PRO_0000037311 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates activity" deubiquitination 9606 31226023 t miannu "Also, SARS-CoVPLPro catalyzed deubiquitination ofTNF-receptor-associatedfactor3(TRAF3)and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist" SIGNOR-260248 "Papain-like proteinase" protein P0C6X9_PRO_0000037340 UNIPROT IFNB1 protein P01574 UNIPROT "down-regulates quantity by repression" 9606 BTO:0000007 17761676 f lperfetto "SARS-CoV PLpro domain inhibits activation of IFN-β promoter following engagement of TLR3 or RIG-I pathways independent of its protease activity" SIGNOR-260277 "PAR-1 (Protease-Activated Receptor) Selective Activating Peptide" smallmolecule CID:71312048 PUBCHEM F2RL1 protein P55085 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-257485 "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 paracetamol chemical CHEBI:46195 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000876 17884974 t Luana "Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man" SIGNOR-257757 "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 PARD6A protein Q9NPB6 UNIPROT PARD6/SMURF1 complex SIGNOR-C112 SIGNOR "form complex" binding 9606 BTO:0004183 15761148 t lperfetto "The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT." SIGNOR-227559 ATM protein Q13315 UNIPROT ABRAXAS1 protein Q6UWZ7 UNIPROT "up-regulates activity" phosphorylation Ser406 GPGEYSRsPTF 9606 BTO:0000007 26778126 t "IR-Induced Double Phosphorylation of Abraxas C Terminus S404 and S406 Is ATM Dependent" SIGNOR-255588 PARD6A protein Q9NPB6 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 22544755 t lperfetto "The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization, and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains." SIGNOR-227489 PARD6A protein Q9NPB6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 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-199530 PARD6/SMURF1 complex SIGNOR-C112 SIGNOR RHOA protein P61586 UNIPROT down-regulates ubiquitination 9606 BTO:0004183 15761148 t lperfetto "The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT." SIGNOR-227492 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 PARL protein Q9H300 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-261364 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 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 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-258739 PARP1 protein P09874 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 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-111680 PARP1 protein P09874 UNIPROT POLA1 protein P09884 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9518481 t Federica "We provide evidence that in proliferating cells: (i) PARP is physically associated with the catalytic subunit of the DNA polymerase α–primase tetramer, an association confirmed by confocal microscopy, demonstrating that both enzymes are co-localized at the nuclear periphery of HeLa cells.|(iii) PARP-deficient cells derived from PARP knock-out mice exhibited reduced DNA polymerase activity," SIGNOR-261270 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 PARP1 protein P09874 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-254528 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 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002423 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." SIGNOR-254892 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 "PAS complex" complex SIGNOR-C190 SIGNOR 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-) smallmolecule CHEBI:85342 ChEBI "up-regulates quantity" "small molecule catalysis" -1 17556371 t miannu "Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. we demonstrate a central function for each component of the core protein machinery for PtdIns(3,5)P2 synthesis and turnover in the formation/detachment (or maturation) of transport vesicle intermediates from early endosomes." SIGNOR-253531 "PAS complex" complex SIGNOR-C190 SIGNOR "1-phosphatidyl-1D-myo-inositol 3-phosphate" smallmolecule CHEBI:17283 ChEBI "down-regulates quantity" "small molecule catalysis" -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 "PAS complex" complex SIGNOR-C190 SIGNOR Multivesicular_body_assembly phenotype SIGNOR-PH83 SIGNOR up-regulates 9606 BTO:0000007 17556371 f miannu "Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. We further demonstrate a key function for each of the three proteins in the biogenesis of ECV/MVB transport intermediates from early endosomes." SIGNOR-253532 PASK protein Q96RG2 UNIPROT EEF1A1 protein P68104 UNIPROT unknown phosphorylation 9606 BTO:0000567 17595531 t gcesareni "Kinase assays, mass spectrometry and site-directed mutagenesis revealed PASKIN auto-phosphorylation as well as eEF1A1 target phosphorylation mainly but not exclusively at Thr432." SIGNOR-245862 PASK protein Q96RG2 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation -1 16275910 t gcesareni "Recombinant human PASK (hPASK) phosphorylates purified muscle glycogen synthase, causing robust inactivation. Furthermore, hPASK interacts directly with glycogen synthase when expressed in cultured cells and this interaction and the phosphorylation of glycogen synthase by human PASK (hPASK) are inhibited by glycogen." SIGNOR-245866 PASK protein Q96RG2 UNIPROT PASK protein Q96RG2 UNIPROT "up-regulates activity" phosphorylation Thr1161 ERGKLFYtFCGTIEY -1 11459942 t lperfetto "We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity." SIGNOR-109481 PASK protein Q96RG2 UNIPROT PASK protein Q96RG2 UNIPROT "up-regulates activity" phosphorylation Thr1165 LFYTFCGtIEYCAPE -1 11459942 t lperfetto "We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity." SIGNOR-109485 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 PATZ1 protein Q9HBE1 UNIPROT RNF4 protein P78317 UNIPROT down-regulates binding 9606 10713105 t miannu "In vitro and in vivo interaction between rnf4 and patz was demonstrated / patz acted as a transcriptional repressor, whereas its partner rnf4 behaved as a transcriptional activator./ the association of patz with rnf4 switches activation to repression" SIGNOR-75775 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 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 PAX1 protein P15863 UNIPROT MEOX2 protein P50222 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-222232 PAX2 protein Q02962 UNIPROT Urogenital_tract phenotype SIGNOR-PH71 SIGNOR "up-regulates activity" 10090 BTO:0000671 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 PAX2 protein Q02962 UNIPROT WT1 protein P19544 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002295 16631587 t "Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter." SIGNOR-252290 PAX2/TLE4 complex SIGNOR-C152 SIGNOR WT1 protein P19544 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0002295 16631587 t "Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1." SIGNOR-252291 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 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR IGF1R protein P08069 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-251568 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR IGF2 protein P01344 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 t miannu "Insulin-like growth factor is required for RMS cell growth and IGF2 is expressed in an autocrine manner by the tumour cells. The IGF2 locus shows a loss of imprinting in both ERMS and ARMS tumours and expression of PAX3-FOXO1 can induce the upregulation of IGF2, thus enhancing the activation of IGF signalling pathway in ARMS" SIGNOR-251573 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR MET protein P08581 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-251570 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR PDGFA protein P04085 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-251571 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 PAX3 protein P23760 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 BTO:0000971 20006729 t gcesareni "Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1." SIGNOR-162100 PAX3 protein P23760 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-222235 PAX3 protein P23760 UNIPROT MEOX2 protein P50222 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-222238 PAX3 protein P23760 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 23384562 f gcesareni "Direct molecular regulation of the myogenic determination gene myf5 by pax3, with modulation by six1/4 factors, is exemplified by the -111 kb-myf5 enhancer." SIGNOR-200862 PAX3 protein P23760 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222 18854138 f gcesareni "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-181621 PAX3 protein P23760 UNIPROT PITX2 protein Q99697 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 21143873 f gcesareni "Pitx genes, such as pitx2, which is positively regulated by pax3, have been implicated in myogenesis." SIGNOR-170343 PAX3 protein P23760 UNIPROT TBX2 protein Q13207 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002267 25211658 t lperfetto "We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3" SIGNOR-249596 PAX6 protein P26367 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-70963 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 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 PAX6 protein P26367 UNIPROT PAX6 protein P26367 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001874 17251190 f Regulation miannu "Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling. TGFβ receptor activation represses Pax6 promoter activity by releasing Pax6 from autoregulating its own promoter." SIGNOR-251873 PAX6 protein P26367 UNIPROT PCSK1 protein P29120 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19034419 f miannu "PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin." SIGNOR-254900 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR FGFR4 protein P22455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 f 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-251565 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR IGF1R protein P08069 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20663909 t lperfetto "We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma." SIGNOR-249595 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887;BTO:0000142 12832520 t gcesareni "Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity." SIGNOR-102652 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR JARID2 protein Q92833 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23435416 t lperfetto "JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells| we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein.| Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS" SIGNOR-249597 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR MET protein P08581 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-251566 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR PDGFA protein P04085 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-251567 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR SUV39H1 protein O43463 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23435416 f lperfetto "In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation. Although not shown directly, the authors speculated that KMT1A levels may be regulated by PAX3-FOXO1, as KMT1A expression was only increased on induction of differentiation in PAX3-FOXO1 positive cell lines" SIGNOR-249598 "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 "PAX7/MLL2 complex" complex SIGNOR-C91 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-198641 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 PAX7 protein P23759 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 SIGNOR-C89 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-198626 PAX7 protein P23759 UNIPROT "MLL1 complex" complex SIGNOR-C89 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t lperfetto "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-217716 PAX7 protein P23759 UNIPROT "MLL2 complex" complex SIGNOR-C88 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t lperfetto "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-217712 PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002314 BTO:0001103 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 PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001103 18066051 t "Simone Vumbaca" "Together, these experiments indicate that Pax7 enforces satellite cell commitment by recruiting a HMT complex to Myf5, resulting in transcriptional activation." SIGNOR-255641 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by destabilization" 10090 BTO:0004058 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 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222 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 PAX7 protein P23759 UNIPROT "PAX7/MLL1 complex" complex SIGNOR-C90 SIGNOR "form complex" binding 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-198632 PAX7 protein P23759 UNIPROT "PAX7/MLL2 complex" complex SIGNOR-C91 SIGNOR "form complex" binding 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-198635 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates 9606 BTO:0000887 15843801 f gcesareni "We have identified a new cell population that expresses the transcription factors pax3 and pax7 (paired box proteins 3 and 7) but no skeletal-muscle-specific markers." SIGNOR-135626 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates BTO:0001103 15501225 f svumbaca "Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell." SIGNOR-255366 PAX7 protein P23759 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto "Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells" SIGNOR-219371 PAX8 protein Q06710 UNIPROT SLC3A1 protein Q07837 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000671 15673291 f miannu "Expression of SLC3A1 mRNA was found to be tenfold higher in postnatal vs. fetal kidney; SLC3A1 expression is doubled by the proximal tubule transcription factor, PAX8. rBAT is expressed in the proximal convoluted and straight tubules in both fetal and adult kidney." SIGNOR-254907 PAX8 protein Q06710 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14623893 t miannu "Pax8 has an essential role in thyroid organogenesis and differentiation, being the main mediator of thyroid gene transcription, including the NIS gene." SIGNOR-251990 PAX8 protein Q06710 UNIPROT TG protein P01266 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11786384 t miannu "The transcription factor Pax8 plays an important role in the expression of the differentiated phenotype of thyroid follicular cells. It has recently been shown that Pax8 is necessary for thyroglobulin (Tg) gene expression." SIGNOR-251998 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 10908331 t miannu "PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. The degree of interaction with the Pax2 C-terminal polypeptides correlates with their transcription transactivation potential and we have therefore designated this factor PTIP for Pax transactivation-domain interacting protein." SIGNOR-236965 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 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 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 pazopanib chemical CHEBI:71219 ChEBI FLT1 protein P17948 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-258260 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 pazopanib chemical CHEBI:71219 ChEBI FLT4 protein P35916 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-258261 pazopanib chemical CHEBI:71219 ChEBI FLT4 protein P35916 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-257739 pazopanib chemical CHEBI:71219 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-258262 pazopanib chemical CHEBI:71219 ChEBI KDR protein P35968 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-257738 pazopanib chemical CHEBI:71219 ChEBI KIT protein P10721 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-257736 pazopanib chemical CHEBI:71219 ChEBI PDGFRB protein P09619 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-257737 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI FGF1 protein P05230 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-259166 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI FGFR3 protein P22607 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-259165 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-200030 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-200809 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI ITK protein Q08881 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-259164 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-201250 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" -1 17620431 t miannu "The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. 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-259168 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 17620431 t miannu "The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. 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-259167 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR "down-regulates activity" "chemical inhibition" -1 17620431 t miannu "The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. 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-259451 "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 "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 "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 PBK protein Q96KB5 UNIPROT GPSM2 protein P81274 UNIPROT up-regulates phosphorylation Thr457 LKGKKYKtNSSTKVL 9606 BTO:0000150 20589935 t lperfetto "We found that the 450th threonine (thr450) of lgn/gpsm2 was phosphorylated by the serine/threonine kinase pbk/topk during mitosis. Western blot analysis indicated the highest expression and the phosphorylated form of lgn/gpsm2 protein in g2/m phase." SIGNOR-166461 PBK protein Q96KB5 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000150 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-149716 PBK protein Q96KB5 UNIPROT PRDX1 protein Q06830 UNIPROT up-regulates phosphorylation Ser32 QFKDISLsDYKGKYV 9606 BTO:0000782;BTO:0000848;BTO:0001286 20647304 t lperfetto "We report that prx1 is newly discovered direct target of topk. Our results demonstrate that topk phosphorylation of prx1 at ser-32 inhibits uvb-induced apoptosis in rpmi7951 melanoma cells by increasing prx1 peroxidase activity and decreasing the intracellular accumulation of h2o2." SIGNOR-166901 PBRM1 protein Q86U86 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 18339845 f miannu "Endogenous wild-type baf180 bound to the p21 promoter and was required for proper p21 expression and g(1) arrest after transforming growth factor-beta and gamma-radiation treatment." SIGNOR-178022 PBRM1 protein Q86U86 UNIPROT CRABP2 protein P29373 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-131552 PBRM1 protein Q86U86 UNIPROT RARB protein P10826 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-132378 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 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 PBX1 protein P40424 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 15149596 t "Pbx is constitutively bound close to the Myogenin promoter and can recruit MyoD" lperfetto "These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site" SIGNOR-124834 PBX1 protein P40424 UNIPROT "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR "form complex" binding 9606 BTO:0001103 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-151700 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 PCBD1 protein P61457 UNIPROT FXYD2 protein P54710 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000482 24204001 f miannu "Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT." SIGNOR-254908 PCBD1 protein P61457 UNIPROT HNF1B protein P35680 UNIPROT "up-regulates activity" binding 9606 BTO:0000482 24204001 t miannu "Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT." SIGNOR-254910 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 PCGF1 protein Q9BSM1 UNIPROT "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR "form complex" binding 10090 25533466 t miannu "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-255279 PCGF2 protein P35227 UNIPROT HSF2 protein Q03933 UNIPROT "down-regulates activity" sumoylation 9606 BTO:0000007 18211895 t miannu "MEL-18, in contrast to the polycomb protein PC2/CBX4, in which SUMO E3 activity stimulates sumoylation of certain proteins, actually functions like an anti-SUMO E3 protein, interacting with both HSF2 and the SUMO E2 UBC9 but acting to inhibit UBC9 activity and thereby decreasing sumoylation of a target protein, in this case that of HSF2. sumoylation of HSF2 is up-regulated during mitosis and is important for the interaction of this factor with a subunit of the condensin complex during the bookmarking process" SIGNOR-226245 PCGF2 protein P35227 UNIPROT UBE2I protein P63279 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18211895 t miannu "Based on this finding of interaction between MEL-18 and UBC9, we envisioned a mechanism in which MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes that approach HSF2." SIGNOR-226248 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 PCM1 protein Q15154 UNIPROT CETN1 protein Q12798 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-94947 PCM1 protein Q15154 UNIPROT CETN2 protein P41208 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-94990 PCM1 protein Q15154 UNIPROT CETN3 protein O15182 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-95016 PCM1 protein Q15154 UNIPROT NEK2 protein P51955 UNIPROT up-regulates relocalization 9606 15659651 t miannu "Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1" SIGNOR-133337 PCM1 protein Q15154 UNIPROT NIN protein Q8N4C6 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-95077 PCM1 protein Q15154 UNIPROT PCNT protein O95613 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-95117 PCNA protein P12004 UNIPROT NCR2 protein O95944 UNIPROT "down-regulates activity" binding 9606 BTO:0000914 22021614 t miannu "NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown." SIGNOR-260043 PCNT protein O95613 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 18042621 t Giulio "Our observation that Cep215 may function downstream of pericentrin suggests that the two proteins affect centrosome cohesion through a common mechanism. |Finally, depletion of pericentrin caused an almost complete loss of Cep215 from centrosomes, a detectable reduction in centrosomal levels of Cep68 and rootletin, but no significant effect on C-Nap1 (Fig. 6C and Table 1). Taken together, these results point to functional (and perhaps molecular) interactions between (1) Cep68 and rootletin and (2) Cep215 and pericentrin." SIGNOR-260309 PCSK6 protein P29122 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000666 25527501 t Giorgia "Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation." SIGNOR-260366 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 PCSK7 protein Q16549 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation 9606 BTO:0000130 19544470 t gcesareni "Addition of active p38a induced phosphorylation of wild-type c/ebp_? (c/ebp_?WT) on serine 21" SIGNOR-186202 PCSK7 protein Q16549 UNIPROT DDB2 protein Q92466 UNIPROT down-regulates 9606 18806262 f "The phosphorylation of DDB2 by p38 promotes its ubiquitination" gcesareni "The data suggest that p38 mapk is involved in serine phosphorylation of ddb2, which may influence its ubiquitylation following irradiation." SIGNOR-181278 PCSK7 protein Q16549 UNIPROT ELK4 protein P28324 UNIPROT up-regulates phosphorylation 9606 9130707 t gcesareni "In contrast, the tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387" SIGNOR-47771 PCSK7 protein Q16549 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation 9606 12435397 t gcesareni "In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site" SIGNOR-95622 PCSK7 protein Q16549 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation 9606 BTO:0000222 BTO:0000887 16364914 t gcesareni "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-143167 PCSK7 protein Q16549 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 f lperfetto "The levels of ikb_? Where reduced in cells overexpressing mkk6 [] these results indicated that mkk6 was able to promote the degradation of the NF-kappaB inhibitor, in a p38-dependent manner." SIGNOR-235837 PCSK7 protein Q16549 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates phosphorylation 9606 11259586 t gcesareni "This together with the rapid kinetics of pp1-pp2a activation following p38 activation suggests that pp1 and/or pp2a complexes are direct targets for p38-mediated phosphorylation" SIGNOR-105783 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 "PD-153035 hydrochloride" chemical CHEBI:91075 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205716 PD173074 chemical CHEBI:63448 ChEBI FGFR3 protein P22607 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205728 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 PD173955 chemical CHEBI:49791 ChEBI SRC protein P12931 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-258264 PD318088 chemical CID:10231331 PUBCHEM MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205737 PD318088 chemical CID:10231331 PUBCHEM MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205740 PD318088 chemical CID:10231331 PUBCHEM MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244927 PDE1A protein P54750 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 22014080 t "PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values" SIGNOR-253398 PDE1C protein Q14123 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 22014080 t "PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values" SIGNOR-253399 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 PDE4DIP protein Q5VU43 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates binding 9606 21569246 t miannu "Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a." SIGNOR-173769 PDE4DIP protein Q5VU43 UNIPROT PRKAR2A protein P13861 UNIPROT up-regulates binding 9606 21569246 t miannu "Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a." SIGNOR-173831 PDE6G protein P18545 UNIPROT PDE6A protein P16499 UNIPROT "down-regulates activity" binding 9606 20940301 t "Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B" SIGNOR-260010 PDGFA protein P04085 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-252286 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 PDGFB protein P01127 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates binding 9606 11331882 t miannu "Pdgf-b activates both pdgfr-alpha and pdgfr-beta" SIGNOR-107400 PDGFRA protein P16234 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 24743741 f "To further investigate the signaling pathway through which PDGFRα promotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα" SIGNOR-254376 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 10733900 t amattioni "Crk could bind to both pdgf alpha- and beta-receptors in vivo." SIGNOR-75881 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni "Crk can interact directly with tyrosine kinase receptors (for example pdgfr?) And can transmit signals downstream" SIGNOR-185664 PDGFRA protein P16234 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24743741 f "To further investigate the signaling pathway through which PDGFRαpromotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα. Thus, both PI3K-Akt and MEK2-MAPK pathways are necessary for PDGFRα-driven proliferation." SIGNOR-254377 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" phosphorylation Tyr1018 RLSADSGyIIPLPDI 9823 BTO:0004007 7535778 t miannu "We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ." SIGNOR-250250 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" phosphorylation Tyr762 SDIQRSLyDRPASYK 9823 BTO:0004007 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 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" phosphorylation Tyr988 RVDSDNAyIGVTYKN 9823 BTO:0004007 7535778 t miannu "We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ." SIGNOR-250252 PDGFRA protein P16234 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-28176 PDGFRA protein P16234 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 BTO:0000567 20802513 t miannu "Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. 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 (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met." SIGNOR-259400 PDGFRA protein P16234 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-247984 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 10733900 t amattioni "Crk could bind to both pdgf alpha- and beta-receptors in vivo" SIGNOR-75884 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni "Crk can interact directly with tyrosine kinase receptors and can transmit signals downstream" SIGNOR-185667 PDGFRB protein P09619 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" phosphorylation Tyr28 SLNQSSGyRYGTDPT -1 9425276 t miannu "PDGF-induced phosphorylation of Tyr28 in the N-terminus of Fyn affects Fyn activation. We show here that Fyn, a member of the Src family, is phosphorylated on Tyr28 in the unique N-terminal part of the molecule after interaction with the intracellular domain of the PDGF beta-receptor. Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn." SIGNOR-250253 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 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 PDGFRB protein P09619 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 10026169 t gcesareni "The sh2 domains of grb2, nck, and grb4 all precipitated activated pdgf receptor with similar efficiency." SIGNOR-64740 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT unknown phosphorylation Tyr751 SKDESVDyVPMLDMK 9606 2550144 t llicata "We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site." SIGNOR-22993 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT unknown phosphorylation Tyr857 DIMRDSNyISKGSTF 9606 2550144 t llicata "We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site." SIGNOR-22997 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr579 VSSDGHEyIYVDPMQ 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-250254 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 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr716 RPPSAELySNALPVG -1 8940081 t miannu "The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues." SIGNOR-250256 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr740 TGESDGGyMDMSKDE -1 8195171 t miannu "Synthetic peptide analysis revealed that certain autophosphorylation sites in the PDGF beta-receptor (Tyr-579, Tyr-740, Tyr-751, and Tyr-771) were able to mediate the specific binding of the Shc SH2 domain as well as intact Shc proteins." SIGNOR-250257 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr763 DMKGDVKyADIESSN 9823 BTO:0004007 10391677 t miannu "Activation of the beta-receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2." SIGNOR-250258 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr775 SSNYMAPyDNYVPSA -1 8940081 t miannu "The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues." SIGNOR-250259 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1009 LDTSSVLyTAVQPNE 9606 1396585 t llicata "These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021." SIGNOR-18575 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 1396585 t llicata "These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021." SIGNOR-18579 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr771 ADIESSNyMAPYDNY 9606 1314164 t llicata "Mutagenesis studies show that tyr740 and 751 are involved in the pdgf-stimulated binding of phosphatidylinositol (pi) 3 kinase, and tyr771 is required for efficient binding of gap, the gtpase activator of ras." SIGNOR-16892 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 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 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-167658 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 PDGFRB protein P09619 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation Tyr546 SKRKGHEyTNIKYSL 10090 BTO:0000944 8041791 t miannu "Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw." SIGNOR-250260 PDGFRB protein P09619 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 11896619 t miannu "The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway" SIGNOR-115843 PDGFRB protein P09619 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 8195171 t gcesareni "In this study, we have characterized the interaction between the pdgf beta-receptor and shc. multiple autophosphorylation sites in the pdgf beta-receptor are responsible for the binding of shc." SIGNOR-36906 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 PDHX protein O00330 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates activity" binding 9606 BTO:0000120 12783165 t 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-254904 PDHX protein O00330 UNIPROT GCG protein P01275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001731 12783165 f miannu "In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%." SIGNOR-254901 PDHX protein O00330 UNIPROT INS protein P01308 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001731 12783165 f miannu "In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%." SIGNOR-254902 PDHX protein O00330 UNIPROT PAX6 protein P26367 UNIPROT "down-regulates activity" binding 9606 BTO:0000120 12783165 t 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-254903 PDIA6 protein Q15084 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT "down-regulates activity" 10116 BTO:0003318 26487694 t "Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling." SIGNOR-256537 PDIA6 protein Q15084 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR "up-regulates activity" 10090 BTO:0004086 17420453 f "Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells." SIGNOR-256533 PDK1 protein Q15118 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t miannu "PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3." SIGNOR-250264 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 PDK1 protein Q15118 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-109551 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 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t gcesareni "Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation." SIGNOR-32977 PDK1 protein Q15118 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t gcesareni "Human pdh1 and rat pdh2 were expressed previously and were shown to have different specific activities and the ability to be phosphorylated by pdk1 and pdk2" SIGNOR-143966 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 PDK2 protein Q15119 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 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. The phosphorylation of AKT on Ser473 by PDK2 acts as a €œgain control€ for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity" SIGNOR-249630 PDK2 protein Q15119 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-109559 PDK2 protein Q15119 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-109563 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t gcesareni "Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation." SIGNOR-33040 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 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 PDK2 protein Q15119 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t gcesareni "Kinetic and regulatory properties of recombinant human pdh2 and pdh1 were compared in this study. Site-specific phosphorylation/dephosphorylation of the three phosphorylation sites by four pdh kinases (pdk1-4) and two pdh phosphatases (pdp1-2) were investigated by substituting serines with alanine or glutamate in pdhs." SIGNOR-143970 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 PDK3 protein Q15120 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-109609 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11486000 t lperfetto "Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes." SIGNOR-109647 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser300 SMSDPGVsYRTREEI -1 11486000 t lperfetto "Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes." SIGNOR-109651 PDK3 protein Q15120 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t miannu "Pdh2 was found to be very similar to pdh1 / in the mechanism of inactivation by phosphorylation of three sites;and (iv) in the phosphorylation of sites 1 and 2 by pdk3 / (ser-264 (site 1), ser-271 (site 2), and ser-203 (site 3)" SIGNOR-143974 PDK4 protein Q16654 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-109621 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 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 PDK4 protein Q16654 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-33197 PDK4 protein Q16654 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-33201 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 t gcesareni "In mammals, pdhc is tightly regulated by phosphorylation-dephosphorylation of three serine residues in the thiamin-dependent pyruvate dehydrogenase (e1) component. In vivo, inactivation of human pdhc correlates mostly with phosphorylation of serine 264, which is located at the entrance of the substrate channel leading to the active site of e1." SIGNOR-154656 PDK4 protein Q16654 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 BTO:0000887;BTO:0001103 14966024 t gcesareni "Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form" SIGNOR-121936 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation 9606 20208177 t "Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation" SIGNOR-251664 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation Ser232 NRYGMGTsVERAAAS -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-252055 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation Ser293 TYRYHGHsMSDPGVS -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-252054 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 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 PDP2 protein Q9P2J9 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation 9606 20208177 t "Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation" SIGNOR-251665 PDP2 protein Q9P2J9 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-144909 PDPK1 protein O15530 UNIPROT AHCYL1 protein O43865 UNIPROT "down-regulates activity" phosphorylation Ser68 RSLSRSIsQSSTDSY 9534 BTO:0004055 17635105 t lperfetto "Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T| We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R" SIGNOR-249174 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000567 15718470 t gcesareni "Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase." SIGNOR-252612 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 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-249629 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000142 10226025 t acerquone "We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies." SIGNOR-67367 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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-252611 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 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000142 10226025 t acerquone "Protein kinase b (pkb) is activated by phosphorylation of thr308 and of ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (pdk1) but the identity of the kinase that phosphorylates ser473 (provisionally termed pdk2) is unknown." SIGNOR-67363 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 phosphorylation:Ser473 RPHFPQFsYSASGTA 12167717 t gcesareni "Together, these results suggest a mechanism in which 3' phosphoinositide lipid-dependent translocation of pkb to the plasma membrane promotes serine 473 phosphorylation, which is, in turn, necessary for pdk1-mediated phosphorylation of threonine 308 and, consequentially, full pkb activation." SIGNOR-91354 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" phosphorylation Ser474 RTHFPQFsYSASIRE 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-134481 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 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" phosphorylation Thr309 SDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto "The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma)" SIGNOR-236785 PDPK1 protein O15530 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t gcesareni "The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma)" SIGNOR-55937 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 15743829 t lperfetto "3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt)," SIGNOR-244469 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 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto "Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown." SIGNOR-244421 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000567 15718470 t gcesareni "Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase." SIGNOR-243203 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto "The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma)" SIGNOR-244480 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 21798082 t lperfetto "Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1." SIGNOR-244396 PDPK1 protein O15530 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 15802604 t gcesareni "We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts." SIGNOR-134866 PDPK1 protein O15530 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t miannu "PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3." SIGNOR-250266 PDPK1 protein O15530 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 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-236633 PDPK1 protein O15530 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 15175348 t gcesareni "The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation." SIGNOR-125176 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 PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto "The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation." SIGNOR-244938 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 PDPK1 protein O15530 UNIPROT PAK1 protein Q13153 UNIPROT "up-regulates activity" phosphorylation Thr423 PEQSKRStMVGTPYW 9534 BTO:0000298 10995762 t miannu "P21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). We identify threonine 423, a conserved threonine in the activation loop of kinase subdomain VIII, as the PDK1 phosphorylation site on PAK1." SIGNOR-250267 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "down-regulates activity" 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 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser25 VVLCSCPsPSMVRTQ 9606 BTO:0000009 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-236777 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 BTO:0000010 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 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 BTO:0000007 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 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 BTO:0000008 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-236772 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Ser241 SKQARANsFVGTAQY 9606 BTO:0000007 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 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Ser241 SKQARANsFVGTAQY 9606 BTO:0000007 11481331 t miannu "In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue." SIGNOR-250268 PDPK1 protein O15530 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates phosphorylation Thr774 GYGDRTStFCGTPEF 9606 10753910 t miannu "It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)" SIGNOR-76640 PDPK1 protein O15530 UNIPROT PKN2 protein Q16513 UNIPROT up-regulates phosphorylation Thr816 GYGDRTStFCGTPEF 9606 10753910 t miannu "It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)" SIGNOR-76710 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 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 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 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 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 PDPK1 protein O15530 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Thr507 FGESRAStFCGTPDY 9606 BTO:0000007 9748166 t miannu "PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. PKCδ was also phosphorylated in the activation loop site (T505)" SIGNOR-250269 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 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 PDPK1 protein O15530 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 15802604 t gcesareni "We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts." SIGNOR-134869 PDPK1 protein O15530 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr410 GPGDTTStFCGTPNY 9606 11141077 t gcesareni "Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylationcytoskeletal reorganization;tnni1(induces);desmin(induces);tpm1(induces);myo1c(induces);tnnt1(induces);" SIGNOR-85501 PDPK1 protein O15530 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 t miannu "Full-length RSK1, RSK2, and RSK3 Are Activated when Coexpressed with PDK1 in COS7 Cells. Ser221 phosphorylation is increased 2–3-fold during ERK-mediated activation of RSK1 in COS1 cells" SIGNOR-250270 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 19956600 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-161924 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr252 HDGTVTHtFCGTIEY -1 9445476 t gcesareni "The results presented here are consistent with PDK1 as the in vivo kinase responsible for mediating Thr252 phosphorylation in the catalytic domain of p70s6k." SIGNOR-243338 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 19864428 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 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. Phosphorylation and activation of p70s6k by pdk1." SIGNOR-188907 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 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 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 t miannu "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." SIGNOR-188911 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 t miannu " Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities." SIGNOR-250371 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Thr228 HEGAVTHtFCGTIEY -1 11733037 t miannu " Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities." SIGNOR-250273 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 t miannu " Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities." SIGNOR-250272 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 15209375 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-126076 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 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-55371 PDPK1 protein O15530 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 t miannu "90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1." SIGNOR-252763 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT "up-regulates activity" phosphorylation Ser422 AEAFLGFsYAPPTDS -1 10191262 t miannu "The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp" SIGNOR-250274 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9534 BTO:0004055 12387817 t lperfetto "Thus, it was suggested that NHERF2 mediates the activation and phosphorylation of SGK1 by PDK1 through its first PDZ domain and PIF motif, as a novel SGK1 activation mechanism." SIGNOR-236800 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 15209375 t lperfetto "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-236637 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 BTO:0000007 10191262 t lperfetto "This is followed by the ptdins(3,4,5)p3-independent phosphorylation at thr256 that activates sgk, and is catalysed by pdk1" SIGNOR-236796 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser293 EESYDTEsEFTEFTE 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-40510 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT "up-regulates activity" phosphorylation Ser416 SSAFLGFsYAPEDDD 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250376 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT "up-regulates activity" phosphorylation Thr253 EPEDTTStFCGTPEY 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250277 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 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-126177 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT "up-regulates activity" phosphorylation Ser486 DDAFVGFsYAPPSED 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250278 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT "up-regulates activity" phosphorylation Thr320 AISDTTTtFCGTPEY 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250279 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 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates phosphorylation Thr320 AISDTTTtFCGTPEY 9606 16790420 t llicata "Full-length sgk3 contains a complete phox homology (px) domain that targets the protein to endosomes. Both a functional px domain and pi3k activation are necessary for phosphorylation of sgk3 at two regulatory sites (thr-320 and ser-486) and subsequent induction of kinase activity. Pdk1 phosphorylates endosome-associated sgk3 at thr-320" SIGNOR-147213 PDPK1 protein O15530 UNIPROT TSSK3 protein Q96PN8 UNIPROT "up-regulates activity" phosphorylation T168 ELSQTFCGSTAYAA -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-260786 PDPK2P protein Q6A1A2 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation 9606 15505410 t gcesareni "Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2." SIGNOR-252628 PDPK2P protein Q6A1A2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 15505410 t gcesareni "Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2." SIGNOR-129965 PDPK2P protein Q6A1A2 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 10191262 t gcesareni "Our results are consistent with a model in which activation of sgk by igf-1 or hydrogen peroxide is initiated by a ptdins(3,4, 5)p3-dependent activation of pdk2, which phosphorylates ser422." SIGNOR-66234 PDX1 protein P52945 UNIPROT GCK protein P35557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000627 8866550 f 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-254911 PDX1 protein P52945 UNIPROT INS protein P01308 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000783;BTO:0002284 11309388 t "In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1." SIGNOR-255541 PDX1 protein P52945 UNIPROT NKX6-1 protein P78426 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000783;BTO:0002284 11309388 t "In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1." SIGNOR-255542 PDX1 protein P52945 UNIPROT SLC2A2 protein P11168 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000783;BTO:0002284 11309388 t "In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1." SIGNOR-255540 PDXP protein Q96GD0 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" dephosphorylation Ser3 sGVAVSDG -1 15580268 t "Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily." SIGNOR-248764 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 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT "up-regulates activity" binding 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-258411 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 PDYN protein P01213 UNIPROT 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-258414 PDZD11 protein Q5EBL8 UNIPROT TSPAN33 protein Q86UF1 UNIPROT "up-regulates activity" binding 10116 BTO:0003618 30463011 t Simone "Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33" SIGNOR-261252 PDZD8 protein Q8NEN9 UNIPROT MSN/PDZD8 complex SIGNOR-C61 SIGNOR "form complex" binding 9606 21549406 t miannu "These results demonstrated that both human moesin and its newly identified binding partner, pdzd8 had similar effects on host mt networks, suggesting that they are likely to function as part of a stable mt regulatory complex." SIGNOR-173650 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 PEA15 protein Q15121 UNIPROT MAPK3 protein P27361 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-111502 PEBP1 protein P30086 UNIPROT RAF1 protein P04049 UNIPROT down-regulates binding 9606 10490027 t gcesareni "Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras." SIGNOR-70838 PELI1 protein Q96FA3 UNIPROT BIRC3 protein Q13489 UNIPROT "up-regulates quantity by stabilization" ubiquitination 9606 BTO:0002552 27248820 t miannu "Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity." SIGNOR-259395 PELI1 protein Q96FA3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates quantity by expression" ubiquitination 9606 17997719 t lperfetto "These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells." SIGNOR-159055 PELI2 protein Q9HAT8 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-159058 PELI3 protein Q8N2H9 UNIPROT ELK1 protein P19419 UNIPROT up-regulates 9606 12874243 f gcesareni "Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab." SIGNOR-103986 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 PELI3 protein Q8N2H9 UNIPROT JUN protein P05412 UNIPROT up-regulates 9606 12874243 f gcesareni "Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab" SIGNOR-103989 pelitinib chemical CHEBI:38927 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205755 PELP1 protein Q8IZL8 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18682536 t gcesareni "MNAR functionally interacts with both NH2- and COOH-terminal GR domains to modulate transactivation" SIGNOR-251681 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 pemetrexed chemical CHEBI:63616 ChEBI DHFR protein P00374 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205819 pemetrexed chemical CHEBI:63616 ChEBI GART protein P22102 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205883 pemetrexed chemical CHEBI:63616 ChEBI TYMS protein P04818 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205933 "pemetrexed disodium" chemical CHEBI:63722 ChEBI ATIC protein P31939 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 14596699 t miannu "Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT)." SIGNOR-259292 "pemetrexed disodium" chemical CHEBI:63722 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 14596699 t miannu "Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT)." SIGNOR-259290 "pemetrexed disodium" chemical CHEBI:63722 ChEBI GART protein P22102 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 14596699 t miannu "Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT)." SIGNOR-259291 "pemetrexed disodium" chemical CHEBI:63722 ChEBI TYMS protein P04818 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 14596699 t miannu "Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT)." SIGNOR-259289 pentazocine chemical CHEBI:7982 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-258934 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 pentazocine chemical CHEBI:7982 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-258766 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 Pentostatin chemical CID:439693 PUBCHEM ADA protein P00813 UNIPROT "down-regulates activity" "chemical inhibition" 9606 2433905 t miannu "2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin." SIGNOR-259261 PER1 protein O15534 UNIPROT SLC5A1 protein P13866 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000195 22526585 f miannu "Our findings suggest that PER1 exerts an indirect suppressive effect on SGLT1, possibly acting via other clock-controlled genes binding to non-E-box sites on the SGLT1 promoter." SIGNOR-254912 PER2 protein O15055 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 22260161 f apalma "We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML)" SIGNOR-256370 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 PER2 protein O15055 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 22260161 f apalma "We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML)" SIGNOR-256371 PER2 protein O15055 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 23836662 f miannu "PER2 Suppresses TWIST1 and SLUG Transcription by Recruiting EZH2, SUZ12, and HDAC2." SIGNOR-254147 PER2 protein O15055 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 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-254153 perifosine chemical CHEBI:67272 ChEBI AKT1 protein P31749 UNIPROT down-regulates "chemical inhibition" 9606 22090271 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-252630 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 perifosine chemical CHEBI:67272 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates "chemical inhibition" 9606 BTO:0001130 14617782 t "Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation" gcesareni "Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.| Our results demonstrate that Akt is an important cellular target of perifosine action. In addition, these studies show that the membrane translocation of certain PH domain-containing molecules can be greatly perturbed by the alkylphospholipid class of drugs and imply further that the PI3K/Akt pathway contributes to regulation of p21(WAF1/CIP1) expression." SIGNOR-119189 PERP protein Q96FX8 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity" ubiquitination 9600 BTO:0000007 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 pertuzumab antibody DB06366 DRUGBANK ERBB2 protein P04626 UNIPROT "down-regulates activity" binding 9606 BTO:0000176 15093539 t miannu "Pertuzumab binds to ErbB2 near the center of domain II, sterically blocking a binding pocket necessary for receptor dimerization and signaling." SIGNOR-259900 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 PEX12 protein O00623 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" 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-253020 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 PEX14 protein O75381 UNIPROT PEX13 protein Q92968 UNIPROT "up-regulates activity" binding -1 15798189 t miannu "Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import" SIGNOR-253029 PEX14 protein O75381 UNIPROT PEX5 protein P50542 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-253027 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 PEX1 protein O43933 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" binding 10029 16314507 t "Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner." SIGNOR-253618 PEX1 protein O43933 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 f "The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis." SIGNOR-253616 PEX26 protein Q7Z412 UNIPROT PEX6 protein Q13608 UNIPROT "up-regulates activity" binding 10029 12717447 t "Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions." SIGNOR-253614 PEX2 protein P28328 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-253021 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 PEX3 protein P56589 UNIPROT PEX19 protein P40855 UNIPROT "up-regulates activity" binding -1 15007061 t miannu "PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes." SIGNOR-253026 PEX6 protein Q13608 UNIPROT PEX1 protein O43933 UNIPROT "up-regulates activity" binding 10029 12717447 t "Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions." SIGNOR-253615 PEX6 protein Q13608 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" binding 10029 16314507 t "Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner." SIGNOR-253619 PEX6 protein Q13608 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 f "The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis." SIGNOR-253617 PF-03814735 chemical CID:49830590 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205953 PF-03814735 chemical CID:49830590 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205956 PF-03814735 chemical CID:49830590 PUBCHEM PTK2 protein Q05397 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205959 PF-04691502 chemical CID:25033539 PUBCHEM AKT1 protein P31749 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;inhibitor of phosphorylation of AktT308 and AktS473" gcesareni SIGNOR-252631 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 PF-5274857 chemical CID:56956240 PUBCHEM SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206058 PFKFB2 protein O60825 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 20640476 f lperfetto "The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes." SIGNOR-209950 PFN1 protein P07737 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 18667433 f areggio " Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration." SIGNOR-258977 PFN1 protein P07737 UNIPROT CDH4 protein P55283 UNIPROT "up-regulates activity" 9606 BTO:0000815 22820501 t lperfetto "Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation." SIGNOR-253111 PGR protein P06401 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 BTO:0000150 12612073 t gcesareni "Here we identify two domains of prb, erid-i and -ii, mediating a direct interaction with the ligand-binding domain of eralpha." SIGNOR-98807 PGR protein P06401 UNIPROT KLK4 protein Q9Y5K2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001248 19147544 f miannu "we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells." SIGNOR-254913 "PH 797804" chemical CHEBI:82715 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206079 PHA-665752 chemical CHEBI:90197 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-258265 PHA-665752 chemical CHEBI:90197 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206088 PHA-680632 chemical CID:11249084 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206097 PHA-680632 chemical CID:11249084 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206100 PHA-680632 chemical CID:11249084 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206103 PHA-767491 chemical CID:11715767 PUBCHEM CDK7 protein P50613 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206112 PHA-767491 chemical CID:11715767 PUBCHEM CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206115 PHA-848125 chemical CID:16718576 PUBCHEM CCNA2 protein P20248 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206148 PHA-848125 chemical CID:16718576 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206151 PHACTR1 protein Q9C0D0 UNIPROT PPP1CA protein P62136 UNIPROT "up-regulates activity" binding 9606 BTO:0001949 21939755 t miannu "Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process." SIGNOR-260062 Phagocytosis phenotype SIGNOR-PH97 SIGNOR IL1B protein P01584 UNIPROT "down-regulates quantity" BTO:0000801 22933625 f apalma "Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype" SIGNOR-255445 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TGFB1 protein P01137 UNIPROT "up-regulates quantity" BTO:0000801 22933625 f apalma "Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype" SIGNOR-255444 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TNF protein P01375 UNIPROT "down-regulates quantity" BTO:0000801 22933625 f apalma "Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype" SIGNOR-255446 PHB2 protein Q99623 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 t lperfetto "Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation." SIGNOR-235840 PHB2 protein Q99623 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 t lperfetto "Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation." SIGNOR-235843 Phenelzine chemical CHEBI:8060 ChEBI MAOA protein P21397 UNIPROT "down-regulates activity" "chemical inhibition" -1 18426226 t Luana "Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine." SIGNOR-257777 Phenelzine chemical CHEBI:8060 ChEBI MAOB protein P27338 UNIPROT "down-regulates activity" "chemical inhibition" -1 18426226 t Luana "Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine." SIGNOR-257778 Phenelzine chemical CHEBI:8060 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 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-258743 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 Phenelzine chemical CHEBI:8060 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 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-258744 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 phentolamine chemical CHEBI:8081 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-258445 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 phentolamine chemical CHEBI:8081 ChEBI ADRA1D protein P25100 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-258444 phenytoin chemical CHEBI:8107 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-258352 phenytoin chemical CHEBI:8107 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-258160 PHF1 protein O43189 UNIPROT HOXA10 protein P31260 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000782;BTO:0003287 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 PHF1 protein O43189 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000782;BTO:0003287 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-260069 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 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT "up-regulates activity" phosphorylation Ser1007 TGIMQLKsEIKQVEF -1 10487978 t miannu "Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)" SIGNOR-250280 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT "up-regulates activity" phosphorylation Ser972 KEFGVERsVRPTDSN -1 10487978 t miannu "Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)" SIGNOR-250281 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT "up-regulates activity" phosphorylation Ser985 SNVSPAIsIHEIGAV -1 10487978 t miannu "Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)" SIGNOR-250282 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser554 RTPPKSPsSAKSRLQ -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250283 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser579 NVKSKIGsTENLKHQ -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250284 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser602 INKKLDLsNVQSKCG -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250285 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser622 KHVPGGGsVQIVYKP -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250286 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser669 DFKDRVQsKIGSLDN -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250287 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 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser82 VDILRKVsGHPNIIQ -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-250389 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 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni "Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth." SIGNOR-252601 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 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-248328 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 17386267 t gcesareni "These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3" SIGNOR-153935 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT unknown dephosphorylation 9606 BTO:0000527 15808505 t gcesareni "These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3" SIGNOR-135008 PHLPP1 protein O60346 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-248330 PHLPP1 protein O60346 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-248331 PHLPP1 protein O60346 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni "Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth." SIGNOR-135005 PHLPP1 protein O60346 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-237043 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 18162466 t "These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms," SIGNOR-248326 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates quantity" dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 t gcesareni "Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle" SIGNOR-237047 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 PHLPP1 protein O60346 UNIPROT RPS6KB1 protein P23443 UNIPROT "down-regulates activity" dephosphorylation Thr390 DSKFTRQtPVDSPDD 9606 21986499 t gcesareni "Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP." SIGNOR-237454 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 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 23431053 t gcesareni "Here, we report that phlpp1 is a binding protein for mst1 and it modulates the hippo pathway by dephosphorylating mst1 at the inhibitory thr(387) of mst1." SIGNOR-201262 PHLPP2 protein Q6ZVD8 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-248728 PHLPP2 protein Q6ZVD8 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni "Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt." SIGNOR-252602 PHLPP2 protein Q6ZVD8 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 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-248729 PHLPP2 protein Q6ZVD8 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 17386267 t gcesareni "Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3alpha through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3" SIGNOR-237439 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 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 PHLPP2 protein Q6ZVD8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni "Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt." SIGNOR-135046 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 PHLPP2 protein Q6ZVD8 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 18162466 t "These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms," SIGNOR-248727 PHLPP2 protein Q6ZVD8 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates quantity" dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 t gcesareni "Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle" SIGNOR-237039 PHLPP2 protein Q6ZVD8 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-248730 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI MAPK1 protein P28482 UNIPROT up-regulates "chemical activation" 9606 BTO:0000887;BTO:0001103 20231899 t gcesareni "In addition, extracellular signal-regulated kinase (erk) is stimulated by ampk-induced pld1 activation through the formation of phosphatidic acid (pa), which is a product of pld" SIGNOR-164289 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI MTOR protein P42345 UNIPROT up-regulates binding 9606 11729323 t gcesareni "Pa directly interacted with the domain in mtor that is targeted by rapamycin, and this interaction was positively correlated with mtor's ability to activate downstream effectors." SIGNOR-112379 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates binding 9606 12401205 t gcesareni "The pkc isoform pkc-zeta appear to be activated by direct interactions with pa" SIGNOR-94867 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI RAC1 protein P63000 UNIPROT up-regulates binding 9606 18480413 t gcesareni "The c-terminal polybasic motif of rac1 is responsible for direct interaction with pa," SIGNOR-178632 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI SOS1 protein Q07889 UNIPROT up-regulates binding 9606 17486115 t gcesareni "Phosphatidic acid interacts with a defined site in the sos ph domain with high affinity and specificity" SIGNOR-154676 "phosphatidylinositol 4-phosphate" smallmolecule CHEBI:37530 ChEBI "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 22253445 f lperfetto "Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment." SIGNOR-260745 "phosphatidylinositol bisphosphate" smallmolecule CHEBI:37328 ChEBI AKT1 protein P31749 UNIPROT "up-regulates activity" binding 9606 BTO:0001931 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 PHT-427 chemical CID:44240850 PUBCHEM PDPK1 protein O15530 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271 21715304 t gcesareni "Consistent with the results described in figures 3c and and4a,4a, treatment of 32d/bcr-abl cells with the bcr-abl inhibitor imatinib, the pi3k inhibitor ly294002 or the akt/pdpk1 inhibitor pht-427 substantially reduced atf5 promoter-directed luciferase activity" SIGNOR-174612 PI-103 chemical CHEBI:90524 ChEBI PIK3C2B protein O00750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206160 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 PI-103 chemical CHEBI:90524 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206163 PI-103 chemical CHEBI:90524 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206166 PI-103 chemical CHEBI:90524 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206169 PI-103 chemical CHEBI:90524 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206172 PI-103 chemical CHEBI:90524 ChEBI PRKDC protein P78527 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206175 PI3K complex SIGNOR-C156 SIGNOR "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" 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 PI3K complex SIGNOR-C156 SIGNOR "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 12040186 t lperfetto "The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]." SIGNOR-252713 PI3K complex SIGNOR-C156 SIGNOR "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24647478 t lperfetto "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478" SIGNOR-252712 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 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 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 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000938 9346240 f lperfetto "Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt" SIGNOR-252708 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 PI3K complex SIGNOR-C156 SIGNOR 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-252716 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 9606 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-252715 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "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-252703 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000830 15526160 t mainnu "C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo." SIGNOR-254950 PI3K complex SIGNOR-C156 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000830 15526160 t miannu "C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo." SIGNOR-254951 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 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 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 PI3K complex SIGNOR-C156 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 18721898 f lperfetto "Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3." SIGNOR-252705 PI3K complex SIGNOR-C156 SIGNOR PIK3CB protein P42338 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-252719 PI3K complex SIGNOR-C156 SIGNOR PIK3CD protein O00329 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-252720 PI3K complex SIGNOR-C156 SIGNOR 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-252721 PI3K complex SIGNOR-C156 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 f apalma "Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation." SIGNOR-255577 PI3K complex SIGNOR-C156 SIGNOR 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-255011 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 PI3K complex SIGNOR-C156 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 f apalma "Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation." SIGNOR-255576 PI4K2A protein Q9BTU6 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser984 ALALCSGsFPTDKEE 9606 18082599 t gcesareni "These results indicate that plx1 phosphorylates claspin on s934, which is relatively close to the plx1-docking site at t906. Human claspin also contains a serine at position 984 in a homologous sequence" SIGNOR-159937 PI4KB protein Q9UBF8 UNIPROT "phosphatidylinositol 4-phosphate" smallmolecule CHEBI:37530 ChEBI "up-regulates quantity" "small molecule catalysis" 9534 22253445 t lperfetto "Interestingly, we found that PI4P, the product of PI4KB catalysis, creates a lipid microenvironment that is required for SARS-CoV S-mediated entry." SIGNOR-260732 PIAS1 protein O75925 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" sumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni "Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity." SIGNOR-252735 PIAS1 protein O75925 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" sumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni "Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity." SIGNOR-252737 PIAS1 protein O75925 UNIPROT DDX5 protein P17844 UNIPROT down-regulates sumoylation Lys53 WNLDELPkFEKNFYQ 9606 17369852 t miannu "We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53." SIGNOR-153723 PIAS1 protein O75925 UNIPROT DDX5 protein P17844 UNIPROT up-regulates sumoylation Lys53 WNLDELPkFEKNFYQ 9606 17369852 t miannu "We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53." SIGNOR-153719 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys144 GTGSFFPkGEDFYCV 9606 17509614 t gcesareni "Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1" SIGNOR-154801 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys300 PRGPGLVkAPVWWPM 9606 17509614 t gcesareni "Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1" SIGNOR-154805 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 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 PIAS1 protein O75925 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation 9606 15028714 t lperfetto "These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4" SIGNOR-123462 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 14699505 t gcesareni "Pias1 inhibits binding of stat1 dimers to the response elements in the promoters of target genes" SIGNOR-120548 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 t milica "Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna." SIGNOR-202039 PIAS1 protein O75925 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni "Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation." SIGNOR-162156 PIAS3 protein Q9Y6X2 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR "form complex" binding 9606 26194464 t mrosina "In summary, the TGF-b/IL-6/TCR-ERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation" SIGNOR-255035 PIAS3 protein Q9Y6X2 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 14691252 t lperfetto "We have further shown that PIAS3, Smad3, and p300 can form a ternary complex, which is significantly increased by TGF-_ treatment. Taken together, these results suggest that PIAS3 stimulates Smad transcriptional activity through formation of a complex with Smad proteins and p300/CBP." SIGNOR-217725 PIAS3 protein Q9Y6X2 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 SIGNOR-C9 14691252 t gcesareni "Taken together, our studies indicate that on tgf-beta treatment, pias3 can form a complex with smads and p300/cbp and activate smad transcriptional activity." SIGNOR-120359 PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" binding 9606 9388184 t lperfetto "PIAS3 blocked the DNA- binding activity of Stat3 and inhibited Stat3-mediated gene activation. Although Stat1 is also phosphorylated in response to IL-6, PIAS3 did not interact with Stat1 or affect its DNA-binding or transcriptional activity. The results indicate that PIAS3 is a specific inhibitor of Stat3." SIGNOR-238648 PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates binding 9606 9388184 t gcesareni "Specific inhibition of stat3 signal transduction by pias3stat3 mediated signaling pathways can be inhibited by pias3 (protein inhibitor of activated stat3), which was recently found to regulate protein stability and function by its sumo (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins." SIGNOR-53572 PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates binding 9606 BTO:0000150;BTO:0000551 15138572 t gcesareni "Specific inhibition of stat3 signal transduction by pias3stat3 mediated signaling pathways can be inhibited by pias3 (protein inhibitor of activated stat3), which was recently found to regulate protein stability and function by its sumo (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins." SIGNOR-124723 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 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 PIAS4 protein Q8N2W9 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 SIGNOR-C9 12904571 t gcesareni "Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity." SIGNOR-104538 PIAS4 protein Q8N2W9 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "down-regulates activity" binding 9606 12904571 t lperfetto "Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity." SIGNOR-217731 PIAS4 protein Q8N2W9 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates binding 9606 SIGNOR-C9 12904571 t gcesareni "Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity." SIGNOR-104541 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 PIAS4 protein Q8N2W9 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni "Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation" SIGNOR-162167 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 PICALM protein Q13492 UNIPROT CLTC protein Q00610 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-144683 PICK1 protein Q9NRD5 UNIPROT ASIC1 protein P78348 UNIPROT "up-regulates activity" relocalization 10116 BTO:0000938 11802773 t miannu "we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction" SIGNOR-223417 PICK1 protein Q9NRD5 UNIPROT BNC1 protein Q01954 UNIPROT "up-regulates activity" relocalization 10116 BTO:0000938 11802773 t miannu "we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction" SIGNOR-223414 pictrelisib chemical CHEBI:65326 ChEBI PI3K complex SIGNOR-C156 SIGNOR 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-252664 pictrelisib chemical CHEBI:65326 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-258113 pictrelisib chemical CHEBI:65326 ChEBI PIK3CA protein P42336 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-176292 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 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 pictrelisib chemical CHEBI:65326 ChEBI PIK3CG protein P48736 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-176301 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 PIGBOS1 protein A0A0B4J2F0 UNIPROT ATF4 protein P18848 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0002181 31653868 f miannu "We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels" SIGNOR-261041 PIGBOS1 protein A0A0B4J2F0 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0002181 31653868 f miannu "We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels" SIGNOR-261043 PIGF protein Q07326 UNIPROT PIGG protein Q5H8A4 UNIPROT "up-regulates quantity by stabilization" binding 10029 BTO:0000246 15632136 t miannu "We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O." SIGNOR-261358 PIGF protein Q07326 UNIPROT PIGO protein Q8TEQ8 UNIPROT "down-regulates quantity by destabilization" 10029 BTO:0000246 15632136 f miannu "We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O." SIGNOR-261360 PIGG protein Q5H8A4 UNIPROT PIGO protein Q8TEQ8 UNIPROT "up-regulates quantity by stabilization" binding 10029 BTO:0000246 15632136 t miannu "We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O." SIGNOR-261359 PIGS protein Q96S52 UNIPROT GPAA1 protein O43292 UNIPROT "up-regulates activity" binding 10090 BTO:0000095 11483512 t miannu "To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8." SIGNOR-261361 PIGS protein Q96S52 UNIPROT PIGK protein Q92643 UNIPROT "up-regulates activity" binding 10090 BTO:0000095 11483512 t miannu "To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8." SIGNOR-261362 PIK3AP1 protein Q6ZUJ8 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000801 22187458 t gcesareni "Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. 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. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling" SIGNOR-252701 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CA protein P42336 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-191664 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CB protein P42338 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-191667 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 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni "Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. 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. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling" SIGNOR-191673 PIK3C2A protein O00443 UNIPROT PIPP smallmolecule CID:24755493 PUBCHEM up-regulates "small molecule catalysis" 9606 BTO:0000150 23119004 t "D3 position" gcesareni "Pi3ks phosphorylate the d3 position of membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (pip3);" SIGNOR-199364 PIK3C2A protein O00443 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 9430633 f gcesareni "Activation of pi 3-kinase causes plc gamma ph domain-mediated membrane targeting and plc gamma activation." SIGNOR-54707 PIK3C3 protein Q8NEB9 UNIPROT "1-phosphatidyl-1D-myo-inositol 3-phosphate" smallmolecule CHEBI:17283 ChEBI up-regulates "small molecule catalysis" 9606 8999962 t gcesareni "Vps34p phosphorylates phosphatidylinositol (ptdins) at the 3?-Position of the inositol ring, but not ptdins." SIGNOR-45606 PIK3C3 protein Q8NEB9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 10698680 f acerquone "Pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1)" SIGNOR-252633 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 PIK3C3 protein Q8NEB9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 10698680 f acerquone "Pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1)" SIGNOR-75376 PIK3C3 protein Q8NEB9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR 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-75370 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 PIK3C3 protein Q8NEB9 UNIPROT "Vps34 Complex I" complex SIGNOR-C242 SIGNOR "form complex" binding -1 30397185 t lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260316 PIK3C3 protein Q8NEB9 UNIPROT "Vps34 Complex II" complex SIGNOR-C241 SIGNOR "form complex" binding -1 30397185 t lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260320 PIK3CA protein P42336 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24367090 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 "Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2" SIGNOR-147948 PIK3CA protein P42336 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "small molecule catalysis" 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 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 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 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 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000938 9346240 f lperfetto "Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt" SIGNOR-236428 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 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "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-236436 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 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 PIK3CA protein P42336 UNIPROT 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-104911 PIK3CA protein P42336 UNIPROT MTOR protein P42345 UNIPROT up-regulates 9606 18721898 f lperfetto "Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3." SIGNOR-180453 PIK3CA protein P42336 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 21779497 f gcesareni "Pi3k can also activate rac, and this activation is involved in cytoskeleton reorganization." SIGNOR-175238 PIK3CA protein P42336 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-242649 PIK3CB protein P42338 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 21779497 t lperfetto "The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)" SIGNOR-175241 PIK3CB protein P42338 UNIPROT PIK3CB protein P42338 UNIPROT "down-regulates activity" phosphorylation Ser1070 TVRKDYRs -1 12502714 t lperfetto "Autophosphorylation sites of both pi3k isoforms were mapped to c-terminal serine residues of the catalytic p110 subunit (i.e. serine 1070 of p110 beta and serine 1101 of p110 gamma). autophosphorylation of p110 beta On serine 1070 results in down-regulation of the lipid kinase activity of pi3k beta" SIGNOR-96776 PIK3CB protein P42338 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-242652 PIK3CD protein O00329 UNIPROT PIK3CD protein O00329 UNIPROT down-regulates phosphorylation Ser1039 NWLAHNVsKDNRQ 9606 10064595 t gcesareni "Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo in vitro autophosphorylation of p110delta completely down-regulates its lipid kinase activity." SIGNOR-65186 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 PIK3CG protein P48736 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI up-regulates "small molecule catalysis" 9606 16847462 t gcesareni "The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)" SIGNOR-147954 PIK3CG protein P48736 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI up-regulates "small molecule catalysis" 9606 21779497 t gcesareni "The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)" SIGNOR-175244 PIK3CG protein P48736 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 f gcesareni "Pi3-k activates downstream molecules like protein kinase b (pkb)." SIGNOR-79353 PIK3CG protein P48736 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9346240 f gcesareni "Akt may be regulated by both phosphorylation and by the direct binding of pi3k to the akt pleckstrin homology (ph) domain." SIGNOR-52870 PIK3CG protein P48736 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 9346240 t lperfetto "Akt may be regulated by both phosphorylation and by the direct binding of pi3k to the akt pleckstrin homology (ph) domain." SIGNOR-244432 PIK3CG protein P48736 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates binding 9606 9768361 t gcesareni "Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (pdk-1), which binds with high affinity to the pi 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (ptdins-3,4,5-p), phosphorylates and potently activates two other pi 3-kinase targets, the protein kinases akt/pkb and p70s6k." SIGNOR-60567 PIK3CG protein P48736 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-242658 PIK3IP1 protein Q96FE7 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "down-regulates activity" binding 9606 24316979 t miannu "We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition." SIGNOR-260073 PIK3R1 protein P27986 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" 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 PIK3R1 protein P27986 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "form complex" binding 9606 19805105 t miannu "Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1)." SIGNOR-255300 PIK3R1 protein P27986 UNIPROT PIK3CA protein P42336 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-242637 PIK3R1 protein P27986 UNIPROT PIK3CB protein P42338 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-242640 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 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 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 PIK3R4 protein Q99570 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates binding 9606 8999962 t gcesareni "Recombinant p150 associated with ptdins 3-kinase in vitro in a stable manner, resulting in a 2-fold increase in lipid kinase activity." SIGNOR-45664 PIK3R4 protein Q99570 UNIPROT "Vps34 Complex I" complex SIGNOR-C242 SIGNOR "form complex" binding -1 30397185 t lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260317 PIK3R4 protein Q99570 UNIPROT "Vps34 Complex II" complex SIGNOR-C241 SIGNOR "form complex" binding -1 30397185 t lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260321 "PIK-75 Hydrochloride" chemical CID:45265864 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252652 "PIK-75 Hydrochloride" chemical CID:45265864 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206211 "PIK-75 Hydrochloride" chemical CID:45265864 PUBCHEM PRKDC protein P78527 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206214 PIK-90 chemical CID:6857685 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252653 PIK-90 chemical CID:6857685 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206223 PIK-90 chemical CID:6857685 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206226 PIK-90 chemical CID:6857685 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206229 PIK-90 chemical CID:6857685 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206232 PIK-93 chemical CID:6852167 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206241 PIKFYVE protein Q9Y2I7 UNIPROT "PAS complex" complex SIGNOR-C190 SIGNOR "form complex" binding 9606 BTO:0000007 17556371 t miannu "Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels." SIGNOR-253529 (+)-pilocarpine chemical CHEBI:8207 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-258627 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM2 protein P08172 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-258629 (+)-pilocarpine chemical CHEBI:8207 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-258626 (+)-pilocarpine chemical CHEBI:8207 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-258628 PIM1 protein P11309 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-250390 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 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 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 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-250392 PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto "Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo" SIGNOR-164642 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 PIM1 protein P11309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr198 PGLRRRQt 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-179300 PIM1 protein P11309 UNIPROT Cell_death phenotype SIGNOR-PH109 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-256657 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 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 PIM1 protein P11309 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada "Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42)." SIGNOR-179308 PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-252966 PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada "Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42)." SIGNOR-252967 PIM1 protein P11309 UNIPROT FZR1 protein Q9UM11 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000567 20663873 t miannu "Pim-1 phosphorylates Cdh1 and impairs binding of this protein to another APC/C complex member, CDC27. These modifications inhibit Skp2 from degradation.Pim-1 Impairs Cdh1 and CDC27 Interaction and Phosphorylates Cdh1." SIGNOR-259820 PIM1 protein P11309 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17643117 t gcesareni "Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation." SIGNOR-156946 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 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Ser96 KTQLNPTsLQKLFRE 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-128260 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 PIM1 protein P11309 UNIPROT 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-178615 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 PIM1 protein P11309 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 19911008 t llicata "In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276." SIGNOR-189125 PIM1 protein P11309 UNIPROT RPS19 protein P39019 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 16266891 t gcesareni "The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay." SIGNOR-141411 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates activity" phosphorylation Ser64 SNLGHPEsPPRKRLK 9606 BTO:0000567 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-259818 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates activity" phosphorylation Ser72 PPRKRLKsKGSDKDF 9606 BTO:0000567 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 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates activity" phosphorylation Thr417 WGIKCRLTLQKPSCL 9606 BTO:0000567 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 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 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 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 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-249604 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 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-250394 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni "Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax" SIGNOR-78015 PIM2 protein Q9P1W9 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto "Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo" SIGNOR-164646 PIM2 protein Q9P1W9 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by stabilization" phosphorylation T454 RAPIIAVTRNPQTAR 9606 BTO:0000007 24142698 t Manara "Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels." SIGNOR-260905 PIM3 protein Q86V86 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-250396 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 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-249605 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 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-250399 pimozide chemical CHEBI:8212 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-258378 pimozide chemical CHEBI:8212 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-258719 pimozide chemical CHEBI:8212 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-258379 pimozide chemical CHEBI:8212 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-258718 pimozide chemical CHEBI:8212 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-258841 pimozide chemical CHEBI:8212 ChEBI STAT5A protein P42229 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001545 23264850 t miannu "We have identified the psychotropic drug pimozide as an effective inhibitor of STAT5 function. Pimozide inhibits the tyrosine phosphorylation of STAT5, leading to the death of AML cells through the induction of apoptosis." SIGNOR-260125 PIM proteinfamily SIGNOR-PF34 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000574 16146838 f miannu "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-255732 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259423 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 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 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 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-259422 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni "Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax" SIGNOR-259418 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto "Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo" SIGNOR-259424 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259426 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr198 PGLRRRQt 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-259425 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259429 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada "Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42)." SIGNOR-259428 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 PIM proteinfamily SIGNOR-PF34 SIGNOR H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17643117 t gcesareni "Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation." SIGNOR-259409 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259410 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Ser96 KTQLNPTsLQKLFRE 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-259432 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 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259430 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 PIM proteinfamily SIGNOR-PF34 SIGNOR 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-259434 PIM proteinfamily SIGNOR-PF34 SIGNOR RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 19911008 t llicata "In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276." SIGNOR-259411 PIM proteinfamily SIGNOR-PF34 SIGNOR RPS19 protein P39019 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 16266891 t gcesareni "The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay." SIGNOR-259412 PIMREG protein Q9BSJ6 UNIPROT PICALM protein Q13492 UNIPROT down-regulates relocalization 9606 BTO:0001271;BTO:0000785 16491119 t miannu "The cats interaction domain of calm was mapped to aa 221-335 of calm. This domain is contained in the calm/af10 fusion protein. Cats localizes to the nucleus and shows a preference for nucleoli. Expression of cats was able to markedly increase the nuclear localization of calm and of the leukemogenic fusion protein calm/af10." SIGNOR-144680 PIN1 protein Q13526 UNIPROT IFNB1 protein P01574 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 16699525 t lperfetto "To investigate the temporal regulation of IRF3-dependent transcription by Pin1, we used a rapid-response luciferase reporter gene. Real-time reporter gene assays showed that suppression of endogenous Pin1 expression substantially prolonged both IRF3-dependent transcription and IFN-beta promoter activation after poly(I)dotpoly(C) stimulation (Fig. 4c,d). Consistent with the inhibitory effects of Pin1 on the IFN-beta promoter" SIGNOR-252289 PIN1 protein Q13526 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 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 PIN1 protein Q13526 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 BTO:0000150 23716601 t esanto "Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated myc and its coactivators to select promoters during gene activation." SIGNOR-202134 PIN1 protein Q13526 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000150 19151708 t gcesareni "Prolyl-isomerase pin1 interacts with notch1 and affects notch1 activation. Pin1 potentiates notch1 cleavage by gamma-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing notch1. pin1 potentiates notch1 cleavage by gamma-secretase" SIGNOR-183461 pindolol chemical CHEBI:8214 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-258884 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 PINK1 protein Q9BXM7 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates phosphorylation Ser142 VPSPPPAsPRSQYNF 9606 BTO:0000142 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 PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 22724072 t llicata "We show that human pink1 is specifically activated by mitochondrial membrane potential (??m) depolarization, enabling it to phosphorylate parkin at ser(65). We further show that phosphorylation of parkin at ser(65) leads to marked activation of its e3 ligase activity that is prevented by mutation of ser(65) or inactivation of pink1." SIGNOR-197976 PINK1 protein Q9BXM7 UNIPROT RAB8A protein P61006 UNIPROT "down-regulates activity" phosphorylation Ser111 RNIEEHAsADVEKMI -1 31361120 t lperfetto "For Rab8a, it was shown that serine 111 phosphorylation (pS111) is dependent on the protein kinase PINK1 and that mimicking the phosphorylation at S111 by a serine/glutamate substitution (S111E) impaired Rab8a activation by its cognate nucleotide exchange factor (GEF) Rabin8." SIGNOR-260268 PINK1 protein Q9BXM7 UNIPROT UBC protein P0CG48 UNIPROT "up-regulates activity" phosphorylation Ser65 DYNIQKEsTLHLVLR 9606 BTO:0000938 24784582 t lperfetto "Ubiquitin is phosphorylated by PINK1 to activate parkin|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells" SIGNOR-249691 PIP5K1A protein Q99755 UNIPROT 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-180800 pipamperone chemical CHEBI:78549 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-258571 pipamperone chemical CHEBI:78549 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000601 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-258575 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 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 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB2 protein Q00722 UNIPROT up-regulates 23994464 t apalma "However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits" SIGNOR-255015 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 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 pirenzepine chemical CHEBI:8247 ChEBI CHRM1 protein P11229 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-258394 pirenzepine chemical CHEBI:8247 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-258396 pirenzepine chemical CHEBI:8247 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-258395 piroxicam chemical CHEBI:8249 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-258608 PITRM1 protein Q5JRX3 UNIPROT APP protein P05067 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000142 16849325 t Giorgia "In the present study we have identified and characterized the human PreP homologue, hPreP, in brain mitochondria, and we show its capacity to degrade the amyloid beta-protein (Abeta). PreP belongs to the pitrilysin oligopeptidase family M16C containing an inverted zinc-binding motif. We show that hPreP is localized to the mitochondrial matrix. In situ immuno-inactivation studies in human brain mitochondria using anti-hPreP antibodies showed complete inhibition of proteolytic activity against Abeta." SIGNOR-260661 "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 PITX1 protein P78337 UNIPROT LHB protein P01229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004467 19106114 f miannu "GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity." SIGNOR-254920 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 PITX2 protein Q99697 UNIPROT GNRH1 protein P01148 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004467 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-254922 PITX2 protein Q99697 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 20978076 f gcesareni "We show that pitx2 is crucial for the onset of myod gene expression in limb muscle progenitors and that it acts on the myod core enhancer." SIGNOR-169107 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Thr291 EDEESYDtESEFTEF 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-40514 PITX2 protein Q99697 UNIPROT TBX1 protein O43435 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20129917 f Regulation miannu "Pitx2 activated Tbx4, Tbx15, and Mga and repressed Tbx1, Tbx2, Tbx5, and Tbx6 expression." SIGNOR-251870 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 pizotifen chemical CHEBI:50212 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-258617 PJA1 protein Q8NG27 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000165 28067271 t "Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2" SIGNOR-255664 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser100 HLSGRKLsLQERSQG 9606 22778263 t lperfetto "Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity" SIGNOR-198146 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser495 KTMIRKRsFGNPFEG 9606 22778263 t lperfetto "Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity" SIGNOR-198150 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 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK1 protein Q15835 UNIPROT "down-regulates activity" phosphorylation S21 AFIAARGSFDGSSSQ 9606 BTO:0000007 15946941 t Luana "Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | 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." SIGNOR-260841 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT "down-regulates activity" phosphorylation S23 YLQARKPSDCDSKEL 9606 BTO:0000007 15946941 t Luana "Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | 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." SIGNOR-260839 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT "down-regulates activity" phosphorylation S36 ELQRRRRSLALPGLQ 9606 BTO:0000007 15946941 t Luana "Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | 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." SIGNOR-260840 PKA proteinfamily SIGNOR-PF17 SIGNOR MOS protein P00540 UNIPROT "down-regulates activity" phosphorylation S56 LGAGGFGSVYKAT 9606 BTO:0001538 8622681 t Manara "The purified PKA catalytic subunit was able to phosphorylate recombinant p37v-mos in vitro, suggesting that the mechanism of in vivo inhibition of v-Mos kinase involves direct phosphorylation by PKA." SIGNOR-260819 PKA proteinfamily SIGNOR-PF17 SIGNOR SMN1 protein Q16637 UNIPROT "up-regulates quantity by stabilization" phosphorylation 9606 BTO:0000007 19103745 t lperfetto "PKA increases SMN complex formation and SMN stability.|As expected, SMN was phosphorylated by PKA (Fig. ​(Fig.6D).6D)." SIGNOR-253114 PKA proteinfamily SIGNOR-PF17 SIGNOR "SMN complex" complex SIGNOR-C158 SIGNOR "up-regulates quantity by stabilization" phosphorylation 9606 BTO:0000007 19103745 t lperfetto "PKA increases SMN complex formation and SMN stability." SIGNOR-253122 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation S162 FDIVSRGSTADLDGL 9606 BTO:0000007 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-260885 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation S189 TDEEFREPST 9606 BTO:0000007 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-260883 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation T175 GLLPFLLTHKKRLTD 9606 BTO:0000007 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-260881 PKCtheta/Nfix complex SIGNOR-C121 SIGNOR MEF2A protein Q02078 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000165 20178747 t llicata "In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A." SIGNOR-238022 PKI-402 chemical CID:44187953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252654 PKI-402 chemical CID:44187953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206250 PKI-402 chemical CID:44187953 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206253 PKI-402 chemical CID:44187953 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206256 PKI-402 chemical CID:44187953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206259 PKI-587 chemical CID:44516953 PUBCHEM MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205986 PKI-587 chemical CID:44516953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252650 PKI-587 chemical CID:44516953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205989 PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 t llicata "Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3" SIGNOR-195766 PKMYT1 protein Q99640 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Thr14 IEKIGEGtYGVVYKG 9606 BTO:0000567 9001210 t "Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2" gcesareni "Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory." SIGNOR-45725 PKMYT1 protein Q99640 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 BTO:0000567 9001210 t "Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2" lperfetto "Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory." SIGNOR-45729 PKN1 protein Q16512 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 14970201 t lperfetto "Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules." SIGNOR-122191 PKN1 protein Q16512 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni "Rho can sensitize the ar to low levels of circulating androgens by promoting the nuclear translocation of a transcriptional co-activator, fhl2 (four and a half lim domains 2), which binds ar, and by stimulating protein kinase n (pkn), which phosphorylates ar directly." SIGNOR-152762 PKN1 protein Q16512 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567 15791647 t lperfetto "A role for PKN1 in mediating arsenite-induced G(2)/M delay was supported by the finding that expression of a constitutively active form of PKN1 (PKN1AF3) in HeLa cells delayed the mitotic entry of cell cycle. Further experiments indicate that PKN1 directly phosphorylated serine 216 (Ser216) in Cdc25C, which then facilitated association between Cdc25C and 14-3-3." SIGNOR-249277 PKN1 protein Q16512 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 21749319 t lperfetto "This identified thr654 in egfr as the pkn1 phosphorylation siteit has been shown that the phosphorylation of egfr at thr654 by pkc reduces the tyrosine kinase activity of the receptor" SIGNOR-174755 PKN1 protein Q16512 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 BTO:0000150 12560069 t lperfetto "Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1." SIGNOR-97882 PKN1 protein Q16512 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 BTO:0000150 12560069 t lperfetto "Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1." SIGNOR-252968 PKN1 protein Q16512 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni "Phosphorylation of mltkalpha by pknalpha enhances its kinase activity" SIGNOR-152768 PKN1 protein Q16512 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni "At the same time, rho signals to c-jun n-terminal kinase (jnk) and p38 through rock and protein kinase n (pkn), leading to the transcriptional regulation of jun" SIGNOR-152765 PKN1 protein Q16512 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser637 VDLSKVTsKCGSLGN 9606 BTO:0000938 BTO:0000975 11104762 t "The effect has been demonstrated using P10636-8" lperfetto "Phosphorylation of tau is regulated by pknthere is a pkn-specific phosphorylation site, ser-320, in mbdsthus pkn serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly." SIGNOR-84958 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8557118 t gcesareni "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-243199 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 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8557118 t gcesareni "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-249671 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL 9534 BTO:0000298 8557118 t lperfetto "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-248937 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9534 BTO:0000298 8557118 t lperfetto "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-248938 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE 9534 BTO:0000298 8557118 t lperfetto "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-248939 PKN1 protein Q16512 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser118 QVKIWRRsYDVPPPP 9606 BTO:0000130 12189148 t llicata "Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity." SIGNOR-91602 PKN1 protein Q16512 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser23 WNLENRFsGWYDADL 9606 BTO:0000130 12189148 t llicata "Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity." SIGNOR-91606 PKN1 protein Q16512 UNIPROT PGM1 protein P36871 UNIPROT up-regulates phosphorylation Thr467 SANDKVYtVEKADNF 9606 BTO:0001271 15378030 t llicata "Pak1-mediated phosphorylation of pgm selectively on threonine 466 significantly increased pgm enzymatic activity" SIGNOR-128722 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 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Thr531 PNATGTGtFSPGASP -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-249020 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 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 11733498 t lperfetto "Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1." SIGNOR-112549 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 15849194 t llicata "P21-activated kinase 1 (pak1)-dependent phosphorylation of raf-1 regulates its mitochondrial localization, phosphorylation of bad, and bcl-2 association. moreover, the mitochondrial translocation of raf-1 and the interaction between raf-1 and bcl-2 are regulated by raf-1 phosphorylation at ser-338/ser-339." SIGNOR-135679 PKN1 protein Q16512 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser246 QACARTFsRMSLLHK 9606 BTO:0000150 15833848 t lperfetto "Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functionswe found for the first time that pak1 promotes transcription repression activity of snail from e-cadherin, occludin, and aromatase promoters. Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions." SIGNOR-135609 PKNOX1 protein P55347 UNIPROT HOXA1 protein P49639 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 9582372 t miannu "Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding." SIGNOR-220242 PKNOX1 protein P55347 UNIPROT HOXB1 protein P14653 UNIPROT "up-regulates activity" binding -1 9482740 t 2 miannu "we observe the formation of a ternary Prep1-Pbx1-HOXB1 complex on a HOXB1-responsive target in vitro. Interaction with Prep1 enhances the ability of the HOXB1-Pbx1 complex to activate transcription in a cooperative fashion from the same target." SIGNOR-241215 PKNOX1 protein P55347 UNIPROT PBX1 protein P40424 UNIPROT "up-regulates activity" binding -1 9482740 t 2 miannu "we show that Pbx proteins exist as stable heterodimers with a novel homeodomain protein, Prep1. Here we show that Prep1-Pbx interaction presents novel structural features: it is independent of DNA binding and of the integrity of their respective homeodomains, and requires sequences in the N-terminal portions of both proteins. The Prep1-Pbx protein-protein interaction is essential for DNA-binding activity." SIGNOR-241212 PKNOX1 protein P55347 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 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-254924 PKNOX1 protein P55347 UNIPROT SYP protein P08247 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 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 PKP2 protein Q99959 UNIPROT DSP protein P15924 UNIPROT "up-regulates quantity by stabilization" binding 10090 BTO:0003264 22781308 t Simone "In contrast to the proper membrane localization of PKP2 and DSP after cotransfection of both WT proteins, mutant PKP2 C796R protein was not able to interact with FLAG-DSP to enable assembly at the junctional plaque, indicating the requirement of functional PKP2 for DSP integration into the desmosome." SIGNOR-261254 PLA2G4A protein P47712 UNIPROT "arachidonic acid" smallmolecule CHEBI:15843 ChEBI up-regulates "small molecule catalysis" 9606 6810878 t acerquone "Alternatively, a phospholipase a2 may indeed deacylate the phosphatidylinositol, but the point of debate here is whether deacylation constitutes a significant component of the arachidonate liberation." SIGNOR-25633 PLAAT3 protein P53816 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates 9606 17374643 f miannu "The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity." SIGNOR-153772 PLAAT3 protein P53816 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates 9606 17374643 f miannu "The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity." SIGNOR-153775 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 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 PLAG1 protein Q6DJT9 UNIPROT Cell_death phenotype SIGNOR-PH109 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-256658 PLAG1 protein Q6DJT9 UNIPROT IGF2 protein P01344 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14695992 f miannu "Plag1 has been shown be a transcriptional activator of igf2" SIGNOR-120363 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 PLAGL2 protein Q9UPG8 UNIPROT SFTPC protein P11686 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000353 17618602 f miannu "nuclear PLAGL2 occupied and transactivated the endogenous SP-C promoter in lung cells." SIGNOR-254927 PLAU protein P00749 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 19055748 f lperfetto "Our data show that functional blockade of SNAI1 (SNAI1-dominant negative (DN)) leads to a partial re-expression of E-cadherin, and induces differential expression of EMT-related genes. This is confirmed by RT-PCR of PA system genes, where PAI-1 and uPA are decreased." SIGNOR-252264 PLAU protein P00749 UNIPROT PLAUR protein Q03405 UNIPROT up-regulates binding 9606 16456079 t gcesareni "The urokinase plasminogen activator binds to its cellular receptor with high affinity and initiates signaling cascades that are implicated in pathological processes including tumor growth, metastasis, and inflammation." SIGNOR-144306 PLAUR protein Q03405 UNIPROT ITGB3 protein P05106 UNIPROT "up-regulates activity" binding 9606 27383564 t "Recent evidence suggests that the activation of b3 integrin in podocytes mediates uPAR-induced cellular events leading to proteinuria" SIGNOR-253333 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 PLCB1 protein Q9NQ66 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI "up-regulates quantity" "Small molecule catalysis" -1 23880553 t "Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate." SIGNOR-256497 PLCB1 protein Q9NQ66 UNIPROT diglyceride smallmolecule CHEBI:18035 ChEBI "up-regulates quantity" "Small molecule catalysis" -1 23880553 t "Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate." SIGNOR-256496 PLCB1 protein Q9NQ66 UNIPROT GNA11 protein P29992 UNIPROT up-regulates binding 9606 1322796 t miannu "Plc-_1 stimulates hydrolysis of gq/11-bound gtp and acts as a gtpase-activating protein (gap) for its physiologic regulator, gq/11" SIGNOR-17239 PLCB2 protein Q00722 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 23994464 f apalma "The first phase of this signal is likely mediated by phospholipase CŒ≤ (PLCŒ≤) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores" SIGNOR-255017 PLCB2 protein Q00722 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-255013 PLCB3 protein Q01970 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 23994464 f apalma "The first phase of this signal is likely mediated by phospholipase CŒ≤ (PLCŒ≤) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores" SIGNOR-255018 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 PLCD4 protein Q9BRC7 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI up-regulates "small molecule catalysis" 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 PLCD4 protein Q9BRC7 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI up-regulates "small molecule catalysis" 9606 9125218 t gcesareni "A key pathway is the hydrolysis of PIP2 . This is mediated by PLC, and yields the two second messengers 1,4,5-IP3 and DAG" SIGNOR-195516 PLCE1 protein Q9P212 UNIPROT Diacylglycerol smallmolecule CID:6026790 PUBCHEM up-regulates "small molecule catalysis" 9606 17251915 t gcesareni "Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases." SIGNOR-152771 PLCE1 protein Q9P212 UNIPROT HRAS protein P01112 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 11022047 t gcesareni "The presence of a rasgef motif in the n terminus of plcepsilon suggests that plcepsilon can activate ras by acting as an exchange factor by promoting the exchange of gtp for bound gdp." SIGNOR-82859 PLCG1 protein P19174 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI up-regulates "small molecule catalysis" 9606 BTO:0000142;BTO:0000763 21918248 t gcesareni "Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag." SIGNOR-176609 PLCG1 protein P19174 UNIPROT Diacylglycerol smallmolecule CID:6026790 PUBCHEM "up-regulates quantity" "small molecule catalysis" 9606 23140367 t "Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)." SIGNOR-251558 PLCG1 protein P19174 UNIPROT Diacylglycerol smallmolecule CID:6026790 PUBCHEM up-regulates "small molecule catalysis" 9606 BTO:0000142;BTO:0000763 21918248 t gcesareni "Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag." SIGNOR-176606 PLCG1 protein P19174 UNIPROT ITPRIPL1 protein Q6GPH6 UNIPROT up-regulates 9606 BTO:0000938 21368195 f 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-172500 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 PLCG1 protein P19174 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 17562871 f gcesareni "We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1." SIGNOR-155747 PLCG1 protein P19174 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 9606 10913276 t gcesareni "We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation." SIGNOR-80024 PLCG2 protein P16885 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 24890514 f apalma "Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway" SIGNOR-255571 PLD1 protein Q13393 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI up-regulates "small molecule catalysis" 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 PLD2 protein O14939 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 18423386 f mrosina "Altogether, these data suggest that PLD acting upstream of the MAP kinases ERK1/2 may play a key role in the regulation of IL-2 production by stimulated Jurkat cells." SIGNOR-254983 PLD3 protein Q8IV08 UNIPROT APP protein P05067 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 24336208 t Monia "Furthermore, PLD3 can be co-immunoprecipitated with APP in cultured cells (Extended Data Figure 4). Together, these studies demonstrate that PLD3 plays a role in APP processing. Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing." SIGNOR-261200 PLEKHA7 protein Q6IQ23 UNIPROT PDZD11 protein Q5EBL8 UNIPROT "up-regulates activity" binding 10116 BTO:0003618 30463011 t Simone "Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33" SIGNOR-261253 PLEKHA7 protein Q6IQ23 UNIPROT TSPAN33 protein Q86UF1 UNIPROT "up-regulates activity" binding 10116 BTO:0003618 30463011 t Simone "Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11." SIGNOR-261250 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 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 PLEKHG4B protein Q96PX9 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-260565 PLEKHG4 protein Q58EX7 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-260564 PLEKHG5 protein O94827 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-260566 PLEKHG6 protein Q3KR16 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-260568 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 PLIN3 protein O60664 UNIPROT IGF2R protein P11717 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-253092 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 PLK1 protein P53350 UNIPROT ANAPC1 protein Q9H1A4 UNIPROT up-regulates phosphorylation Ser355 AALSRAHsPALGVHS 9606 14657031 t gcesareni "Our analysis revealed an unexpected and unprecedented complexity of mitotic phosphorylation sites and suggests that other kinases than cdk1 and plk1 also contribute to apc phosphorylation." SIGNOR-119881 PLK1 protein P53350 UNIPROT ATXN10 protein Q9UBB4 UNIPROT down-regulates phosphorylation Thr82 ASSLQLItECFRCLR 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-176126 PLK1 protein P53350 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Ser20 FLKDHRIsTFKNWPF 9606 21148584 t lperfetto "Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation" SIGNOR-170460 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18378770 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178150 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18521620 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178803 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 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Thr501 QMDSGYNtQNCGSNI 9606 18521620 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178807 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Ser193 AEVDPDMsWSSSLAT 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-102486 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 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Ser206 ATPPTLSsTVLIVRN 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-102494 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Thr203 SSLATPPtLSSTVLI 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-102498 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Thr207 TPPTLSStVLIVRNE 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-102502 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser193 AEVDPDMsWSSSLAT 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-249217 GNAI3 protein P08754 UNIPROT TNFAIP8 protein O95379 UNIPROT "up-regulates activity" binding 9606 20607800 t "TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation" SIGNOR-256490 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 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser206 ATPPTLSsTVLIVRN 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-249219 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 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr207 TPPTLSStVLIVRNE 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-249221 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Ser676 LSPIIEDsREATHSS 9606 17785528 t lperfetto "We identify s676 as a plk1-specific phosphorylation site on bubr1. These findings describe the first in vivo verified phosphorylation site for human bubr1, identify plk1 as the kinase responsible for causing the characteristic mitotic bubr1 upshift, and attribute a kt-specific function to the hyperphosphorylated form of bubr1 in the stabilization of kt-mt interactions." SIGNOR-157646 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr1008 LNANDEAtVSVLGEL 9606 17376779 t gcesareni "Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1" SIGNOR-153863 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr680 IEDSREAtHSSGFSG 9606 23079597 t lperfetto "Phosphorylation of kard by plk1 promotes direct interaction of bubr1 with the pp2a-b56_ phosphatase that counters excessive aurora b activity at kinetochores. We propose that plk1 and bubr1 cooperate to stabilize kinetochore-microtubule interactions. Phosphorylation of t680 by plk1 is essential for kard function" SIGNOR-199222 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 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser128 LVDTASPsPMETSGC 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-105711 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser133 SPSPMETsGCAPAEE 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-105715 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 PLK1 protein P53350 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 11897663 t lperfetto "The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase." SIGNOR-115993 PLK1 protein P53350 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Thr37 SDAKLEPtNVQTVTC 9606 21041660 t lperfetto "Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression." SIGNOR-169184 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Ser77 TFDPPLHsTAIYADE 9606 17081991 t lperfetto "S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions" SIGNOR-150453 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Thr78 FDPPLHStAIYADEE 9606 17081991 t lperfetto "S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions" SIGNOR-150457 PLK1 protein P53350 UNIPROT CEP55 protein Q53EZ4 UNIPROT up-regulates phosphorylation Ser436 PTAALNEsLVECPKC 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-140898 PLK1 protein P53350 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 12493754 t gcesareni "Plk1 overexpression enhances phosphorylation of chk2 at thr-68." SIGNOR-96637 PLK1 protein P53350 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates phosphorylation Ser195 LTKTASEsISNLSEA 9606 20664522 t gcesareni "Furthermore, we provide evidence that plk1 phosphorylation of clip-170 at s195 enhances its association with ck2" SIGNOR-167172 PLK1 protein P53350 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser30 EADSPSDsGQGSYET 9606 16885021 t gcesareni "We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase" SIGNOR-148442 PLK1 protein P53350 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser30 EADSPSDsGQGSYET 9606 16885022 t gcesareni "We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase" SIGNOR-148447 PLK1 protein P53350 UNIPROT CTNNB1 protein P35222 UNIPROT unknown phosphorylation Ser718 QDDPSYRsFHSGGYG 9606 19001871 t lperfetto "Ser-718 of beta-catenin was directly phosphorylated by recombinant plk1thus it may be possible that function of the additional phosphorylation site(s) in cooperation with the ser-718 is required for the regulation of _-catenin at m phase" SIGNOR-182150 PLK1 protein P53350 UNIPROT DCTN1 protein Q14203 UNIPROT up-regulates phosphorylation Ser179 SASAGELsSSEPSTP 9606 20679239 t lperfetto "Plk1-mediated phosphorylation of p150(glued) at ser-179 positively regulates its accumulation at the nuclear envelope during prophase." SIGNOR-167281 PLK1 protein P53350 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr206 MTSELEStSLGDSDE 9606 20823832 t lperfetto "Dvl2 bound to and was phosphorylated at thr206 by a mitotic kinase, polo-like kinase 1 (plk1), and this phosphorylation was required for spindle orientation and stable microtubule (mt)-kt attachment" SIGNOR-167858 PLK1 protein P53350 UNIPROT ERCC6L protein Q2NKX8 UNIPROT up-regulates relocalization 9606 17218258 t lperfetto "Human pich was identified as an interaction partner and substrate of plk1. Our data indicate that plk1 prevents the association of pich with chromosome arms and restricts its localization to the kt/centromere region" SIGNOR-152136 PLK1 protein P53350 UNIPROT FADD protein Q13158 UNIPROT down-regulates phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 BTO:0000567 20890306 t gcesareni "Plk1 phosphorylates fadd at ser-194 in response to treatment with taxol. Overexpression of a phosphorylation-mimicking mutant, fadd s194d, caused degradation of plk1 in an ubiquitin-independent manner, and delayed cytokinesis, consistent with the expected cellular phenotype of plk1 deficiency" SIGNOR-168204 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 15469984 t gcesareni "Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering scfbetatrcp-dependent destruction of the apc inhibitor emi1." SIGNOR-129813 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 16439210 t gcesareni "We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity." SIGNOR-142949 PLK1 protein P53350 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser730 VLDTMNDsLSKILLD 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-187888 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 PLK1 protein P53350 UNIPROT GTSE1 protein Q9NYZ3 UNIPROT up-regulates phosphorylation Ser435 RSIRRRDsCLNSKTK 9606 20577264 t lperfetto "In this study, we show that g2 and s-phase-expressed 1 (gtse1) protein, a negative regulator of p53, is required for g2 checkpoint recovery and that plk1 phosphorylation of gtse1 at ser 435 promotes its nuclear localization, and thus shuttles p53 out of the nucleus to lead to its degradation during the recovery." SIGNOR-166417 PLK1 protein P53350 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser216 IPLMLNDsGSAHSMP 9606 18794143 t lperfetto "Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway." SIGNOR-180915 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser733 TVREQDQsFTALDWS 9606 BTO:0000567 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 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser740 SFTALDWsWLQTEEE 9606 BTO:0000567 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-181802 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser750 QTEEEEHsCLEQAS 9606 BTO:0000567 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-181806 PLK1 protein P53350 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 15849359 t lperfetto "Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinaseirs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin." SIGNOR-135688 PLK1 protein P53350 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Ser57 SQSSQDSsPVRNLQS 9606 18250300 t lperfetto "Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate." SIGNOR-160751 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT "up-regulates activity" phosphorylation Ser204 HLDSSKIsVLEPPQE 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-252050 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 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 PLK1 protein P53350 UNIPROT MAP9 protein Q49MG5 UNIPROT up-regulates phosphorylation Ser289 SDENKENsFSADHVT 9606 20615875 t lperfetto "We also demonstrate that asap is a novel substrate of plk1 phosphorylation and have identified serine 289 as the major phosphorylation site by plk1 in vivo. Asap phosphorylated on serine 289 is localized to centrosomes during mitosis, but this phosphorylation is not required for its plk1-dependent localization at the spindle poles. We show that phosphorylated asap on serine 289 contributes to spindle pole stability in a microtubule-dependent manner" SIGNOR-166564 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 12383858 t gcesareni "Here we show that the oncogenic and cell cycle-regulatory protein kinase, polo-like kinase-1 (plk1), phosphorylates mdm2 at one of these residues, ser260, and stimulates mdm2-mediated turnover of p53. These data are consistent with the idea that deregulation of plk1 during tumourigenesis may help suppress p53 function." SIGNOR-94272 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 19833129 t gcesareni "Polo-like kinase-1 phosphorylates mdm2 at ser260 and stimulates mdm2-mediated p53 turnover." SIGNOR-188471 PLK1 protein P53350 UNIPROT MYC protein P01106 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-243522 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Ser686 LEELHEKsQEVIWGL -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-103348 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Ser87 VRPSDEDsSSLESAA -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-103352 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 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 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 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT "up-regulates activity" phosphorylation Ser274 KKINPENsKLSDLDS 9606 BTO:0000567 12852857 t lperfetto "Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites." SIGNOR-103403 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT "up-regulates activity" phosphorylation Ser326 QHPEMDFsKAKFN 9606 BTO:0000567 12852857 t lperfetto "Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites." SIGNOR-103407 PLK1 protein P53350 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates phosphorylation Ser65 SHLLVKHsQSRRPSS 9606 BTO:0000567 16118204 t llicata "Here we demonstrate that ser-65 in pin1 is the major site for plk1-specific phosphorylation, and the polo-box domain of plk1 is required for this phosphorylation. Interestingly, the phosphorylation of pin1 by plk1 does not affect its isomerase activity but rather is linked to its protein stability. pin1 is ubiquitinated in hela s3 cells, and substitution of glu for ser-65 reduces the ubiquitination of pin1." SIGNOR-139919 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser110 SDKKEKKsFSLEEKS 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-166317 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser117 SFSLEEKsKISKNRV 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-166321 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser226 ATGKDVEsYLQPKAK 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-166325 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 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 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Ser426 CSLLLDSsLSSNWDD 9606 BTO:0000567 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-249207 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Thr495 LLSLFEDtLDPT 9606 BTO:0000567 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 PLK1 protein P53350 UNIPROT PLEKHG6 protein Q3KR16 UNIPROT up-regulates phosphorylation Thr574 HLVVTEDtDEDAPLV 9606 BTO:0000567 18694934 t lperfetto "We reported previously that a guanine nucleotide exchange factor, myogef, localizes to the central spindle, activates rhoa, and is required for cytokinesis. In this study, we have found that plk1 (polo-like kinase 1) can phosphorylate myogef, thereby recruiting myogef to the central spindle as well as enhancing myogef activity toward rhoa. The in vitro kinase assay shows that plk1 can phosphorylate myogef on threonine 574." SIGNOR-179954 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser157 GSILSDIsFDKTDES 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-185746 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser170 ESLDWDSsLVKTFKL 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-185750 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 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Thr260 QPWNSDStLNSRQLE 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-185758 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 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 PLK1 protein P53350 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000142 21849493 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-176063 PLK1 protein P53350 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000938 BTO:0000142 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-189045 PLK1 protein P53350 UNIPROT TERF1 protein P54274 UNIPROT up-regulates phosphorylation Ser435 KKLKLISsDSED 9606 18625707 t lperfetto "Plk1 phosphorylation of trf1 is essential for its binding to telomeres" SIGNOR-179461 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1337 LDSDEDFsDFDEKTD 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-160233 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 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 t gcesareni "Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin" SIGNOR-182844 PLK1 protein P53350 UNIPROT TOPORS protein Q9NS56 UNIPROT down-regulates 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 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 PLK1 protein P53350 UNIPROT TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr27 SSLEPDStYFDLPQS 9606 BTO:0000093 18418051 t llicata "P73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. tap73 is phosphorylated by this kinase on threonine-27 (thr-27) within the ta domain." SIGNOR-178253 PLK1 protein P53350 UNIPROT TPT1 protein P13693 UNIPROT down-regulates phosphorylation Ser46 TEGNIDDsLIGGNAS 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-91344 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 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr2229 QAEEREHtLRRCQQE 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-198353 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 PLK1 protein P53350 UNIPROT VIM protein P08670 UNIPROT up-regulates phosphorylation Ser83 GVRLLQDsVDFSLAD 9606 BTO:0000150 18056432 t gcesareni "We observed that plk1 phosphorylates vimentin on ser82, which in turn regulates cell surface levels of 1 integrin." SIGNOR-159386 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-139473 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 15350223 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-128643 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 15070733 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-123832 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 16085715 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-139477 PLK1 protein P53350 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Thr39 PVETIETtVVGEEEE 9606 23226345 t lperfetto "More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis" SIGNOR-200087 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 PLK2 protein Q9NYY3 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 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. Plk4 also phosphorylates s595 of cpap" SIGNOR-166003 PLK2 protein Q9NYY3 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates phosphorylation Ser176 KRKLDHGsEVRSFSL 9606 22399798 t lperfetto "Plk2 regulates centriole duplication through phosphorylation-mediated degradation of fbxw7 (human cdc4).Plk2 phosphorylates fbxw7 on serine 176" SIGNOR-196448 PLK2 protein Q9NYY3 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-125720 PLK2 protein Q9NYY3 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000142 21849493 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-176067 PLK2 protein Q9NYY3 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000938 BTO:0000142 19004816 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 PLK2 protein Q9NYY3 UNIPROT SNCB protein Q16143 UNIPROT up-regulates phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 BTO:0000142 21849493 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-176071 PLK2 protein Q9NYY3 UNIPROT SNCB protein Q16143 UNIPROT up-regulates phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 BTO:0000938 BTO:0000142 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-189049 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 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-163270 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 21098032 t gcesareni "Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro." SIGNOR-170004 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 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 21098032 t gcesareni "Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro." SIGNOR-170008 PLK3 protein Q9H4B4 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates phosphorylation Ser49 ESEMETPsAINGNPS 9606 21336504 t lperfetto "Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest." SIGNOR-172230 PLK3 protein Q9H4B4 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Thr80 RMGSSEStDSGFCLD 9606 18167338 t lperfetto "Here, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cdc25a to promote its proteolysis in early cell-cycle phases. Phosphorylation by gsk-3beta requires priming of cdc25a, and this can be catalyzed by polo-like kinase 3 (plk-3)" SIGNOR-160228 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 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 14968113 t lperfetto "Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation" SIGNOR-122094 PLK3 protein Q9H4B4 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser576 DDDFQLRsFDQLSPL 9606 BTO:0000567 18519666 t lperfetto "Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation" SIGNOR-178739 PLK3 protein Q9H4B4 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser657 ETTSATSsPYRDTQS 9606 BTO:0000567 18519666 t lperfetto "Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation" SIGNOR-178743 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 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-157721 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 18650425 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-179551 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 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 18650425 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-179555 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 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 PLK3 protein Q9H4B4 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000142 21849493 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-176075 PLK3 protein Q9H4B4 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 BTO:0000938 BTO:0000142 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-189053 PLK3 protein Q9H4B4 UNIPROT SNCB protein Q16143 UNIPROT up-regulates phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 BTO:0000142 21849493 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 PLK3 protein Q9H4B4 UNIPROT SNCB protein Q16143 UNIPROT up-regulates phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 BTO:0000938 BTO:0000142 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-189057 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 PLK3 protein Q9H4B4 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000452 11447225 t lperfetto "Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3." SIGNOR-109239 PLK3 protein Q9H4B4 UNIPROT VRK1 protein Q99986 UNIPROT up-regulates phosphorylation Ser342 DDGKLDLsVVENGGL 9606 19103756 t llicata "Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process." SIGNOR-182858 PLK4 protein O00444 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 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. Plk4 also phosphorylates s595 of cpap" SIGNOR-166007 PLK4 protein O00444 UNIPROT PLK4 protein O00444 UNIPROT up-regulates phosphorylation Ser305 SSTSISGsLFDKRRL 9606 20032307 t llicata "Autophosphorylation probably plays a role in the process of centriole duplication, because mimicking s305 phosphorylation enhances the ability of overexpressed plk4 to induce centriole amplification. Importantly, we show that s305-phosphorylated plk4 is specifically sequestered at the centrosome contrary to the nonphosphorylated form." SIGNOR-162559 PLN protein P26678 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates activity" binding 10090 BTO:0003265 12838339 t "Heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor." SIGNOR-252031 PLRG1 protein O43660 UNIPROT HNRNPM protein P52272 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 20467437 t 1 miannu "hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay." SIGNOR-239444 PLX-4720 chemical CHEBI:90295 ChEBI BRAF protein P15056 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-258267 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 PMCH protein P20382 UNIPROT MCHR2 protein Q969V1 UNIPROT up-regulates binding 9606 BTO:0000142 10471841 t gcesareni "Upon several purification steps, followed by mass spectrometric analysis and peptide sequencing, the ligand was identified as melanin concentrating hormone (mch), revealing that the orphan slc-1 is the mch receptor." SIGNOR-70520 PML protein P29590 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0001271 15093545 f gcesareni "The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor" SIGNOR-256659 PML protein P29590 UNIPROT KAT6A/PML complex SIGNOR-C55 SIGNOR "form complex" binding 9606 BTO:0001271 23431171 t miannu "We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression" SIGNOR-201489 PML protein P29590 UNIPROT SMAD2 protein Q15796 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-128738 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 15356634 t gcesareni "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-128735 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 PML protein P29590 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 15356634 t gcesareni "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-128741 PML protein P29590 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates binding 9606 15356634 t gcesareni "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-128744 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" 9606 BTO:0000093 8415704 f miannu "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-261507 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 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001412 11090075 f "Overexpression of cyclin A1 observed in APL cells is caused by the expression of the aberrant fusion proteins, PML-RARα and PLZF-RARα. PML-RARα itself can lead to activation of the cyclin A1 promoter.Since both fusion proteins disrupt the normal RARα function, our results strongly suggested that the RARα pathway negatively regulates the expression of cyclin A1 and that this negative regulation is disrupted by the aberrant fusion proteins." SIGNOR-255725 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19797526 f "We therefore conclude that PML-RARα–mediated repression of C/EBPα is driven through a DNA methylation pathway. In accordance with this finding, a recent study in human APL samples described increased C/EBPα promoter methylation, consistent with the ability of PML-RARα to recruit corepressor complexes. Moreover, the PML-RARα effect on C/EBPα repression does not seem to be mediated via direct binding." SIGNOR-255726 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 20966922 f "APL cells closely resemble normal promyelocytes, a specific stage of the granulocytic differentiation pathway, suggesting that PML–RARα blocks the normal myeloid differentiation programme." SIGNOR-255724 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-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-255723 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR GATA2 protein P23769 UNIPROT "up-regulates activity" binding 10090 BTO:0001516 10938104 t "We provide evidence that GATA-2 can physically associate with PML-RARα. Functional experiments further demonstrated that this interaction has the capacity to render GATA-dependent transcription inducible by retinoic acid, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL." SIGNOR-259941 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000972 18025157 f "We show that the ID1 and ID2 promoters are activated by PML-RARα but, unexpectedly, not by wild-type RARα/RXR. In contrast, PML-RARα transactivated the promoter more than 12-fold in an ATRA-dependent fashion." SIGNOR-255728 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR ID2 protein Q02363 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000972 18025157 f "Also comparable with ID1, RARα, RXR, PML, PLZF-RARα, and RARα/RXR did not transactivate the ID2 promoter, whereas PML-RARα did. Together, these data show that like ID1, ID2 may also be transactivated by PML-RARα without direct DNA binding of the fusion protein." SIGNOR-255727 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR MYB protein P10242 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0005790 30335887 t "PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms." SIGNOR-259939 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR MYC protein P01106 UNIPROT "up-regulates activity" 9606 19855079 t apalma "We demonstrate that in addition to blocking myeloid differentiation, PLZF-RARα also promotes proliferation/self-renewal via the aberrant regulation of cell cycle–associated genes such as c-Myc, providing a basis for studying the aberrant response of this leukemia subtype to retinoic acid." SIGNOR-256374 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR NFY complex SIGNOR-C1 SIGNOR "up-regulates activity" binding 9606 BTO:0000972 18025157 t "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-255747 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 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 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 BTO:0001412 18025157 t "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-255749 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 PMP22 protein Q01453 UNIPROT MPZ protein P25189 UNIPROT "up-regulates activity" binding 9606 10212299 t miannu "Our data provide the first direct evidence for the formation of P0–PMP22 complexes at the plasma membrane. These protein interactions probably participate in holding adjacent Schwann cell membranes together and in stabilizing myelin compaction." SIGNOR-251898 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 PMS1 protein P54277 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-257597 PMS1 protein P54277 UNIPROT MLH1/PMS1 complex SIGNOR-C58 SIGNOR "form complex" binding 9606 10542278 t miannu "We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_." SIGNOR-71774 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 PMS2 protein P54278 UNIPROT MLH1/PMS2 complex SIGNOR-C59 SIGNOR "form complex" binding 9606 10542278 t miannu "Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_" SIGNOR-71777 PNCK protein Q6P2M8 UNIPROT EIF4G3 protein O43432 UNIPROT up-regulates phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 BTO:0000938 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-197190 PNPLA6 protein Q8IY17 UNIPROT Glycerophosphocholine smallmolecule "CID: 439285" PUBCHEM "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000938 25033069 t "PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus" SIGNOR-253611 PNPLA6 protein Q8IY17 UNIPROT Lysophosphatidylcholine smallmolecule CID:5311264 PUBCHEM "down-regulates quantity" "small molecule catalysis" 9606 BTO:0000938 25033069 t "PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus" SIGNOR-253610 POFUT1 protein Q9H488 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 12909620 t Fucosylation gcesareni "Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling." SIGNOR-104627 POFUT1 protein Q9H488 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 12909620 t Fucosylation gcesareni "Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling." SIGNOR-254326 POGLUT1 protein Q8NBL1 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates glycosylation 9606 22872643 t O-glycosilation gcesareni "O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus." SIGNOR-198713 POGLUT1 protein Q8NBL1 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22872643 t gcesareni "O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. O-glucose can be elongated by xylose to the trisaccharide, xylalfa1-3xylalfa1-3glcbeta1-o-ser, whose synthesis is catalyzed by the consecutive action of three glycosyltransferases. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus." SIGNOR-198716 POGLUT1 protein Q8NBL1 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates glycosylation 9606 22872643 t O-glycosilation gcesareni "O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus." SIGNOR-254319 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 POLA1 protein P09884 UNIPROT DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 19608746 f lperfetto "Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin." SIGNOR-261275 POLA2 protein Q14181 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-261342 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 POLR2A protein P24928 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "up-regulates activity" relocalization -1 20457598 t lperfetto "The pol II CTD specifically mediates recruitment of Integrator to the promoter of snRNA genes to activate transcription and direct 3' end processing of the transcripts." SIGNOR-261476 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 POMC protein P01189 UNIPROT CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 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-252377 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 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 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 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 POMC protein P01189 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-258409 POMC protein P01189 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-258410 ponatinib chemical CHEBI:78543 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-259268 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 ponatinib chemical CHEBI:78543 ChEBI FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 23563700 t miannu "Ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1." SIGNOR-259276 ponatinib chemical CHEBI:78543 ChEBI FGFR2 protein P21802 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-259278 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 ponatinib chemical CHEBI:78543 ChEBI FGFR4 protein P22455 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-259280 ponatinib chemical CHEBI:78543 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001669 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-259272 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 ponatinib chemical CHEBI:78543 ChEBI RET protein P07949 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001271;BTO:0000184 23526464 t miannu "The RET tyrosine kinase encoding gene acts as a dominantly transforming oncogene in thyroid carcinoma and other malignancies. Ponatinib (AP24534) is an oral ATP-competitive tyrosine kinase inhibitor that is in advanced clinical experimentation in leukemia.Ponatinib is a potent inhibitor of RET kinase and has promising preclinical activity in models of RET-driven medullary thyroid carcinoma." SIGNOR-259275 ponatinib chemical CHEBI:78543 ChEBI RIPK1 protein Q13546 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000661 25801024 t Federica "Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3" SIGNOR-261082 ponatinib chemical CHEBI:78543 ChEBI RIPK3 protein Q9Y572 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000661 25801024 t Federica "Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3" SIGNOR-261083 ponatinib chemical CHEBI:78543 ChEBI STAT5A protein P42229 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-259274 PORCN protein Q9H237 UNIPROT WNT3A protein P56704 UNIPROT "up-regulates activity" palmitoylation Ser209 KCKCHGLsGSCEVKTC 9606 BTO:0000007 20826466 t "And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane." SIGNOR-256598 porfimer chemical CHEBI:60652 ChEBI FCGR1A protein P12314 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000876 2544592 t miannu "Inhibition of the high affinity Fc receptor (Fc gamma RI) on human monocytes by porphyrin photosensitization is highly specific and mediated by the generation of superoxide radicals." SIGNOR-259303 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 POT1 protein Q9NUX5 UNIPROT POT1/ACD complex SIGNOR-C64 SIGNOR "form complex" 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-152324 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 POU1F1 protein P28069 UNIPROT GH1 protein P01241 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15998782 f miannu "Such findings are consistent with the existence, in humans, of an LHX4-driven pathway leading to the expression of GH through transcriptional activation of POU1F1." SIGNOR-254559 POU2AF1 protein Q16633 UNIPROT POU2F1 protein P14859 UNIPROT up-regulates binding 9606 BTO:0000776 12727885 t miannu "Obf1 enhances transcriptional potential of oct1." SIGNOR-100968 CIITA protein P33076 UNIPROT HLA-A protein P30443 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 10329350 f "Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression." SIGNOR-254020 POU2AF1 protein Q16633 UNIPROT POU2F2 protein P09086 UNIPROT up-regulates binding 9606 BTO:0000776 8654375 t miannu "We have shown previously that both octamer binding transcription factors, namely the ubiquitous oct-1 and the b cell-specific oct-2a protein, can be enhanced in transcriptional activity by their association with the b cell-specific coactivator protein bob1, also calledobf-1or oca-b." SIGNOR-42278 POU2F1 protein P14859 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-254432 POU2F1 protein P14859 UNIPROT HOXD10 protein P28358 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25301728 f miannu "Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11" SIGNOR-205540 POU2F1 protein P14859 UNIPROT HOXD11 protein P31277 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25301728 f miannu "Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11" SIGNOR-205564 POU2F1 protein P14859 UNIPROT IL4 protein P05112 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782 11781715 f "Here we show that NFAT proteins are unable to bind to a combined octamer/NFAT site unless the octamer proteins are competed away" SIGNOR-254505 POU2F1 protein P14859 UNIPROT MYH10 protein P35580 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-238772 POU2F1 protein P14859 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-238760 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 POU2F1 protein P14859 UNIPROT SNAI2 protein O43623 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 23836662 f 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. 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-254149 POU2F1 protein P14859 UNIPROT TWIST1 protein Q15672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 23836662 f 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. 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-254152 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 POU3F2 protein P20265 UNIPROT MITF protein O75030 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 18628967 t lperfetto "We further demonstrate that BRN2 induces MITF transcription through a binding site located at ˆ’50/ˆ’36 of the MITF promoter" SIGNOR-249616 POU3F2 protein P20265 UNIPROT POU3F2 protein P20265 UNIPROT "up-regulates activity" binding 9606 BTO:0002269 11029584 t miannu "These experiments lead to the conclusion that the full-length Brn-2 protein can interact with full-length Brn-2. Assay of homodimerization properties of Brn-2 protein on the b2s1 dimer recognition sequence also demonstrated cooperativity, indicating that protein-protein contacts would be important for synergistic interactions between the Brn-2 subunits." SIGNOR-221824 POU3F4 protein P49335 UNIPROT POU3F2 protein P20265 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-220080 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 POU4F1 protein Q01851 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" binding 9606 BTO:0000093 9448000 t 2 miannu "the POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect." SIGNOR-241275 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 POU4F2 protein Q12837 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" binding 9606 BTO:0000093 9448000 t 2 miannu "the POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect." SIGNOR-241208 POU5F1 protein Q01860 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004180 23041284 t flangone "Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription." SIGNOR-252635 POU5F1 protein Q01860 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004180 23041284 t flangone "Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription." SIGNOR-242103 POU5F1 protein Q01860 UNIPROT BMP4 protein P12644 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-254932 POU5F1 protein Q01860 UNIPROT CDX2 protein Q99626 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-254933 POU5F1 protein Q01860 UNIPROT DKK1 protein O94907 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-254934 POU5F1 protein Q01860 UNIPROT DLX5 protein P56178 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-254935 POU5F1 protein Q01860 UNIPROT DNMT1 protein P26358 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003298 22795133 t lperfetto "Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation" SIGNOR-253158 POU5F1 protein Q01860 UNIPROT DPPA4 protein Q7L190 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-254941 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 POU5F1 protein Q01860 UNIPROT FOXA2 protein Q9Y261 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-253165 POU5F1 protein Q01860 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-253161 POU5F1 protein Q01860 UNIPROT GATA6 protein Q92908 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-253159 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 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 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 POU5F1 protein Q01860 UNIPROT LEFTY2 protein O00292 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-254940 POU5F1 protein Q01860 UNIPROT NANOG protein Q9H9S0 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-254939 POU5F1 protein Q01860 UNIPROT PAX6 protein P26367 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-253163 POU5F1 protein Q01860 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 f flangone "Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes." SIGNOR-242070 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 POU5F1 protein Q01860 UNIPROT SOX17 protein Q9H6I2 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-253167 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 POU5F1 protein Q01860 UNIPROT SOX2 protein P48431 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-254942 POU5F1 protein Q01860 UNIPROT TBX18 protein O95935 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-254945 POU5F1 protein Q01860 UNIPROT TBXT protein O15178 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-254929 POU5F1 protein Q01860 UNIPROT TDGF1 protein P13385 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-254943 POU5F1 protein Q01860 UNIPROT THY1 protein P04216 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-254931 POU5F1 protein Q01860 UNIPROT ZFP42 protein Q96MM3 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-254944 PP121 chemical CHEBI:50915 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252655 PP121 chemical CHEBI:50915 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206292 PP121 chemical CHEBI:50915 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206295 PP121 chemical CHEBI:50915 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206298 PP121 chemical CHEBI:50915 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206301 PP121 chemical CHEBI:50915 ChEBI PRKDC protein P78527 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206304 PP2B proteinfamily SIGNOR-PF18 SIGNOR JUN protein P05412 UNIPROT up-regulates dephosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000938;BTO:0000017 17215518 t lperfetto "Importantly, pp2b not only dephosphorylates the c-jun at ser-243 but also interacts with c-jun in pma-treated cells. Pma stimulates the association of the pp2b/c-jun/sp1 complex with the promoter. These findings indicate the dephosphorylation of c-jun c terminus is required for the c-jun/sp1 interaction" SIGNOR-152006 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser516 GDRSGYSsPGSPGTP 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-164659 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser579 NVKSKIGsTENLKHQ 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-164663 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 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr522 SSPGSPGtPGSRSRT 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-164671 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 PP2Ca_R1A_Ba complex SIGNOR-C132 SIGNOR AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 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-252613 PP2Ca_R1A_Ba 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 PP2Ca_R1A_Ba complex SIGNOR-C132 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-243534 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR AR protein P10275 UNIPROT "down-regulates activity" dephosphorylation Ser83 QQQQQETsPRQQQQQ 9606 27858941 t miannu "DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway" SIGNOR-254759 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR GSK3B protein P49841 UNIPROT "up-regulates activity" dephosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 20080667 t miannu "DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation." SIGNOR-254754 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR MAP3K5 protein Q99683 UNIPROT "up-regulates activity" dephosphorylation Ser966 NEYLRSIsLPVPVLV 9606 27858941 t miannu "DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1" SIGNOR-254756 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR PDPK1 protein O15530 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0001914 21075311 t gcesareni "Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation." SIGNOR-243515 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 PP2 chemical CHEBI:78331 ChEBI SRC protein P12931 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000142 11782488 t gcesareni "Herbimycin a and pp2, specific inhibitors of src family kinases, both inhibited h2o2-mediated c-src and bmk1 activation." SIGNOR-113776 PP2 chemical CHEBI:78331 ChEBI SRC protein P12931 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001760 12351660 t gcesareni "Treatment of l6 cells with pp2 or su6656, specific inhibitors of src family kinases, and transient transfection of dominant-inhibitory src inhibited the formation of myotubes and expression of myogenin." SIGNOR-93549 PPARA protein Q07869 UNIPROT ACSL1 protein P33121 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003204 17150915 f miannu "To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA." SIGNOR-255044 PPARA protein Q07869 UNIPROT AQP3 protein Q92482 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003204 17150915 f miannu "To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA." SIGNOR-255045 PPARA protein Q07869 UNIPROT CPT1A protein P50416 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003204 17150915 f miannu "To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA." SIGNOR-255047 PPARA protein Q07869 UNIPROT LPL protein P06858 UNIPROT "up-regulates activity" 9606 16511610 f Regulation miannu "The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha-dependent stimulation of lipoprotein lipase and of apolipoprotein (apo)A-V and to an inhibition of apoC-III expression, whereas the increase in plasma HDL-cholesterol depends partly on an overexpression of apoA-I and apoA-II. " SIGNOR-251849 PPARA protein Q07869 UNIPROT PLIN2 protein Q99541 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003204 17150915 f miannu "To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA." SIGNOR-255046 PPARA protein Q07869 UNIPROT SLC25A20 protein O43772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000759 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-255049 PPARD protein Q03181 UNIPROT CAT protein P04040 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001949 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-255051 PPARD protein Q03181 UNIPROT HSD11B2 protein P80365 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001975 15591138 f miannu "Peroxisome proliferator-activated receptor delta suppresses 11beta-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells." SIGNOR-255050 PPARD protein Q03181 UNIPROT SLC25A20 protein O43772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000759 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 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 PPARD protein Q03181 UNIPROT TXN protein P10599 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001950 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-255052 PPARGC1A protein Q9UBK2 UNIPROT ALDOB protein P05062 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255055 PPARGC1A protein Q9UBK2 UNIPROT APOA5 protein Q6Q788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255058 PPARGC1A protein Q9UBK2 UNIPROT APOC3 protein P02656 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255059 PPARGC1A protein Q9UBK2 UNIPROT CAV3 protein P56539 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0001538 15199055 f "Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle." SIGNOR-254261 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 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 PPARGC1A protein Q9UBK2 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0001538 15199055 f "Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle." SIGNOR-254262 PPARGC1A protein Q9UBK2 UNIPROT CYCS protein P99999 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-253097 PPARGC1A protein Q9UBK2 UNIPROT CYP7A1 protein P22680 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255057 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 PPARGC1A protein Q9UBK2 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001103 20404331 f lperfetto "capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression" SIGNOR-217966 PPARGC1A protein Q9UBK2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 19491292 f gcesareni "Nuclear pgc-1alpha and foxo3a respond in a reciprocal manner following aicar treatment." SIGNOR-252970 PPARGC1A protein Q9UBK2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001103 20404331 f lperfetto "Capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression" SIGNOR-252969 PPARGC1A protein Q9UBK2 UNIPROT GPX1 protein P07203 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-253396 PPARGC1A protein Q9UBK2 UNIPROT IGF1 protein P05019 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000887 23217713 t miannu "PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy" SIGNOR-256152 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 PPARGC1A protein Q9UBK2 UNIPROT MSTN protein O14793 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 10090 BTO:0000887 23217713 t miannu "PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy" SIGNOR-256151 PPARGC1A protein Q9UBK2 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001103 SIGNOR-C13 20404331 f lperfetto "In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB" SIGNOR-217969 PPARGC1A protein Q9UBK2 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001103 20404331 f lperfetto "In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB" SIGNOR-217978 PPARGC1A protein Q9UBK2 UNIPROT NRF1 protein Q16656 UNIPROT "up-regulates activity" 9606 26971449 f lperfetto "PGC-1 family transcriptional coactivators enhance the activities of the nuclear respiratory factors NRF1 and NRF2, which induce transactivation of many genes encoding mitochondria-specific proteins involved in respiratory chain, mitochondrial DNA transcription/replication and protein import/assembly" SIGNOR-253391 PPARGC1A protein Q9UBK2 UNIPROT OTC protein P00480 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255056 PPARGC1A protein Q9UBK2 UNIPROT PCK2 protein Q16822 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255060 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 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 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 PPARG protein P37231 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002042 16785230 f miannu "these results uncovered a mechanism by which up-regulation of functional ABCG2 expression can be achieved via exogenous or endogenous activation of the lipid-activated transcription factor, PPARgamma." SIGNOR-255054 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 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 f lperfetto "Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor" SIGNOR-228622 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 f lperfetto "Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor" SIGNOR-256229 PPARG protein P37231 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 BTO:0002572;BTO:0000011;BTO:0005065 16431920 f "Dislodging hdac1 from the promoter" lperfetto "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-235358 PPARG protein P37231 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 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-254581 PPARG protein P37231 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20303941 f gcesareni "The results from mammalian one-hybrid experiments showed that functional ppar gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation." SIGNOR-164516 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000975 8943212 f fspada "We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells" SIGNOR-45294 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT up-regulates "transcriptional regulation" 10116 8943212 f fspada "We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells" SIGNOR-210149 PPARG protein P37231 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates relocalization 9606 16431920 t 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-143961 PPARG protein P37231 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" 9606 BTO:0000801 17681149 f lperfetto "Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways" SIGNOR-249558 PPARG protein P37231 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates quantity by repression" 9606 BTO:0000801 17681149 f lperfetto "Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways" SIGNOR-249555 PPARG protein P37231 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" 9606 23128507 t "PAX8-PPARγ fusion protein" miannu "The PAX8-PPARγ rearrangement leads to strong induction of the PPARγ protein and the consequent abrogation of the normal PPARγ function. PPARγ overexpression abolishes the PTEN-inhibitory effect on immunoactive AKT, which in turn induces the PI3K signaling pathway." SIGNOR-251997 PPARG protein P37231 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 17681149 f lperfetto "Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways" SIGNOR-249556 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 PPBP protein P02775 UNIPROT OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" 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-258413 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates dephosphorylation 9606 SIGNOR-C110 10644691 t acerquone "Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin." SIGNOR-74231 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity by destabilization" dephosphorylation 9606 10644691 t "In addition, PP2C expression relieves Axin-mediated repression of LEF-1-dependent transcription. PP2C utilizes Axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that PP2C is a positive regulator of Wnt signal transduction and mediates its effects through the dephosphorylation of Axin." SIGNOR-248488 PPM1A protein P35813 UNIPROT CDK9 protein P50750 UNIPROT "down-regulates activity" dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t "Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-loop|Cdk9 is the catalytic subunit of a general RNA polymerase II elongation factor known as positive transcription elongation factor b (P-TEFb). The kinase function of P-TEFb requires phosphorylation of Thr-186 in the T-loop of Cdk9 to allow substrates to access the catalytic core of the enzyme." SIGNOR-248490 PPM1A protein P35813 UNIPROT CDK9 protein P50750 UNIPROT unknown dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t gcesareni "Phosphatase ppm1a regulates phosphorylation of thr-186 in the cdk9 t-loop" SIGNOR-181340 PPM1A protein P35813 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates dephosphorylation 9606 10644691 t lperfetto "Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin." SIGNOR-227955 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000007 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248486 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 BTO:0000007 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248487 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 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 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-181659 PPM1A protein P35813 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 9707433 t lperfetto "Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay" SIGNOR-59618 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 t "Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop." SIGNOR-248492 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser57 KKDRFYRsILPGDKT 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-248493 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t "Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop." SIGNOR-248491 PPM1A protein P35813 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t "Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2C_ dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity" SIGNOR-252724 PPM1A protein P35813 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t "Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2Cα dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity" SIGNOR-248489 PPM1A protein P35813 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16931515 t lpetrilli "In this study, we have found that ppm1a, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates smad1 both in vitro and in vivo. considering the highly conserved nature of the sxs motif in all r-smads, we reasoned that ppm1a might also recognize the sxs motif in the bmp-activated smad1." SIGNOR-149077 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation 9606 16751101 t lperfetto "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-217628 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 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" dephosphorylation 9606 16751101 t lperfetto "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-232110 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 16751101 t lpetrilli "Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads." SIGNOR-146922 PPM1B protein O75688 UNIPROT CDK9 protein P50750 UNIPROT unknown dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t gcesareni "Phosphatase ppm1a regulates phosphorylation of thr-186 in the cdk9 t-loop" SIGNOR-181396 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000007 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248343 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 BTO:0000007 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248344 PPM1B protein O75688 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-181663 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 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-181667 PPM1B protein O75688 UNIPROT PAX2 protein Q02962 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000007 25631048 t "PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation" SIGNOR-251712 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT "down-regulates activity" dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 16949371 t "Here, we report that deficiency of Wip1 resulted in activation of the ataxia-telangiectasia mutated (ATM) kinase. In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage. Wip1 dephosphorylated ATM Ser1981, a site critical for ATM monomerization and activation" SIGNOR-248325 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates dephosphorylation 9606 19360021 t gcesareni "The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity." SIGNOR-185135 PPM1D protein O15297 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 15870257 t "Here we show that the oncogenic p53-induced serine/threonine phosphatase, PPM1D (or Wip1), dephosphorylates two ATM/ATR targets, Chk1 and p53. PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity." SIGNOR-248317 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 PPM1D protein O15297 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Ser140 GKKATQAsQEY 9606 20118229 t gcesareni "Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-h2ax and suppresses dna double strand break repair. Here, we demonstrate that the wild-type p53-induced phosphatase 1 (wip1) also dephosphorylates gamma-h2ax at serine 139 in vitro and in vivo." SIGNOR-163693 PPM1D protein O15297 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates dephosphorylation Thr183 RQADSEMtGYVVTRW 9606 15870257 t gcesareni "Ppm1d selectively inhibits p38 activation by dephosphorylating thr 180." SIGNOR-135976 PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 11101524 t lperfetto "Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue" SIGNOR-84793 PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 19713933 t lperfetto "In addition, wip1 can dephosphorylate atm, as well as other components of the dna damage checkpoint, such as p38." SIGNOR-187770 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 t "Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase." SIGNOR-248324 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 t gcesareni "Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation." SIGNOR-158328 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 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT "down-regulates activity" dephosphorylation Ser369 TAKTPKDsPGIPPSA 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-248321 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 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT "down-regulates activity" dephosphorylation Thr577 AENGLLMtPCYTANF 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-248323 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t "PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair." SIGNOR-248319 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t lperfetto "PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair." SIGNOR-135980 PPM1E protein Q8WY54 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser57 KKDRFYRsILPGDKT 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-248760 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 PPM1F protein P49593 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates dephosphorylation Thr286 SCMHRQEtVDCLKKF 9606 BTO:0000938 15140879 t gcesareni "Ppm1f specifically dephosphorylates the phospho-thr-286 in autophosphorylated camkii substrate and thus deactivates the camkii in vitro." SIGNOR-124309 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser57 KKDRFYRsILPGDKT 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-248530 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 PPM1F protein P49593 UNIPROT PAK2 protein Q13177 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 t gcesareni "Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity." SIGNOR-162149 PPM1K protein Q8N3J5 UNIPROT BCKDHA protein P12694 UNIPROT "up-regulates activity" dephosphorylation Ser337 TYRIGHHsTSDDSSA 10090 19411760 t "BCKD is inhibited by phosphorylation of its E1alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates" SIGNOR-248758 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 PPP1CA protein P62136 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-248555 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 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-252603 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 t gcesareni "Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival." SIGNOR-163961 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 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-248559 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 20186153 t lperfetto "Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival." SIGNOR-244436 PPP1CA protein P62136 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-248553 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser469 AHEENPEsILDEHVQ 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-248554 PPP1CA protein P62136 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-248551 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser77 YEPEGSAsPTPPYLK 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-248552 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 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 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 PPP1CA protein P62136 UNIPROT CASP2 protein P42575 UNIPROT "up-regulates activity" dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t llicata "nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2." SIGNOR-248564 PPP1CA protein P62136 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" dephosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16888006 t "ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr(125) dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1alpha (PP1alpha) associates with phosphorylated caspase-9." SIGNOR-248565 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 PPP1CA protein P62136 UNIPROT CDC25C protein P30307 UNIPROT up-regulates binding 9606 14592972 t gcesareni "Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus." SIGNOR-118917 PPP1CA protein P62136 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 BTO:0001271 21750978 t miannu "Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-174859 PPP1CA protein P62136 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)" SIGNOR-103152 PPP1CA protein P62136 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t 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-103155 PPP1CA protein P62136 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 t "Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity." SIGNOR-248566 PPP1CA protein P62136 UNIPROT NEK2 protein P51955 UNIPROT down-regulates dephosphorylation 9606 17283141 t gcesareni "Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1" SIGNOR-152949 PPP1CA protein P62136 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-248558 PPP1CA protein P62136 UNIPROT PFN1 protein P07737 UNIPROT up-regulates dephosphorylation Ser138 MASHLRRsQY 9606 22479341 t lperfetto "Knockdown of the catalytic subunit of pp1 (pp1c_), but not pp2a (pp2ac_), increased ps137-pfn1 levels. Pp1c_ binds pfn1 in cultured cells, and this interaction was increased by a phosphomimetic mutation of pfn1 at ser-137 (s137d). Together, these data define pp1 as the principal phosphatase for ser-137 of pfn1" SIGNOR-196816 R547 chemical CID:6918852 PUBCHEM CCND1 protein P24385 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206352 PPP1CA protein P62136 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16630891 t "We have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins" SIGNOR-251649 PPP1CA protein P62136 UNIPROT SP1 protein P08047 UNIPROT "down-regulates activity" dephosphorylation 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-251952 PPP1CA protein P62136 UNIPROT SP3 protein Q02447 UNIPROT "down-regulates activity" dephosphorylation 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-251953 PPP1CA protein P62136 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000599;BTO:0001594 19440292 t "Avicins dephosphorylate Stat3 in a variety of human tumor cell lines, leading to a decrease in the transcriptional activity of Stat3.| However, PD98059, an inhibitor of MEK1/2, had no significant effects on avicin-induced dephosphorylation of Stat3 (Ser 727)" SIGNOR-248563 PPP1CA protein P62136 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-248556 PPP1CA protein P62136 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 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-248557 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 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 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-252604 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 t gcesareni "Akt activation is achieved through a series of phosphorylation steps, the first being akt phosphorylation at thr-450 by jnk kinases. Pp-1 acts as a major phosphatase to dephosphorylate akt at thr-450 and thus modulate its functions." SIGNOR-163965 PPP1CB protein P62140 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 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 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 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser469 AHEENPEsILDEHVQ 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-248570 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 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser77 YEPEGSAsPTPPYLK 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-248568 PPP1CB protein P62140 UNIPROT CASP2 protein P42575 UNIPROT "up-regulates activity" dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t llicata "nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2." SIGNOR-248576 PPP1CB protein P62140 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 BTO:0001271 21750978 t miannu "Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-174862 PPP1CB protein P62140 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 t "Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity." SIGNOR-248577 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 PPP1CB protein P62140 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 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-248573 PPP1CC protein P36873 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-248498 PPP1CC protein P36873 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 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-252605 PPP1CC protein P36873 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 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-248502 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 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser469 AHEENPEsILDEHVQ 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-248497 PPP1CC protein P36873 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-248494 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser77 YEPEGSAsPTPPYLK 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-248495 PPP1CC protein P36873 UNIPROT CASP2 protein P42575 UNIPROT "up-regulates activity" dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t llicata "nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2." SIGNOR-248503 PPP1CC protein P36873 UNIPROT CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Ser175 FGLARAFsLAKNSQP 9606 21533037 t gcesareni "Protein phosphatase-1 activates cdk9 by dephosphorylating ser175" SIGNOR-173450 PPP1CC protein P36873 UNIPROT CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 21533037 t amattioni "Pp1 is an activator of cdk9. Pp1 dephosphorylates cdk9 thr186." SIGNOR-173454 PPP1CC protein P36873 UNIPROT EIF2S1 protein P05198 UNIPROT "up-regulates activity" dephosphorylation 9606 27629041 t miannu "Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning. 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-254119 PPP1CC protein P36873 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 BTO:0001271 21750978 t miannu "Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-174865 PPP1CC protein P36873 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 t "Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity." SIGNOR-248504 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 PPP1CC protein P36873 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates dephosphorylation 9606 14718519 t lpetrilli "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 t?RI." SIGNOR-121277 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 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 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-248500 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 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 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates relocalization 9606 14718519 t lpetrilli "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 t?RI." SIGNOR-120734 PPP1R3A protein Q16821 UNIPROT GYS1 protein P13807 UNIPROT up-regulates dephosphorylation 9606 BTO:0000887;BTO:0001103 8250835 t gcesareni "In skeletal muscle, the activation of glycogen synthase by insulin involves the dephosphorylation of serine residues that are phosphorylated by gsk3 and dephosphorylated by the glycogen-associated form of protein phosphatase-l (pp1g)." SIGNOR-37301 PPP1R8 protein Q12972 UNIPROT EZH2 protein Q15910 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 phosphorylation:Thr416 EANSRCQtPIKMKPN 23241245 t "Recruited NIPP1 enables the net phosphorylation of EZH2 by inhibiting its dephosphorylation by PP1." SIGNOR-255665 PPP1R8 protein Q12972 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" binding -1 1322907 t "We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity." SIGNOR-255657 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 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 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 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-252614 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 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-248626 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 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-248631 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 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-248632 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 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 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 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-248652 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 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Thr305 TDAATMKtFCGTPEY 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-248654 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Thr305 TDAATMKtFCGTPEY 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-248651 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 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "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-248627 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 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-248629 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 11839802 t gcesareni "Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta" SIGNOR-114767 PPP2CA protein P67775 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-248644 PPP2CA protein P67775 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates activity" dephosphorylation Ser87 AAAGPALsPVPPVVH 9606 15225643 t "The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A." SIGNOR-248624 PPP2CA protein P67775 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-248650 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248616 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248615 PPP2CA protein P67775 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" dephosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0001023 16596250 t "Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation." SIGNOR-248617 PPP2CA protein P67775 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 BTO:0002181 15988018 t lperfetto "In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif." SIGNOR-138428 PPP2CA protein P67775 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates dephosphorylation Tyr159 SKPPYTDyVSTRWYR 9606 BTO:0002181 15988018 t lperfetto "In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif." SIGNOR-138432 PPP2CA protein P67775 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates dephosphorylation 9606 19061640 t gcesareni "In the absence of the wt apc protein, phosphorylated beta-catenin is rapidly dephosphorylated by serine/threonine protein phosphatase 2a (pp2a). phosphorylated beta-catenin associated with the wild-type apc protein is recruited to the scf(beta-trcp) complex, ubiquitin conjugated, and degraded." SIGNOR-182637 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr57 RAGETRFtDTRKDEQ 9606 phosphorylation:Thr57 RAGETRFtDTRKDEQ 8386634 t gcesareni "Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2" SIGNOR-38561 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 PPP2CA protein P67775 UNIPROT EIF4E protein P06730 UNIPROT down-regulates dephosphorylation Ser209 DTATKSGsTTKNRFV 9606 20927323 t tpavlidou "A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function." SIGNOR-168306 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 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation 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 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 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates dephosphorylation Thr32 QSRPRSCtWPLQRPE 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-163684 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 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-252973 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Thr32 QSRPRSCtWPLQRPE 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-252974 PPP2CA protein P67775 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates dephosphorylation Ser298 ACSSAPGsGPSSPNN 9606 18045992 t lperfetto "Different signal-regulated serine/threonine kinases phosphorylate class ii histone deacetylases (hdacs) to promote nuclear export, cytosolic accumulation, and activation of gene transcriptionhere we show that hdac4 forms a complex with the pp2a holoenzyme c alpha, a alpha, b/pr55 alpha. In vitro and in vivo binding studies demonstrate that the n-terminus of hdac4 interacts with the catalytic subunit of pp2a. Hdac4 is dephosphorylated by pp2a" SIGNOR-159492 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser155 FPLRKTVsEPNLKLR 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-248646 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 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser358 WPLSRTRsEPLPPSA 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-248648 PPP2CA protein P67775 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.|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-248649 PPP2CA protein P67775 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000007 24726876 t miannu "RACK1 Negatively Regulates the Type I IFN pathway. 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-260944 PPP2CA protein P67775 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni "In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a." SIGNOR-166649 PPP2CA protein P67775 UNIPROT MAP2K2 protein P36507 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni "In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a." SIGNOR-166652 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser520 RLQTICMsGTGMRSV 9606 20448038 t lperfetto "Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation." SIGNOR-165229 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser526 MSGTGMRsVTGTPYW 9606 20448038 t lperfetto "Pp2ac binds to the phosphorylated mekk3 and subsequently dephosphorylate mekk3 at thr-516, ser-520, and ser-526 residues to terminate mekk3-mediated ikkbeta/Nf-kappaB Activation" SIGNOR-165233 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Thr516 GASKRLQtICMSGTG 9606 20448038 t lperfetto "Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation." SIGNOR-165237 PPP2CA protein P67775 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 17079228 t gcesareni "Our results demonstrate that pp6 specifically down-regulates tak1 through dephosphorylation of thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via tak1 signaling pathways." SIGNOR-150369 PPP2CA protein P67775 UNIPROT MAPK15 protein Q8TD08 UNIPROT down-regulates dephosphorylation Thr175 GPEDQAVtEYVATRW 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-142977 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7780739 t "Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts." SIGNOR-248625 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 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni "In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a . p38 mapks activity stimulates the physical association between pp2a and erk complex, leading to mkk1/2 dephosphorylation by pp2a." SIGNOR-166655 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 PPP2CA protein P67775 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)." SIGNOR-103162 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 PPP2CA protein P67775 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" dephosphorylation Thr216 RSSSSEStGTPSNPD 10090 11983168 t "cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells" SIGNOR-248636 PPP2CA protein P67775 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates dephosphorylation 9606 20626350 t lperfetto "In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a." SIGNOR-244941 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 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 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser199 PRPEHTKsVYTRSVI 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-248642 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser57 KKDRFYRsILPGDKT 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-248641 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 PPP2CA protein P67775 UNIPROT PP2Ca_R1A_Ba complex SIGNOR-C132 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-243424 PPP2CA protein P67775 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-243442 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 PPP2CA protein P67775 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-248645 PPP2CA protein P67775 UNIPROT PRKCB protein P05771-2 UNIPROT "down-regulates activity" dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 t "Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform" SIGNOR-248621 PPP2CA protein P67775 UNIPROT PRKCB protein P05771-2 UNIPROT "down-regulates activity" dephosphorylation Thr641 TRHPPVLtPPDQEVI 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-248622 PPP2CA protein P67775 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-248620 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Ser645 LNEKARLsYSDKNLI 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-248638 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Ser664 QSAFAGFsFVNPKFE 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-248639 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 PPP2CA protein P67775 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT down-regulates dephosphorylation Ser387 ETGLYRIsGCDRTVK 9606 18201571 t gcesareni "We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners." SIGNOR-160398 PPP2CA protein P67775 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT down-regulates dephosphorylation Thr588 PEHQLLKtPSSSSLS 9606 18201571 t gcesareni "We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners." SIGNOR-160402 RAD50 protein Q92878 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 17713585 t fstefani "To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50." SIGNOR-157478 PPP2CA protein P67775 UNIPROT RAF1 protein P04049 UNIPROT up-regulates dephosphorylation 9606 BTO:0000671 16239230 t miannu "Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1." SIGNOR-141170 PPP2CA protein P67775 UNIPROT RB1 protein P06400 UNIPROT up-regulates dephosphorylation 9606 10702384 t gcesareni "This dephosphorylation returns prb to its active, growth suppressive state." SIGNOR-75398 PPP2CA protein P67775 UNIPROT RBL1 protein P28749 UNIPROT up-regulates dephosphorylation 9606 15467457 t miannu "Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation." SIGNOR-129749 PPP2CA protein P67775 UNIPROT RBL2 protein Q08999 UNIPROT up-regulates dephosphorylation 9606 15467457 t miannu "Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation." SIGNOR-129752 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 PPP2CA protein P67775 UNIPROT RPS3 protein P23396 UNIPROT down-regulates dephosphorylation Ser6 sKKRKFVA 9606 15950189 t lperfetto "We identified that pp2a interacts with wild-type rps3, but not with mutants (s6a/t221a) (fig. 8), and that it associates with the n-terminal region of rps3 (fig. 2). From our results presented here, we conclude that pp2a is involved in the dephosphorylation of phosphorylated rps3 by pkc, and that serine 6 on the n-terminal region of rps3 appears to mediate the pp2a recruitment." SIGNOR-137963 PPP2CA protein P67775 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates dephosphorylation 9606 2826472 t gcesareni "Protein phosphatase 2a inactivates the mitogen-stimulated s6 kinase from swiss mouse 3t3 cells" SIGNOR-23575 PPP2CA protein P67775 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 19951945 t gcesareni "Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a." SIGNOR-161919 PPP2CA protein P67775 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 20704570 t gcesareni "Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a." SIGNOR-167480 PPP2CA protein P67775 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" dephosphorylation Ser129 NEAYEMPsEEGYQDY 9606 21562258 t "α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129" SIGNOR-248635 PPP2CA protein P67775 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" dephosphorylation Ser59 GGQESQPsPLALLAA 9606 BTO:0000599 24382322 t gcesareni "These results indicate that the signals from TCDD or OP caused PP2A-mediated dephosphorylation of Sp1 at Ser-59 and induced CYP1A1 transcription" SIGNOR-248223 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 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 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 PPP2CA protein P67775 UNIPROT TFCP2 protein Q12800 UNIPROT up-regulates dephosphorylation Ser291 TYVNNSPsPGFNSSH 9606 20682773 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. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a" SIGNOR-167385 PPP2CA protein P67775 UNIPROT TFCP2 protein Q12800 UNIPROT up-regulates dephosphorylation Ser309 SLGEGNGsPNHQPEP 9606 20682773 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. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a" SIGNOR-167389 PPP2CA protein P67775 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates dephosphorylation Ser23 PAPIRRRsSNYRAYA 9606 BTO:0000887 15769444 t lperfetto "The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2." SIGNOR-134597 PPP2CA protein P67775 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates dephosphorylation Ser24 APIRRRSsNYRAYAT 9606 BTO:0000887 15769444 t lperfetto "The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2." SIGNOR-134601 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 t "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-248619 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 17245430 t "A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis" SIGNOR-248618 PPP2CA protein P67775 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates activity" dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 BTO:0002572 17188031 t "We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity." SIGNOR-248640 PPP2CB protein P62714 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation 9606 8650155 t gcesareni "These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity" SIGNOR-252636 PPP2CB protein P62714 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 8650155 t gcesareni "These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity" SIGNOR-42123 PPP2CB protein P62714 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-248610 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser474 HFPQFSYsASGRE 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-248609 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Thr305 TDAATMKtFCGTPEY 9606 18160256 t llicata "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-248611 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Thr309 TMKTFCGtPEYLAPE 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-248612 PPP2CB protein P62714 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-248614 PPP2CB protein P62714 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 8650155 t gcesareni "These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity" SIGNOR-42050 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 PPP2CB protein P62714 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates activity" dephosphorylation Ser87 AAAGPALsPVPPVVH 9606 15225643 t "The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A." SIGNOR-248589 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 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248579 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248578 PPP2CB protein P62714 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" dephosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0001023 16596250 t "Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation." SIGNOR-248582 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 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser155 FPLRKTVsEPNLKLR 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-248603 PPP2CB protein P62714 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." SIGNOR-248604 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser358 WPLSRTRsEPLPPSA 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-248605 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 PPP2CB protein P62714 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000176 19607706 t "Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac)" SIGNOR-248581 PPP2CB protein P62714 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 BTO:0000176 19607706 t "Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac)" SIGNOR-248580 PPP2CB protein P62714 UNIPROT KRT8 protein P05787 UNIPROT unknown dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000182 16554440 t "K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts." SIGNOR-248588 PPP2CB protein P62714 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7780739 t "Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts." SIGNOR-248590 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" dephosphorylation Thr216 RSSSSEStGTPSNPD 10090 11983168 t "cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells" SIGNOR-248593 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Thr216 RSSSSEStGTPSNPD 9606 11983168 t fstefani "Cyclin g also binds in vivo and in vitro to mdm2 and markedly stimulates the ability of pp2a to dephosphorylate mdm2 at t216. Our data imply that the function of cyclin g is to serve as a negative regulator of p53 by activating mdm2 through dephosphorylation." SIGNOR-86736 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 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser199 PRPEHTKsVYTRSVI 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-248599 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser57 KKDRFYRsILPGDKT 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-248598 PPP2CB protein P62714 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-248600 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 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT "down-regulates activity" dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 t "Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform" SIGNOR-248586 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT "down-regulates activity" dephosphorylation Thr641 TRHPPVLtPPDQEVI 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-248587 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 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Ser645 LNEKARLsYSDKNLI 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-248595 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 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 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser183 RARKMEDsKEKNGKK 9606 17540176 t miannu "Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function" SIGNOR-155349 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser194 NGKKKRKsLAKRIRE 9606 17540176 t miannu "Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function" SIGNOR-155353 PPP2CB protein P62714 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" dephosphorylation Ser129 NEAYEMPsEEGYQDY 9606 21562258 t "α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129" SIGNOR-248592 PPP2CB protein P62714 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 t "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 PPP2CB protein P62714 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 17245430 t "A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis" SIGNOR-248583 PPP2CB protein P62714 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates activity" dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 BTO:0002572 17188031 t "We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity." SIGNOR-248597 PPP2R1A protein P30153 UNIPROT MAPT protein P10636 UNIPROT down-regulates dephosphorylation 9606 BTO:0000938;BTO:0000195 15525651 t gcesareni "Galpha12 directly interacts with pp2a: evidence for galpha12-stimulated pp2a phosphatase activity and dephosphorylation of microtubule-associated protein, tau." SIGNOR-130136 PPP2R1A protein P30153 UNIPROT PP2Ca_R1A_Ba complex SIGNOR-C132 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-243427 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 PPP2R1A protein P30153 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-243436 PPP2R1A protein P30153 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates binding 9606 16039140 t miannu "Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme" SIGNOR-138883 PPP2R1A protein P30153 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates binding 9606 16039140 t miannu "Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme" SIGNOR-138886 PPP2R1A protein P30153 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates binding 9606 BTO:0000567 16580887 t miannu "Identification of subunits of protein phosphatase 2a (pp2a) as sgo1 binding proteins / pp2a is required for proper chromosome segregation and centromeric localization of sgo1 in hela cells" SIGNOR-145486 PPP2R1B protein P30154 UNIPROT PPP2CA protein P67775 UNIPROT "up-regulates activity" binding 9606 19114990 t lperfetto "Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity" SIGNOR-217872 PPP2R2A protein P63151 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" binding 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 |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B)." SIGNOR-252637 PPP2R2A protein P63151 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" binding 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 |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B)." SIGNOR-243526 PPP2R2A protein P63151 UNIPROT PP2Ca_R1A_Ba complex SIGNOR-C132 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-243430 PPP2R2A protein P63151 UNIPROT PPP2CA protein P67775 UNIPROT "down-regulates activity" binding 9606 19114990 t lperfetto "Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity" SIGNOR-217875 PPP2R2A protein P63151 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" binding 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-243417 PPP2R2A protein P63151 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 9774674 t lperfetto "In this report, we show that another WD-40 repeat protein, the B_ subunit of protein phosphatase 2A, associates with the cytoplasmic domain of type I TGF-_ receptors. [...] We therefore conclude that B_ specifically and directly associates with the type I receptor cytoplasmic domain in vitro." SIGNOR-227517 PPP2R2B protein Q00005 UNIPROT PDPK1 protein O15530 UNIPROT "down-regulates activity" binding 9606 BTO:0001914 21075311 t gcesareni "Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation." SIGNOR-243511 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 PPP2R2C protein Q9Y2T4 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" binding 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-247966 PPP2R5A protein Q15172 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 9774674 t gcesareni "In this report, we show that another wd-40 repeat protein, the balpha subunit of protein phosphatase 2a, associates with the cytoplasmic domain of type i tgf-beta receptors..[..] Furthermore, balpha enhances the growth inhibition activity of tgf-beta in a receptor-dependent manner" SIGNOR-60743 PPP2R5B protein Q15173 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 t gcesareni "Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt." SIGNOR-252615 PPP2R5B protein Q15173 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 t gcesareni "Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt." SIGNOR-144808 PPP2R5B protein Q15173 UNIPROT BCL2 protein P10415 UNIPROT down-regulates dephosphorylation Ser70 RDPVARTsPLQTPAA 9606 18845789 t gcesareni "Pp2a directly interacts with the bh4 domain of bcl2 as a docking site to potentially bridge pp2a to bcl2's flexible loop domain containing the target serine 70 phosphorylation site." SIGNOR-181559 PPP2R5B protein Q15173 UNIPROT CASP3 protein P42574 UNIPROT up-regulates dephosphorylation Ser150 FRGDRCRsLTGKPKL 9606 BTO:0000130 15569672 t gcesareni "Dephosphorylation of caspase-3 at ser150 site by pp2a increased caspase-3 activity,which was essential to trigger apoptosis in neutrophils." SIGNOR-131435 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser36 AQQVSSLsESEESQD 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 atf1" SIGNOR-167560 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 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 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 PPP2R5C protein Q13362 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 16456541 t gcesareni "B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk" SIGNOR-144325 PPP2R5C protein Q13362 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates binding 9606 16456541 t gcesareni "B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk" SIGNOR-144328 PPP2R5C protein Q13362 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates binding 9606 20444422 t gcesareni "The human homolog of pp2a-b', ppp2r5c, also counteracts s6k1 phosphorylation, indicating a conserved mechanism in mammals" SIGNOR-165224 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 PPP2R5D protein Q14738 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" binding 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-243420 PPP3CA protein Q08209 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-248694 PPP3CA protein Q08209 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-248695 PPP3CA protein Q08209 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-255291 PPP3CA protein Q08209 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-248677 PPP3CA protein Q08209 UNIPROT FLNA protein P21333 UNIPROT down-regulates dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t gcesareni "We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells" SIGNOR-143979 PPP3CA protein Q08209 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18177723 f 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-251733 PPP3CA protein Q08209 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-84035 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT "up-regulates activity" dephosphorylation 9606 23015147 t "Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT)." SIGNOR-253329 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 14722106 t gcesareni "Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes" SIGNOR-84038 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 15276472 t gcesareni "Once activated, calcineurin directly dephosphorylates members of the nuclear factor of activated t-cells (nfat) transcription factor family in the cytoplasm, promoting their translocation into the nucleus." SIGNOR-127248 PPP3CA protein Q08209 UNIPROT 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-248678 PPP3CA protein Q08209 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-248679 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser172 LCLSPASsGSSASFI 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-248680 PPP3CA protein Q08209 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-248681 PPP3CA protein Q08209 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-248682 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser177 ASSGSSAsFISDTFS 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-248683 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 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 PPP3CA protein Q08209 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-248686 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser221 PRTSPIMsPRTSLAE 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-248687 PPP3CA protein Q08209 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-248688 PPP3CA protein Q08209 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-248689 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 PPP3CA protein Q08209 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-248691 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser326 PPKMWKTsPDPSPVS 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-248692 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 PPP3CA protein Q08209 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-84041 PPP3CA protein Q08209 UNIPROT NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-176376 PPP3CA protein Q08209 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-176379 PPP3CA protein Q08209 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-248693 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 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 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 PPP3CB protein P16298 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-248363 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 PPP3CB protein P16298 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18177723 f 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-251734 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Ser198 IRTHLSQsPRVPSKC 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-248380 PPP3CB protein P16298 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-248382 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Thr290 NKLKPPGtPPPSSRK 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-248381 PPP3CB protein P16298 UNIPROT NFATC1 protein O95644 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-84047 PPP3CB protein P16298 UNIPROT 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-248364 PPP3CB protein P16298 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-248365 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser172 LCLSPASsGSSASFI 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-248366 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 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 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser177 ASSGSSAsFISDTFS 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-248369 PPP3CB protein P16298 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-248370 PPP3CB protein P16298 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-248371 PPP3CB protein P16298 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-248372 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser221 PRTSPIMsPRTSLAE 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-248373 PPP3CB protein P16298 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-248374 PPP3CB protein P16298 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-248375 PPP3CB protein P16298 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-248376 PPP3CB protein P16298 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-248377 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser326 PPKMWKTsPDPSPVS 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-248378 PPP3CB protein P16298 UNIPROT 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-233438 PPP3CB protein P16298 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-248379 PPP3CB protein P16298 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" dephosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 26000950 t "Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation." SIGNOR-255307 PPP3CB protein P16298 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" dephosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000007 26000950 t "Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation." SIGNOR-255306 PPP3CC protein P48454 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-248528 PPP3CC protein P48454 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-248529 PPP3CC protein P48454 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-248506 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 PPP3CC protein P48454 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-248507 PPP3CC protein P48454 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18177723 f 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-251735 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Ser198 IRTHLSQsPRVPSKC 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-248525 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 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT "up-regulates activity" dephosphorylation Thr290 NKLKPPGtPPPSSRK 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-248526 PPP3CC protein P48454 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-83740 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 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 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-84053 PPP3CC protein P48454 UNIPROT 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-248509 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 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser172 LCLSPASsGSSASFI 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-248511 PPP3CC protein P48454 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-248512 PPP3CC protein P48454 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-248513 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser177 ASSGSSAsFISDTFS 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-248514 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 PPP3CC protein P48454 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-248516 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 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 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 PPP3CC protein P48454 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-248521 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 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser326 PPKMWKTsPDPSPVS 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-248523 PPP3CC protein P48454 UNIPROT 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-233441 PPP3CC protein P48454 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-84056 PPP3CC protein P48454 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-248524 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 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 16495336 t lperfetto "Herein, we demonstrate 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. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit." SIGNOR-144779 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 24265311 t lperfetto "Herein, we demonstrate 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. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit." SIGNOR-203281 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 PPP4C protein P60510 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "down-regulates activity" dephosphorylation Thr219 ASLSLPAtPVGKGTE 9606 18347064 t "Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation|PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome.|We next examined the ability of PP4c to dephosphorylate a Cdk1 phosphorylation site, phospho-T219" SIGNOR-248550 PPP4C protein P60510 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" dephosphorylation Thr435 PTQAGEGtLSEALLQ 9606 BTO:0002210 15073167 t "Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation" SIGNOR-248549 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 PPP5C protein P53041 UNIPROT CILK1 protein Q9UPZ9 UNIPROT "down-regulates activity" dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 16954377 t llicata "MAK and MRK require dual phosphorylation in a TDY motif catalyzed by an unidentified human threonine kinase and tyrosine autophosphorylation.| Protein phosphatase 5 (PP5) interacts with MRK in a complex and dephosphorylates MRK at T157 in vitro and in situ." SIGNOR-248541 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000567 11689443 t lperfetto "Pp5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ask1 and thereby inactivated ask1 activity in vitro and in vivo." SIGNOR-111301 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" dephosphorylation Thr842 CTETFTGtLQYMAPE 10090 11689443 t llicata "After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845." SIGNOR-248540 PPP5C protein P53041 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" dephosphorylation Ser211 PGKETNEsPWRSDLL 9606 BTO:0000093 19586900 t "Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription." SIGNOR-248538 PPP5C protein P53041 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" dephosphorylation Ser338 RPRGQRDsSYYWEIE -1 16892053 t "Protein phosphatase 5 (PP5) was identified as an inactivator that associates with Raf-1 on growth factor stimulation and selectively dephosphorylates an essential activating site, Ser 338. The PP5-mediated dephosphorylation of Ser 338 inhibited Raf-1 activity and downstream signalling to MEK" SIGNOR-248537 PPP6C protein O00743 UNIPROT MAP3K7 protein O43318 UNIPROT "down-regulates activity" dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 BTO:0000007 17079228 t "Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway|From proteomic analysis of TAK1-binding proteins, we identified protein phosphatase 6 (PP6), a type-2A phosphatase, and demonstrated that PP6 associated with and inactivated TAK1 by dephosphorylation of Thr-187." SIGNOR-248292 PPP6C protein O00743 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 17079228 t gcesareni "Our results demonstrate that pp6 specifically down-regulates tak1 through dephosphorylation of thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via tak1 signaling pathways." SIGNOR-150408 PPY protein P01298 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 7592911 t gcesareni "Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid." SIGNOR-24230 practolol chemical CHEBI:258351 ChEBI ADRB1 protein P08588 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 10079020 t Luana "In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue" SIGNOR-258336 pralatrexate chemical CHEBI:71223 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23409799 t miannu "Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase." SIGNOR-259353 pralatrexate chemical CHEBI:71223 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002207 19221750 t Luana "This study reports a head-to-head comparison of in vitro and in vivo activities of three antifolates: pralatrexate, methotrexate, and pemetrexed. A clear difference was demonstrated among the antifolates in regulation of enzymatic activity. Pralatrexate demonstrated a unique activity profile relative to methotrexate and pemetrexed" SIGNOR-257815 pralatrexate chemical CHEBI:71223 ChEBI TYMS protein P04818 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23409799 t miannu "Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase." SIGNOR-259352 pralidoxime chemical CHEBI:8354 ChEBI ACHE protein P22303 UNIPROT "up-regulates activity" "chemical activation" -1 21215642 t Luana "These compounds were synthesized, evaluated in vitro on human AChE (hAChE) inhibited by tabun, paraoxon, methylparaoxon and DFP and then compared to commercial hAChE reactivators (pralidoxime, HI-6, trimedoxime, obidoxime, methoxime) or previously prepared compounds (K027, K203). Three of these novel compounds showed a promising ability to reactivate hAChE comparable or better than the used standards. " SIGNOR-257889 Pravadoline chemical CID:56463 PUBCHEM PTGS2 protein P35354 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206322 pravastatin chemical CHEBI:63618 ChEBI HMGCR protein P04035 UNIPROT "down-regulates activity" "chemical inhibition" -1 1597859 t miannu "A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2)." SIGNOR-258350 prazosin chemical CHEBI:8364 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-258473 prazosin chemical CHEBI:8364 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-258469 prazosin chemical CHEBI:8364 ChEBI ADRA1D protein P25100 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-258468 PRC2 complex SIGNOR-C130 SIGNOR CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 22469984 t irozzo "The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a" SIGNOR-256122 PRC2 complex SIGNOR-C130 SIGNOR CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001271 22469984 t irozzo "The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a" SIGNOR-259360 PRC2 complex SIGNOR-C130 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 21248841 f lperfetto "The importance of polycomb function for stem cells is best illustrated by various PcG-knockout mice. Deletion of any of the PRC2 members results in embryonic lethality. In vitro studies with ES cells demonstrated that cells lacking EED or Suz12 could not maintain their pluripotency and were prone to differentiation." SIGNOR-241910 PRC2 complex SIGNOR-C130 SIGNOR H3C1 protein P68431 UNIPROT "up-regulates activity" methylation Lys27 K-->R 9606 24987060 t miannu "The presence of trimethylation of H3K27 (H3K27me3) at promoter regions is associated with gene repression. This modification is generated by the Polycomb repressive complex 2 (PRC2), composed of the SET domain-containing histone methyltransferase (HMT) EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1, and core accessory proteins (EED, SUZ12, and RbAp48) (Fig. 1A)." SIGNOR-260449 PRC2 complex SIGNOR-C130 SIGNOR HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000782;BTO:0003287 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 PRC2 complex SIGNOR-C130 SIGNOR PAX7 protein P23759 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 20887952 t "The results presented above demonstrate a signal-dependent interaction between p38a, YY1, and EZH2 on the chromatin of the Pax7 regulatory elements that coincides with p38-mediated repression of Pax7 at early stages of myoblast differentiation." SIGNOR-253598 PRCC protein Q92733 UNIPROT MAD2L2 protein Q9UI95 UNIPROT up-regulates relocalization 9606 15218244 t miannu "We found that the human papillary renal cell carcinoma-associated proteinprccinteracts with the cell cycle control proteinmad2b, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function." SIGNOR-126516 PRCP protein P42785 UNIPROT POMC protein P01189 UNIPROT "down-regulates activity" 10090 20694162 f miannu "Prolylcarboxypeptidase (PRCP) was found to be responsible for the control of food intake and energy expenditure at a central level. The molecular mechanisms underlying the suppression of food intake in PRCP-deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of α-MSH" SIGNOR-252372 PRDM14 protein Q9GZV8 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 20953172 f miannu "We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer." SIGNOR-255067 PRDM16 protein Q9HAZ2 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 f fspada "Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells." SIGNOR-180295 PRDM16 protein Q9HAZ2 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 t "_activating its transcriptional function" fspada "Prdm16 stimulates brown adipogenesis by binding to ppar-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function" SIGNOR-180298 PRDM16 protein Q9HAZ2 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 f fspada "Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells." SIGNOR-180301 PRDM16 protein Q9HAZ2 UNIPROT SKI protein P12755 UNIPROT up-regulates binding 9606 19049980 t miannu "Biochemical analysis demonstrated that mel1 interacts with ski and inhibits tgf-_ signaling by stabilizing the inactive smad3-ski complex on the promoter of tgf-_ target genes." SIGNOR-182529 PRDM1 protein O75626 UNIPROT CIITA protein P33076 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 12626569 f miannu "The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b" SIGNOR-99116 PRDM1 protein O75626 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-253926 PRDM1 protein O75626 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253828 PRDM1 protein O75626 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 12626569 f miannu "The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b" SIGNOR-99119 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 8335191 t "Crohn's Disease" gcesareni SIGNOR-251701 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 8342904 t ashma gcesareni SIGNOR-251698 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 3930339 t "ulcerative colitis" gcesareni SIGNOR-251702 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 4188963 t dermatitis gcesareni SIGNOR-251705 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 4344326 t "Bell's palsy" gcesareni SIGNOR-251704 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 8143061 t asthma gcesareni SIGNOR-251706 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 9753485 t "Crohn's Disease" gcesareni SIGNOR-251703 PREX1 protein Q8TCU6 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-260569 PREX2 protein Q70Z35 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-260572 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 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 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 PREX2 protein Q70Z35 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-260570 PRIM1 protein P49642 UNIPROT "DNA primase complex" complex SIGNOR-C261 SIGNOR "form complex" binding -1 24043831 t lperfetto "Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit." SIGNOR-261339 PRIM2 protein P49643 UNIPROT "DNA primase complex" complex SIGNOR-C261 SIGNOR "form complex" binding -1 24043831 t lperfetto "Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit." SIGNOR-261340 PRKAA1 protein Q13131 UNIPROT ACACA protein Q13085 UNIPROT "down-regulates activity" phosphorylation Ser1201 IPTLNRMsFSSNLNH 10116 BTO:0000759 7907095 t miannu "We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase" SIGNOR-250400 PRKAA1 protein Q13131 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "form complex" binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 t lperfetto "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-139158 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 PRKAA1 protein Q13131 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates activity" phosphorylation T198 PGLRRRQT 10090 BTO:0005300 30033086 t Luana "P27Kip1-Mediated Cell Survival Is Dependent on AMPK-Specific Thr198 Phosphorylation" SIGNOR-259859 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation S737 EPLERRLSLVPDSEQ 9606 19095655 t Luana " We demonstrate that CFTR normally remains closed at baseline, but nevertheless, opens after inhibition of AMPK. AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as “inhibitory” PKA sites. Replacement of both serines by alanines (i) reduced phosphorylation of the R domain, with Ser768 having dramatically greater impact, (ii) produced CFTR channels that were partially open in the absence of any stimulation, (iii) significantly augmented their activation by IBMX/forskolin, and (iv) eliminated CFTR inhibition post AMPK activation." SIGNOR-259858 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation S768 LQARRRQSVLNLMTH 9606 19095655 t Luana " We demonstrate that CFTR normally remains closed at baseline, but nevertheless, opens after inhibition of AMPK. AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as “inhibitory” PKA sites. Replacement of both serines by alanines (i) reduced phosphorylation of the R domain, with Ser768 having dramatically greater impact, (ii) produced CFTR channels that were partially open in the absence of any stimulation, (iii) significantly augmented their activation by IBMX/forskolin, and (iv) eliminated CFTR inhibition post AMPK activation." SIGNOR-259867 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 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 PRKAA1 protein Q13131 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser170 PSALNRTsSDSALHT 9606 SIGNOR-C15 21892142 t gcesareni "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-176426 PRKAA1 protein Q13131 UNIPROT CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 SIGNOR-C15 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 t gcesareni "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-176472 PRKAA1 protein Q13131 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser158 REGTRVQsVEQIREV 9606 SIGNOR-C15 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-200250 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 PRKAA1 protein Q13131 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation S30 EDLQEVLSSDENGGT 10090 BTO:0003292 27650555 t Luana "Here, we report that phosphorylation of CHOP at Ser30 by AMPKα1 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo." SIGNOR-259864 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL -1 14709557 t miannu " AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase" SIGNOR-250402 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 t miannu " AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. phosphorylation at Ser-78 may also decrease the activity of eEF2 kinase" SIGNOR-250314 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser398 DSLPSSPsSATPHSQ -1 14709557 t miannu "Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity." SIGNOR-250157 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 SIGNOR-C15 22669845 t gcesareni "In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation" SIGNOR-197734 PRKAA1 protein Q13131 UNIPROT EP300 protein Q09472 UNIPROT down-regulates phosphorylation Ser89 SELLRSGsSPNLNMG 9606 BTO:0000801;BTO:0001271;BTO:0000876 21940946 t gcesareni "The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity." SIGNOR-176637 PRKAA1 protein Q13131 UNIPROT FOXO1 protein Q12778 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." SIGNOR-157941 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "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-219247 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation BTO:0000759 22848740 t "When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form." SIGNOR-255755 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249667 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "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-249677 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser555 RALSNSVsNMGLSES 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249681 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser588 QTLSDSLsGSSLYST 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249684 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249687 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-238804 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 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 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252975 PRKAA1 protein Q13131 UNIPROT 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-252976 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser555 RALSNSVsNMGLSES 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252977 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser588 QTLSDSLsGSSLYST 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252978 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252979 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252980 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-252981 PRKAA1 protein Q13131 UNIPROT G6PC protein P35575 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21892142 f gcesareni "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-176475 PRKAA1 protein Q13131 UNIPROT GAPDH protein P04406 UNIPROT "up-regulates activity" phosphorylation S122 GAKRVIISAPSADAP 10090 BTO:0002572 26626483 t Luana " Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated. " SIGNOR-259857 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 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 PRKAA1 protein Q13131 UNIPROT GFPT1 protein Q06210 UNIPROT up-regulates phosphorylation Ser261 CNLSRVDsTTCLFPV 9606 17941647 t gcesareni "Amp-activated protein kinase and calcium/calmodulin-dependent kinase ii were identified to phosphorylate specifically ser243 in vitro. Phosphorylation by these two kinases results in an increase of enzymatic activity by 1.4-fold. These findings suggest for the first time that hgfat1 may be regulated by kinases other than pka." SIGNOR-158490 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation S102 LQTVIRTSPSSLVAF 9606 BTO:0002181 26190112 t Luana "AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-259861 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation S408 GPLPRAPSISTVEPK 9606 BTO:0002181 26190112 t Luana "AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-259860 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation S408 GPLPRAPSISTVEPK 9606 BTO:0004328 26190112 t Luana "AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-259863 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation T1074 QRGSSGHTPPPSGPP 9606 BTO:0002181 26190112 t Luana "AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-259862 PRKAA1 protein Q13131 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887 SIGNOR-C15 21565617 t gcesareni "We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases." SIGNOR-173689 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 SIGNOR-C15 21892142 t gcesareni "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-176479 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 SIGNOR-C15 21892142 t gcesareni "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-176483 PRKAA1 protein Q13131 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 SIGNOR-C15 21892142 t gcesareni "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-176487 PRKAA1 protein Q13131 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 SIGNOR-C15 21892142 t gcesareni "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-176491 PRKAA1 protein Q13131 UNIPROT HNF4A protein P41235 UNIPROT "down-regulates activity" phosphorylation Ser303 DPDAKGLsDPGKIKR 9606 BTO:0001131 SIGNOR-C15 12740371 t lperfetto "Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect" SIGNOR-101101 PRKAA1 protein Q13131 UNIPROT KLC2 protein Q9H0B6 UNIPROT up-regulates phosphorylation Ser582 PRMKRASsLNFLNKS 9606 SIGNOR-C15 21725060 t gcesareni "Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582" SIGNOR-174681 PRKAA1 protein Q13131 UNIPROT KPNA2 protein P52292 UNIPROT up-regulates phosphorylation Ser105 QAARKLLsREKQPPI 9606 SIGNOR-C15 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-128629 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 PRKAA1 protein Q13131 UNIPROT 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-245953 PRKAA1 protein Q13131 UNIPROT 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-249656 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 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 PRKAA1 protein Q13131 UNIPROT NAMPT protein P43490 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000165 18477450 f gcesareni "Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt" SIGNOR-238598 PRKAA1 protein Q13131 UNIPROT NOS2 protein P35228 UNIPROT down-regulates 9606 BTO:0000801 BTO:0000887 14985344 f gcesareni "Ampk by insulin-sensitizing drugs markedly inactivates in- ducible nitric-oxide synthase (inos)." SIGNOR-120827 PRKAA1 protein Q13131 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-251619 PRKAA1 protein Q13131 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 SIGNOR-C15 18303014 t gcesareni "The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner" SIGNOR-160838 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 PRKAA1 protein Q13131 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates phosphorylation Ser351 HVISRDQsTPIIEVE 9606 SIGNOR-C15 21478464 t gcesareni "Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression" SIGNOR-173118 PRKAA1 protein Q13131 UNIPROT NRF1 protein Q16656 UNIPROT up-regulates 9606 BTO:0000887 15509864 f gcesareni "In muscle, it causes increased dna binding by the transcription factors nrf1 (bergeron et al., 2001) and mef2 (zheng et al., 2001), which may be involved in regulation of mitochondrial genes and glut4, respectively." SIGNOR-130076 PRKAA1 protein Q13131 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 PRKAA1 protein Q13131 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 SIGNOR-C15 11069105 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-84061 PRKAA1 protein Q13131 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSSN 10116 11069105 t "AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. AMPK-mediated PFK-2 activation is likely to be involved in the stimulation of heart glycolysis during ischaemia." SIGNOR-260012 PRKAA1 protein Q13131 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 SIGNOR-C15 12065600 t llicata "Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro." SIGNOR-89760 PRKAA1 protein Q13131 UNIPROT PIAS1 protein O75925 UNIPROT "up-regulates activity" phosphorylation S510 SPVSRTPSLPAVDTS 9606 BTO:0004577 27256105 t Luana "Mechanically, we found that AMPKα1 directly phosphorylated protein inhibitor of activated STAT-1 (PIAS1), the SUMO E3-ligase of Runx2, at serine 510, to promote its SUMO E3-ligase activity. Finally, mutation of protein inhibitor of activated STAT-1 at serine 510 suppressed m" SIGNOR-259866 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 PRKAA1 protein Q13131 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser385 RRRKKRTsIETNIRV 9606 9368058 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-53254 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Ser539 SLFNVSPsCSSFNSP 10090 BTO:0001103 SIGNOR-C15 17609368 t lperfetto "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-228654 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 17609368 t lperfetto "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." SIGNOR-156780 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 PRKAA1 protein Q13131 UNIPROT PRKAB1 protein Q9Y478 UNIPROT up-regulates phosphorylation Ser108 SKLPLTRsHNNFVAI 9606 SIGNOR-C15 SIGNOR-C15 17728241 t gcesareni "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 amp" SIGNOR-157553 PRKAA1 protein Q13131 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser621 PKINRSAsEPSLHRA 9606 SIGNOR-C15 9091312 t gcesareni "Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259" SIGNOR-47148 PRKAA1 protein Q13131 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 BTO:0000938 BTO:0000142 SIGNOR-C15 19217427 t gcesareni "Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site." SIGNOR-184052 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 SIGNOR-C15 SIGNOR-C3 21460634 t lperfetto "Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2." SIGNOR-173035 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT "down-regulates activity" phosphorylation Ser792 DKMRRASsYSSLNSL 10090 BTO:0002572 SIGNOR-C15 SIGNOR-C3 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-161375 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 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 PRKAA1 protein Q13131 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 19262508 f gcesareni "The acute actions of ampk on lipid oxidation alter the balance between cellular nad+ and nadh, which acts as a messenger to activate sirt1" SIGNOR-184473 PRKAA1 protein Q13131 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni "Several in vivo studies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochrome c, uncoupling protein 3 (ucp-3)] and proteins involved in glucose uptake (glut4)are increased at the transcriptional level in skeletal muscle." SIGNOR-156786 RBPJ protein Q06330 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates binding 10090 BTO:0000165 17158101 t gcesareni "Notch induction of mkp-1 depends on an rbp-j-dependent mechanism." SIGNOR-236851 PRKAA1 protein Q13131 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 19923321 t lperfetto "Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively." SIGNOR-161779 PRKAA1 protein Q13131 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser92 VAELTSLsDEDSGKG 9606 19923321 t lperfetto "Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively." SIGNOR-161783 PRKAA1 protein Q13131 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates activity" phosphorylation 9606 SIGNOR-C15 21892142 t lperfetto "Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation" SIGNOR-176497 PRKAA1 protein Q13131 UNIPROT SYN1 protein P17600 UNIPROT down-regulates 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 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 PRKAA1 protein Q13131 UNIPROT 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-256134 PRKAA1 protein Q13131 UNIPROT TGFB1 protein P01137 UNIPROT down-regulates 9606 BTO:0000887 23324179 f gcesareni "Amp-activated protein kinase inhibits tgf-__-, angiotensin ii-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition." SIGNOR-200404 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 PRKAA1 protein Q13131 UNIPROT UCP3 protein P55916 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-156831 PRKAA1 protein Q13131 UNIPROT ULK1 protein O75385 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 SIGNOR-C15 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-173038 PRKAA1 protein Q13131 UNIPROT ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 SIGNOR-C15 17097062 t gcesareni "Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp." SIGNOR-150590 PRKAA2 protein P54646 UNIPROT ACACA protein Q13085 UNIPROT down-regulates phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 12015362 t gcesareni "Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed." SIGNOR-87583 PRKAA2 protein P54646 UNIPROT ACACB protein O00763 UNIPROT "down-regulates activity" phosphorylation Ser222 PTMRPSMsGLHLVKR 9606 BTO:0000887 9148944 t miannu "The results suggest that the decrease in ACC activity during muscle contraction is caused by an increase in its phosphorylation, most probably due, at least in part, to activation of the alpha2 isoform of AMPK." SIGNOR-250318 PRKAA2 protein P54646 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-139161 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 SIGNOR-C15 19933840 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-161810 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 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 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-195102 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 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 16148943 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-140238 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 16308421 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-142211 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 20577053 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-166365 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL -1 14709557 t miannu " AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase" SIGNOR-250319 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 t miannu " AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. phosphorylation at Ser-78 may also decrease the activity of eEF2 kinase" SIGNOR-250321 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser398 DSLPSSPsSATPHSQ -1 14709557 t miannu "Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity." SIGNOR-250158 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 PRKAA2 protein P54646 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000876 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 PRKAA2 protein P54646 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 BTO:0000876 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-174405 PRKAA2 protein P54646 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0000876 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-217457 PRKAA2 protein P54646 UNIPROT INSR protein P06213 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C15 22207502 t gcesareni "Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway." SIGNOR-195324 PRKAA2 protein P54646 UNIPROT PAK2 protein Q13177 UNIPROT unknown phosphorylation Ser20 APPVRMSsTIFSTGG 9606 SIGNOR-C15 22137581 t llicata "Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells." SIGNOR-195110 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 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 PRKAA2 protein P54646 UNIPROT PPP1R12C protein Q9BZL4 UNIPROT down-regulates phosphorylation Ser452 AGLQRSAsSSWLEGT 9606 SIGNOR-C15 22137581 t lperfetto "Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo." SIGNOR-195148 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C15 SIGNOR-C3 20083114 t lperfetto "A recent study revealed that ampk can inhibit mtorc1 independently of tsc2 by phosphorylating raptor at ser863." SIGNOR-163463 PRKAA2 protein P54646 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 SIGNOR-C15 21459323 t gcesareni "Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372" SIGNOR-173031 PRKAA2 protein P54646 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 14651849 t gcesareni "Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity." SIGNOR-119541 PRKAA2 protein P54646 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 SIGNOR-C15 16959574 t gcesareni "We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels." SIGNOR-149388 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 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" SIGNOR-244576 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 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 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 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 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-186641 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 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 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 PRKAB1 protein Q9Y478 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-139164 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 PRKAB1 protein Q9Y478 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 SIGNOR-C3 21460634 t gcesareni "Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2." SIGNOR-173041 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 PRKAB2 protein O43741 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-139167 PRKACA protein P17612 UNIPROT AANAT protein Q16613 UNIPROT "up-regulates activity" phosphorylation Ser205 HPFLRRNsGC -1 11336675 t miannu "AANAT1–207 was phosphorylated in vitro at both PKA sites, Thr-31 and Ser-205. 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-250324 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 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT "up-regulates activity" phosphorylation Ser1042 GGMQRKLsVALAFVG 10090 BTO:0000801 12196520 t miannu "Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins." SIGNOR-250326 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT "up-regulates activity" phosphorylation Ser2054 GGNKRKLsTAMALIG 10090 BTO:0000801 12196520 t miannu "Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins." SIGNOR-250327 PRKACA protein P17612 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Ser455 PAPSRTAsFSESRAD -1 10653665 t miannu "Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA)" SIGNOR-250328 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT "down-regulates activity" phosphorylation Ser408 REKSKKYsDVEVPAS -1 8810272 t miannu "Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250329 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT "down-regulates activity" phosphorylation Ser436 TCSPLRHsFQKQQRE -1 8810272 t miannu "Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250330 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT "down-regulates activity" phosphorylation Ser481 KEDGHRTsTSAVPNL -1 8810272 t miannu "Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250331 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT "down-regulates activity" phosphorylation Ser713 KKKFRTPsFLKKSKK -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-250332 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 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Ser38 YVVKRRDsATSFSLD 9606 BTO:0000776 18417471 t llicata "We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43" SIGNOR-178244 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Thr27 WAKGRREtYLCYVVK 9606 BTO:0000776 18417471 t llicata "We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43" SIGNOR-178248 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 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT up-regulates phosphorylation Ser2733 SVSPKRNsISRTHKD 9606 15383279 t llicata "Using a combination of biochemical, enzymatic, and immunofluorescence techniques, we show that the anchoring protein contributes to pkd activation in two ways: it recruits an upstream kinase pkceta and coordinates pka phosphorylation events that release activated protein kinase d. Thus, akap-lbc synchronizes pka and pkc activities in a manner that leads to the activation of a third kinase." SIGNOR-129345 PRKACA protein P17612 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" phosphorylation 10116 BTO:0002135 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256111 PRKACA protein P17612 UNIPROT APC protein P25054 UNIPROT "down-regulates activity" phosphorylation Ser2054 MPKKKKPsRLKGDNE 9606 BTO:0000007 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 PRKACA protein P17612 UNIPROT APOBEC3G protein Q9HC16 UNIPROT up-regulates phosphorylation Thr32 PILSRRNtVWLCYEV 9606 18836454 t llicata "Here we show that pka binds and specifically phosphorylates a3g at thr32 in vitro and in vivo. This phosphorylation event reduces the binding of a3g to vif and its subsequent ubiquitination and degradation, and thus promotes a3g antiviral activity." SIGNOR-181526 PRKACA protein P17612 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 18768928 t llicata "The results indicate that phosphorylation of gdi_ at ser174 by pka suppresses rhoa activity, providing a potential protective signaling mechanism for inflammatory injury." SIGNOR-180576 PRKACA protein P17612 UNIPROT ASIC1 protein P78348 UNIPROT unknown phosphorylation Ser479 QKEAKRSsADKGVAL 9606 BTO:0000142 12578970 t llicata "We found that protein kinase a phosphorylation of ser-479 in the asic1 c terminus interfered with pick1 binding." SIGNOR-98196 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 PRKACA protein P17612 UNIPROT AURKA protein O14965 UNIPROT "up-regulates activity" phosphorylation Thr288 APSSRRTtLCGTLDY -1 11039908 t miannu "Aurora2 is regulated by phosphorylation. phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro." SIGNOR-250337 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9534 BTO:0000298 10880354 t miannu "Ser(155) is phosphorylated preferentially by PKA in vitro and is the only residue in BAD that becomes phosphorylated when cells are exposed to cAMP-elevating agents. The phosphorylation of BAD at Ser(155) prevents it from binding to Bcl-X(L) and promotes its interaction with 14-3-3 proteins." SIGNOR-250338 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 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 t gcesareni "Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death" SIGNOR-180780 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 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 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000150;BTO:0001573 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 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000150;BTO:0001573 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 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 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-67387 PRKACA protein P17612 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-81137 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 PRKACA protein P17612 UNIPROT CA9 protein Q16790 UNIPROT up-regulates phosphorylation Thr443 RRQHRRGtKGGVSYR 9606 22037869 t llicata "Here, we report that thr443 phosphorylation at the intracellular domain of ca ix by protein kinase a (pka) is critical for its activation in hypoxic cells, with the fullest activity of ca ix also requiring dephosphorylation of ser448." SIGNOR-176973 PRKACA protein P17612 UNIPROT CACNA1C protein Q13936 UNIPROT "up-regulates activity" phosphorylation Ser1897 LLRKANPsRCHSRES 10090 BTO:0000087 28119464 t "These findings reveal an essential role for _1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes" SIGNOR-251709 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 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT "up-regulates activity" phosphorylation Ser533 KKSQHRSsSSAPHHN 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-250340 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT "up-regulates activity" phosphorylation Ser534 KSQHRSSsSAPHHNH 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-250341 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT "down-regulates activity" phosphorylation Ser1406 GAGGRRLsSFVTKGY 11986331 t miannu "CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation." SIGNOR-250344 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 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT unknown phosphorylation Ser1859 PPRIHRAsDPGLPAE 11986331 t miannu "CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation." SIGNOR-250343 PRKACA protein P17612 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT "down-regulates activity" phosphorylation Thr108 SPRAWRRPtIESHHVAI 10116 BTO:0001009 10187789 t "In vitro, CaMKK is phosphorylated by PKA and this is associated with inhibition of enzyme activity. The major site of phosphorylation is threonine 108, although additional sites are phosphorylated with lower efficiency." SIGNOR-256115 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 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser183 GLRTRTGsNIDCEKL 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-133880 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 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser99 NRQAAKLsKPTLENL 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-133888 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 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 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser90 NYLDRFLsLEPVKKS -1 8058338 t miannu "PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234." SIGNOR-250347 PRKACA protein P17612 UNIPROT CD44 protein P16070 UNIPROT up-regulates phosphorylation Ser697 AVEDRKPsGLNGEAS 9606 16785995 t lperfetto "Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains." SIGNOR-147208 PRKACA protein P17612 UNIPROT CDK16 protein Q00536 UNIPROT down-regulates phosphorylation Ser153 SRRLRRVsLSEIGFG 9606 BTO:0000142 22184064 t llicata "Here, we report that cdk16 is activated by membrane-associated cyclin y (ccny). Treatment of transfected human cells with the protein kinase a (pka) activator forskolin blocked, while kinase inhibition promoted, ccny-dependent targeting of cdk16-green fluorescent protein (gfp) to the cell membrane. Ccny binding to cdk16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential pka phosphorylation site." SIGNOR-191623 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 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 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser737 EPLERRLsLVPDSEQ -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-250350 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser813 DIYSRRLsQETGLEI -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-250351 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 1716180 t lperfetto "Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response." SIGNOR-21312 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 1716180 t lperfetto "Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response." SIGNOR-21316 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser768 LQARRRQsVLNLMTH 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-72708 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser768 LQARRRQsVLNLMTH 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-18141 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 1716180 t lperfetto "Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response." SIGNOR-21320 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1716180 t lperfetto "Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response." SIGNOR-21324 PRKACA protein P17612 UNIPROT CLDN3 protein O15551 UNIPROT unknown phosphorylation Thr192 PPREKKYtATKVVYS 9606 BTO:0001023 15905176 t llicata "Our results suggest that claudin-3 phosphorylation by pka, a kinase frequently activated in ovarian cancer, may provide a mechanism for the disruption of tjs in this cancer." SIGNOR-137291 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000669 15568017 t gcesareni "Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression." SIGNOR-131307 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000742 15568017 t gcesareni "We demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for Wnt-directed myogenic gene expression." SIGNOR-255799 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001103 21902831 t gcesareni "Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5." SIGNOR-176560 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 10116 BTO:0001009 8336722 t gcesareni "The degree of CREB phosphorylation, assessed with antiserum specific for CREB phosphorylated at Ser-133, correlated with the amount of PKA liberated. The time course of phosphorylation closely paralleled the nuclear entry of the catalytic subun" SIGNOR-166342 PRKACA protein P17612 UNIPROT CSK protein P41240 UNIPROT "up-regulates activity" phosphorylation Ser364 ALREKKFsTKSDVWS 9606 BTO:0000782 11181701 t lperfetto "Activation of the cooh-terminal src kinase (csk) by camp-dependent protein kinase inhibits signaling through the t cell receptor.Pka phosphorylates csk at s364 in vitro and in vivo leading to a two- to fourfold increase in csk activity that is necessary for camp-mediated inhibition of tcr-induced interleukin 2 secretion." SIGNOR-105229 PRKACA protein P17612 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates phosphorylation 9606 16481469 t lperfetto "Mutation of either the three pka sites or pka-primed cki sites prevents phosphorylation of ci by cki in vitro and blocks ci cleavage in embryos" SIGNOR-144557 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 16199882 t gcesareni "Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro." SIGNOR-140902 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser552 QDTQRRTsMGGTQQQ 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-144478 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 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 PRKACA protein P17612 UNIPROT CUL5 protein Q93034 UNIPROT "up-regulates activity" phosphorylation Ser730 MKMRKKIsNAQLQTE 9534 BTO:0000298 10898738 t miannu "Elimination of the S730 but not the T325 PKA phosphorylation site of VACM-1 resulted in a complete inhibition of the VACM-1 activity, thus suggesting a direct effect of PKA on the VACM-1 receptor." SIGNOR-250352 PRKACA protein P17612 UNIPROT DNAJC5 protein Q9H3Z4 UNIPROT unknown phosphorylation Ser10 DQRQRSLsTSGESLY 9606 BTO:0000938 18951872 t gcesareni "Csp is phosphorylated in vivo on a single residue, ser10, and this phosphorylation regulates its cellular functions,[...]PKA Phosphorylation of full-length csp protein stimulated 14-3-3 binding, and this was abolished in a ser10-ala mutant csp, confirming the binding site as phospho-ser10" SIGNOR-181788 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 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser1217 SHHFRRRsFRGFWLT 9606 19144650 t llicata "We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade" SIGNOR-183445 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser955 KDLCRRAsYISQDMI 9606 19144650 t llicata "We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade" SIGNOR-183449 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 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser500 RLHLPRAsAVALEVQ -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-250444 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 PRKACA protein P17612 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser236 IDKNRRKsCQACRLR 9606 9891036 t lperfetto "Phosphorylation of human estrogen receptor alpha by protein kinase a regulates dimerizationeralpha is phosphorylated by protein kinase a (pka) on serine-236 within the dna binding domain. Mutation of serine-236 to glutamic acid prevents dna binding by inhibiting dimerization by eralpha" SIGNOR-63984 PRKACA protein P17612 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser305 IKRSKKNsLALSLTA 9606 BTO:0000150 15193262 t lperfetto "We show that phosphorylation of serine-305 in the hinge region of er_ by protein kinase a (pka) induced resistance to tamoxifenactivation of pka prevents tamoxifen-mediated inhibition of er transactivation" SIGNOR-125779 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 t lperfetto "The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)ser(191) and ser(216), were identified, whose mutation to alanine reduces er81 activity upon erk-mapk stimulation." SIGNOR-92447 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 12213813 t lperfetto "The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)" SIGNOR-92451 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation Ser334 PTYQRRGsLQLWQFL 9606 12213813 t lperfetto "Pka targets er81 on ser(334) in vivo. Surprisingly, phosphorylation of ser(334) severely reduces the dna-binding ability of er81 but also enhances the transactivation potential of er81. These counteractive effects of pka phosphorylation on er81-dependent transcription may cause the selective up-regulation of promoters with high but not low affinity for er81." SIGNOR-92455 PRKACA protein P17612 UNIPROT ETV5 protein P41161 UNIPROT "up-regulates activity" phosphorylation Ser367 PPYQRRGsLQLWQFL 9606 BTO:0002909 11682477 t lperfetto "We further show that the increase in erm transcriptional activity after pka phosphorylation is closely correlated with a drastic reduction in the dna binding of the transcription factor. These results indicate that the phosphorylation of erm by pka is involved in erm-mediated transcription and suggest that the activation of erm is probably related to conformational changes." SIGNOR-111239 PRKACA protein P17612 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 15228085 t gcesareni "Site-directed mutagenesis analysis indicated that serine 2152 is the unique substrate in the c-terminal region of abp for endogenously activated pka." SIGNOR-126659 PRKACA protein P17612 UNIPROT FOS protein P01100 UNIPROT "down-regulates quantity by repression" phosphorylation Ser362 AAAHRKGsSSNEPSS 9534 BTO:0000298 1545828 t miannu "Human c-Fos protein is phosphorylated in vitro by PKA. phosphorylation of Fos occurs at serine residue 362. Modification of the Fos protein by phosphorylation with PKA then allows it to act as a regulator of its own synthesis by downregulating fos gene expression at a transcriptional level" SIGNOR-250356 PRKACA protein P17612 UNIPROT FRAT1 protein Q92837 UNIPROT down-regulates phosphorylation Ser188 RLQQRRGsQPETRTG 9606 16982607 t lperfetto "Phosphorylation of ser188 by pka inhibited the ability of frat1 to activate beta-catenin-dependent transcription." SIGNOR-149689 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT unknown phosphorylation Ser83 EEGTFRSsIRRLSTR 9606 21220422 t llicata "We conclude that phosphorylation of plm increases its oligomerization into tetramers, decreases its binding to nka, and alters the structures of both the tetramer and nka regulatory complex." SIGNOR-171184 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT unknown phosphorylation Ser88 RSSIRRLsTRRR 9606 21220422 t llicata "We conclude that phosphorylation of plm increases its oligomerization into tetramers, decreases its binding to nka, and alters the structures of both the tetramer and nka regulatory complex." SIGNOR-171188 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 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 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -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-249713 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Thr7 tSAARRSY -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-249712 PRKACA protein P17612 UNIPROT GJA5 protein P36382 UNIPROT "up-regulates activity" phosphorylation Ser120 RAKEVRGsGSYEYPV 9606 BTO:0003477 10728420 t miannu "Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345" SIGNOR-250357 PRKACA protein P17612 UNIPROT GJA5 protein P36382 UNIPROT "up-regulates activity" phosphorylation Ser345 HSDKRRLsKASSKAR 9606 BTO:0003477 10728420 t miannu "Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345" SIGNOR-249982 PRKACA protein P17612 UNIPROT GJB1 protein P08034 UNIPROT unknown phosphorylation Ser233 NPPSRKGsGFGHRLS -1 8390988 t miannu "connexin- 32 is proteolyzed by pcalpain and mcalpain. phosphorylation of connexin-32 by protein kinase C, but not by protein kinase A, efficiently prevents its proteolysis by both calpain isoforms. major phosphorylation sites: Ser233(for protein kinase A). Phosphorylation of connexin-32 by protein kinase C,but not by protein kinase A, prevents the proteolytic attack of p-calpain and m-calpain. Phosphorylation of connexin-32 by protein kinase A and protein kinase C does not prevent its proteolysis by papain, a-chymotrypsin, proteinase K, and trypsin" SIGNOR-249715 PRKACA protein P17612 UNIPROT GLI1 protein P08151 UNIPROT down-regulates phosphorylation 16293631 t "We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1." SIGNOR-253539 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16885213 t gcesareni "In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed 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-148478 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni "In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed 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-154273 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0000938 19056373 t gcesareni "These results indicate that phosphorylation of Gli2 by PKA induces Gli2 processing and destabilization" SIGNOR-182573 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 10693759 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-75362 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 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser1006 GHGVRRAsDPVRTGS 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-75339 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 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser865 YLSSRRSsGISPCFS 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-75347 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser877 CFSSRRSsEASQAEG 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-75351 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser907 TDASRRSsEASQSDG 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-75355 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" phosphorylation Ser980 VHAPRRCsDGGAHGY 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-75359 PRKACA protein P17612 UNIPROT GLIS2 protein Q9BZE0 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 16537363 t lperfetto "Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity" SIGNOR-145131 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 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT "up-regulates activity" phosphorylation Thr27 KFRFRKEtNNAAIIM -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-249984 PRKACA protein P17612 UNIPROT GNA13 protein Q14344 UNIPROT "down-regulates activity" phosphorylation Thr203 ILLARRPtKGIHEYD 9534 BTO:0000298 12399457 t miannu "PKA directly phosphorylates Galpha(13). Galpha(13)-T203A mutant (in COS-7 cells) could not be phosphorylated by PKA. PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203)." SIGNOR-249985 PRKACA protein P17612 UNIPROT GP1BB protein P13224 UNIPROT "down-regulates activity" phosphorylation Ser191 ARAAARLsLTDPLVA -1 2504723 t miannu "Platelet glycoprotein Ib beta is phosphorylated on serine 166 by cyclic AMP-dependent protein kinase. phosphorylation of this residue may contribute to the inhibitory actions of cyclic AMP by inhibiting collagen-induced polymerization of actin." SIGNOR-249986 PRKACA protein P17612 UNIPROT GRIA1 protein P42261 UNIPROT "up-regulates activity" phosphorylation Ser863 TSTLPRNsGAGASSG 9606 BTO:0000007 8663994 t miannu "Phosphorylation of Ser-845 on GluR1 by PKA potentiates its response to glutamate." SIGNOR-249987 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 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 PRKACA protein P17612 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Ser685 VPLVQRGsANGL -1 11278469 t miannu "PKA directly phosphorylates GRK2 on serine 685. This modification increases G subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor." SIGNOR-250334 PRKACA protein P17612 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 t gcesareni "Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a." SIGNOR-83221 PRKACA protein P17612 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto "Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka)." SIGNOR-188577 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser698 PEWPRRAsCTSSTSG -1 196939 t "The results presented in this paper show that the phosphorylation of glycogen synthetase a by cyclic AMP-dependent protein kinase results in the phosphorylation of two distinct serines termed site-l and site-2, which account for 90% of the total phosphorylation" SIGNOR-253009 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser8 MPLNRTLsMSSLPGL -1 6263629 t "A reinvestigation of the phosphorylation of Rabbit Skeletal-muscle glycogen synthase by cyclic AMP dependent Protein Kinase: identification of the third site of phosphorylation at Serine-7" SIGNOR-253008 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser8 MPLNRTLsMSSLPGL -1 2117608 t miannu "Phosphorylation of rabbit muscle glycogen synthase by cyclic AMP-dependent protein kinase has been shown to enhance subsequent phosphorylation by casein kinase I . phosphorylation at Ser7 is required for modification of Ser10 by casein kinase I." SIGNOR-249988 PRKACA protein P17612 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t gcesareni "Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation." SIGNOR-70424 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT "down-regulates activity" phosphorylation Ser109 KERRRTEsINSAFAE 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-249989 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 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 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-249990 PRKACA protein P17612 UNIPROT HDAC8 protein Q9BY41 UNIPROT down-regulates phosphorylation Ser39 AKIPKRAsMVHSLIE 9606 14701748 t lperfetto "Negative regulation of histone deacetylase 8 activity by cyclic amp-dependent protein kinase athe pka phosphoacceptor site of hdac8 is ser(39)" SIGNOR-120643 PRKACA protein P17612 UNIPROT HMGCR protein P04035 UNIPROT "down-regulates activity" phosphorylation Ser872 SHMIHNRsKINLQDL 10116 BTO:0000759 2369897 t miannu "The intact, 100 kd microsomal enzyme and the 53 kd catalytic fragment of rat HMG-CoA reductase are both phosphorylated and inactivated by the AMP-activated protein kinase. this site is highly phosphorylated in intact liver under these conditions (Ser872 in the human enzyme)." SIGNOR-249992 PRKACA protein P17612 UNIPROT HMGN1 protein P05114 UNIPROT "down-regulates activity" phosphorylation Ser7 sSAEGAAK 9606 BTO:0000567 11438671 t miannu "PKA preferentially phosphorylates serine 6 in human HMGN1. specific phosphorylation of the NBD of HMGN proteins serves to prevent the interaction of these proteins with their chromatin targets during mitosis." SIGNOR-249993 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 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 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 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-128415 PRKACA protein P17612 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation Ser320 ASPGRPSsVDTLLSP 9606 21085490 t lperfetto "Protein kinase a binds and activates heat shock factor 1hsf1 binds avidly to the catalytic subunit of pka, (pkac_) and becomes phosphorylated on a novel serine phosphorylation site within its central regulatory domain (serine 320 or s320), both in vitro and in vivo. Intracellular pkac_ levels and phosphorylation of hsf1 at s320 were both required for hsf1 to be localized to the nucleus, bind to response elements in the promoter of an hsf1 target gene" SIGNOR-169853 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 PRKACA protein P17612 UNIPROT HSPB6 protein O14558 UNIPROT down-regulates phosphorylation Ser16 PSWLRRAsAPLPGLS 9606 BTO:0000887;BTO:0001260 10196226 t llicata "Hosphorylation of hsp20 at ser16 is not only associated with cyclic nucleotide-dependent vasorelaxation but also inhibits agonist-induced contractile responses." SIGNOR-66493 PRKACA protein P17612 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2347 TTCCRRSsNVSYKYS 9606 8318012 t lperfetto "Pka phosphorylates the cytoplasmic mpr 300 domain at ser20 and at a non-identified site," SIGNOR-37839 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1100 QGCRRRHsSETFSST 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-235675 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1222 ESSSTRRsSEDLSAY 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-236729 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1223 SSSTRRSsEDLSAYA 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-236603 PRKACA protein P17612 UNIPROT ITGA4 protein P13612 UNIPROT "up-regulates activity" phosphorylation Ser1021 QEENRRDsWSYINSK 9606 BTO:0000782 11533025 t lperfetto "PKA phosphorylationin vitro blocks the binding of the alpha4 tail to paxillin. A mutation that mimics alpha4 phosphorylation disrupts paxillin binding and promotes cell spreading" SIGNOR-110119 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 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 PRKACA protein P17612 UNIPROT ITPKB protein P27987 UNIPROT "down-regulates activity" phosphorylation -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-249995 PRKACA protein P17612 UNIPROT ITPR1 protein Q14643 UNIPROT "down-regulates activity" phosphorylation Ser1598 RNAARRDsVLAASRD -1 12529267 t miannu "IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site." SIGNOR-249996 PRKACA protein P17612 UNIPROT ITPR1 protein Q14643 UNIPROT "down-regulates activity" phosphorylation Ser1764 RPSGRREsLTSFGNG -1 12529267 t miannu "IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site." SIGNOR-249997 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser283 CASVRRAsSADDIEA 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-70722 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser890 RQRKRKLsFRRRTDK 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-70726 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 PRKACA protein P17612 UNIPROT KCNJ12 protein Q14500 UNIPROT "down-regulates activity" phosphorylation Ser431 QRPYRREsEI 9534 BTO:0001538 11181181 t miannu "Phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97.‚ " SIGNOR-249998 PRKACA protein P17612 UNIPROT KCNJ13 protein O60928 UNIPROT up-regulates phosphorylation Ser287 EICQRRTsYLPSEIM 9606 18976636 t gcesareni "Pka activation induced an increase of kir7.1 currents. This effect was absent in mutant kir7.1 channels lacking pka consensus site (287)s" SIGNOR-181859 CSNK1A1 protein P48729 UNIPROT FOXG1 protein P55316 UNIPROT up-regulates phosphorylation Ser19 MIPKSSFsINSLVPE 9606 BTO:0000938 BTO:0000142 17435750 t llicata "Cki phosphorylation of ser 19 of foxg1 promotes nuclear import" SIGNOR-154386 PRKACA protein P17612 UNIPROT KCNJ3 protein P48549 UNIPROT unknown phosphorylation Ser385 NSKERHNsVECLDGL 9606 19151997 t llicata "Using this approach, we identified s385 as an in vitro phosphorylation site. Mutation of this residue to alanine resulted in a reduced sensitivity of kir3.1* currents to h89 and forskolin, confirming an in vivo role for this novel site of the kir3.1 channel subunit in its regulation by pka." SIGNOR-183475 PRKACA protein P17612 UNIPROT KCNK3 protein O14649 UNIPROT up-regulates phosphorylation Ser393 GLMKRRSsV 9606 BTO:0000007 21357689 t lperfetto "Mutation of the ser393 to alanine, which can neither be phosphorylated nor mimic a phosphorylated residue, resulted in the channel failing to pass current all of our findings support the conclusion that camp-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both k2p3.1 and k2p9.1." SIGNOR-172430 PRKACA protein P17612 UNIPROT KCNK9 protein Q9NPC2 UNIPROT up-regulates phosphorylation Ser373 RLMKRRKsV 9606 BTO:0000007 21357689 t llicata "Patch clamp analysis, flow cytometry, and immunocytochemistry studies of hek293 transfected with wt hk2p3.1 and cultured in the presence of pka activators or inhibitors all confirm that activation of pka resulted in an increase in hk2p3.1 current expression (figs. 4_4?6) and demonstrate the dynamic regulatory effect of pka activity on k2p3.1 channel expression." SIGNOR-172466 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 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser567 SSSRRRRsSSTAPPT 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-145032 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser568 SSRRRRSsSTAPPTS 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-145040 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 PRKACA protein P17612 UNIPROT KDELR1 protein P24390 UNIPROT up-regulates phosphorylation Ser209 VLKGKKLsLPA 9606 14517323 t llicata "We conclude that pka phosphorylation of serine 209 is required for the retrograde transport of the kdel receptor from the golgi complex to the er from which the retrieval of proteins bearing the kdel signal depends." SIGNOR-118257 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates 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 LASP1 protein Q14847 UNIPROT down-regulates phosphorylation Ser146 MEPERRDsQDGSSYR 9606 BTO:0000150 12571245 t lperfetto "Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration" SIGNOR-97938 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "up-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 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "up-regulates activity" phosphorylation Ser99 KNKGKGFsVVADTPE -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-250075 PRKACA protein P17612 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation 10090 BTO:0000944 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 PRKACA protein P17612 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation 10090 BTO:0000944 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-236994 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 PRKACA protein P17612 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-58259 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser853 IAEPMRRsVSEAALA 10090 BTO:0000944 11581251 t lperfetto "HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme" SIGNOR-249202 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser950 EGFHPRRsSQGATQM 10090 BTO:0000944 11581251 t lperfetto "HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme" SIGNOR-249203 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser951 GFHPRRSsQGATQMP 10090 BTO:0000944 11581251 t lperfetto "HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme" SIGNOR-249204 PRKACA protein P17612 UNIPROT LRP1 protein Q07954 UNIPROT "up-regulates activity" phosphorylation Ser4520 GGHGSRHsLASTDEK 10029 BTO:0000246 11158305 t miannu "LRP phosphorylation is mediated by PKA at residue serine 76 of its cytoplasmic tail and that this phosphorylation contributes to receptor-mediated endocytosis." SIGNOR-250000 PRKACA protein P17612 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0001593 18981475 t gcesareni "These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit." SIGNOR-181979 PRKACA protein P17612 UNIPROT LRRK2 protein Q5S007 UNIPROT "down-regulates activity" phosphorylation Ser1444 NIKARASsSPVILVG -1 24351927 t gcesareni "Furthermore, our work establishes S1444 as a PKA-regulated 14-3-3 docking site€.Strikingly, 14-3-3 binding to phospho-S1444 decreased LRRK2 kinase activity in vitro." SIGNOR-237444 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1679 NVKSKIGsTDNIKYQ 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-250001 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 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1742 KAQAKVGsLDNAHHV 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-250003 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT up-regulates phosphorylation Ser1679 NVKSKIGsTDNIKYQ 9606 BTO:0000567;BTO:0000938 BTO:0000142 11029056 t lperfetto "Kxgs sites s319, s350, and s382 are major targets for in vitro phosphorylation of map2c by pka.Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains" SIGNOR-83088 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT up-regulates phosphorylation Ser1710 HVTSKCGsLKNIRHR 9606 BTO:0000567;BTO:0000938 BTO:0000142 11029056 t lperfetto "Kxgs sites s319, s350, and s382 are major targets for in vitro phosphorylation of map2c by pka.Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains" SIGNOR-83092 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT up-regulates phosphorylation Ser1742 KAQAKVGsLDNAHHV 9606 BTO:0000567;BTO:0000938 BTO:0000142 11029056 t lperfetto "Kxgs sites s319, s350, and s382 are major targets for in vitro phosphorylation of map2c by pka.Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains" SIGNOR-83096 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT up-regulates phosphorylation Ser1782 GAEIITQsPGRSSVA 9606 BTO:0000567;BTO:0000938 BTO:0000142 11029056 t gcesareni "Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains" SIGNOR-83100 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser531 GSRSRTPsLPTPPTR -1 9614189 t miannu "S214 can be rapidly and selectively phosphorylated in vitro by PKA, and this single site strongly affects tau's ability to bind and stabilize microtubules." SIGNOR-250006 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser579 NVKSKIGsTENLKHQ -1 12435421 t miannu "Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly" SIGNOR-250008 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser673 RVQSKIGsLDNITHV -1 12435421 t miannu "Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly" SIGNOR-250007 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser726 DTSPRHLsNVSSTGS -1 12435421 t miannu "Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly" SIGNOR-250009 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t "The effect has been demonstrated using P10636-8" gcesareni "Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase." SIGNOR-60659 PRKACA protein P17612 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-171066 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser141 MASQKRPsQRHGSKY -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-161" SIGNOR-250010 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser146 RPSQRHGsKYLATAS -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-161" SIGNOR-250011 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -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-162" SIGNOR-250012 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser266 FGYGGRAsDYKSAHK -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-163" SIGNOR-250013 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -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-164" SIGNOR-250014 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 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT "up-regulates activity" phosphorylation Ser329 LGGLCDLsSRY 9606 BTO:0000007 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 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT "up-regulates activity" phosphorylation Thr312 RSQELRKtFKEIICC 9606 BTO:0000007 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-250017 PRKACA protein P17612 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT down-regulates phosphorylation Ser557 SGKFRRGsGSACSLL 9606 17988215 t llicata "The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1." SIGNOR-158946 PRKACA protein P17612 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT down-regulates phosphorylation Ser559 KFRRGSGsACSLLCC 9606 17988215 t llicata "The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1." SIGNOR-158950 PRKACA protein P17612 UNIPROT MIP protein P30301 UNIPROT "down-regulates activity" phosphorylation Ser229 LLFPRLKsISERLSV -1 2176601 t miannu "Phosphorylation at one of these sites (serine 243) could be increased by A kinase in vitro. phosphorylation of MIP reconstituted into single bilayers increased the voltage dependence and long-term closures of the channels observed." SIGNOR-250018 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 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 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-163756 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 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-163760 PRKACA protein P17612 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-163764 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 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000551 22505454 t gcesareni "Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites." SIGNOR-196961 PRKACA protein P17612 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation Thr131 LERAKRAtIMSLEDF 9606 BTO:0000142 21677187 t lperfetto "Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple" SIGNOR-174410 PRKACA protein P17612 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15328345 t gcesareni "Nedd4-2 was a substrate for phosphorylation by pka in vitro and in cells;three nedd4-2 residues were phosphorylated by pka and were required for camp to inhibit nedd4-2 (relative functional importance ser-327 > ser-221 > thr-246)." SIGNOR-128429 PRKACA protein P17612 UNIPROT NEFL protein P07196 UNIPROT "down-regulates activity" phosphorylation 9606 8019002 t miannu "Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L." SIGNOR-252401 PRKACA protein P17612 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto "Merlin localizes to the cell membrane where it links the actin cytoskeleton to membrane proteins.we identify a novel pka phosphorylation site, serine 10, in the n terminus of merlin. s10a reduces the amount of cellular f-actin and merlin s10d stabilizes f-actin filaments." SIGNOR-159844 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 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser245 PSTSPRAsVTEESWL 9606 12351631 t lperfetto "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 domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3)" SIGNOR-93531 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser269 PCNKRKYsLNGRQPP 9606 12351631 t lperfetto "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 domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3)" SIGNOR-93535 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 t lperfetto "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 domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3)" SIGNOR-93539 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 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser937 ETSFRKLsFTESLTS 19531803 t lperfetto "Ser940 of p105 was phosphorylated by PKA to a similar extent, whereas no phosphorylation of the same sequence occurred when Ser940 was substituted by Ala|Mechanistically, phosphorylation of p105 at Ser940 by PKA appeared to attenuate the extent of IKK-dependent phosphorylation of p105 at Ser935, which could in turn influence the rate of activation of NF-kappaB" SIGNOR-260327 PRKACA protein P17612 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17959673 t lperfetto "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-217391 PRKACA protein P17612 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 9660950 t lperfetto "The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka)." SIGNOR-217364 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT "up-regulates activity" phosphorylation Ser622 KKGEKRAsSPFRRVR -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-250019 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 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates phosphorylation Ser623 KGEKRASsPFRRVRE 9606 12167624 t gcesareni "Here we demonstrate that protein kinase a (pka)-dependent phosphorylation of nopp140 at ser 627, together with c/ebpbeta, induces agp gene expression synergistically." SIGNOR-91186 PRKACA protein P17612 UNIPROT NOS1 protein P29475 UNIPROT unknown phosphorylation -1 1375933 t miannu "NOS is stoichiometrically phosphorylated by PKA, PKC, and CaMK, with each enzyme predominantly phosphorylating a distinct serine. CPT-CAMP has no effect on NOS activity" SIGNOR-250021 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 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" phosphorylation Ser633 WRRKRKEsSNTDSAG 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-251616 PRKACA protein P17612 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 aon serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no." SIGNOR-112371 PRKACA protein P17612 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 BTO:0000007 20110267 t llicata "We identified ser-282 as target of mapk and ser-172 as target of pkc and pka in vitro and in a transfected human embryonic kidney 293 (hek293) cell model using site directed mutagenesis and phosphopeptide mapping analysis. In hek293 cells, phosphorylation of these sites occurred at a basal level and down-regulated constitutive nox1 activity. I" SIGNOR-163663 PRKACA protein P17612 UNIPROT PDE10A protein Q9Y233 UNIPROT unknown phosphorylation Thr15 SQHLTGLtDEKVKAY 9606 BTO:0000007 20610737 t llicata "When coexpressed with the catalytic subunit of pka in transfected hek293 cells, wild-type (wt) pde10a2 (pde10a2wt) was phosphorylated at thr-16 these data confirm the previously reported findings that pka phosphorylation of pde10a2 on thr-16 results in a cytosolic localization" SIGNOR-166559 PRKACA protein P17612 UNIPROT PDE3A protein Q14432 UNIPROT unknown phosphorylation Ser312 SKSHRRTsLPCIPRE 9606 BTO:0000567 16153182 t llicata "Ser312 of pde3a was phosphorylated in an h-89-sensitive response to forskolin, indicative of phosphorylation by pka (camp-dependent protein kinase), but phosphorylation at this site did not stimulate 14-3-3 binding." SIGNOR-140289 PRKACA protein P17612 UNIPROT PDE4B protein Q07343 UNIPROT "up-regulates activity" phosphorylation Ser56 NLQLPPLsQRQSERA 9534 BTO:0000298 12441002 t miannu "PKA-mediated phosphorylation of Ser-56 in UCR1 of PDE4B4 leads to activation of this long isoform" SIGNOR-250024 PRKACA protein P17612 UNIPROT PDE4D protein Q08499 UNIPROT up-regulates phosphorylation 9606 8663227 t llicata "Phosphorylation and activation of a camp-specific phosphodiesterase by the camp-dependent protein kinase." SIGNOR-42515 PRKACA protein P17612 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS -1 12853467 t miannu "PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚ " SIGNOR-250025 PRKACA protein P17612 UNIPROT PHKA1 protein P46020 UNIPROT "up-regulates activity" phosphorylation Ser1018 QVEFRRLsISAESQS 10487978 t miannu "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. Ser1018 within this multiphosphorylation domain is phosphorylated by PKA and is a major site of regulatory phosphorylation in vivo" SIGNOR-250026 PRKACA protein P17612 UNIPROT PHOX2A protein O14813 UNIPROT down-regulates phosphorylation Ser153 RKQERAAsAKGAAGA 9606 BTO:0000938 19564421 t llicata "Phox2a becomes phosphorylated by protein kinase a (pka) on ser153, which prevents association of phox2a with dna and terminates p27(kip1) transcription." SIGNOR-186462 PRKACA protein P17612 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates activity" phosphorylation Ser65 HSHSPRHsLRHSPGS 9606 BTO:0000007 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 PRKACA protein P17612 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 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-259413 PRKACA protein P17612 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates phosphorylation Ser1105 LDRKRHNsISEAKMR 9606 BTO:0000567 10893237 t llicata "These data indicate that pkc and pka act similarly in that they inhibit galpha(q)-stimulated plcbeta(3) as a result of phosphorylation of ser(1105)." SIGNOR-79148 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 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT "down-regulates activity" phosphorylation Ser220 KAKPSLLsRVGALTN 10090 11751901 t miannu "PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276)" SIGNOR-250028 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT "down-regulates activity" phosphorylation Ser277 QAVSRRRsEVRVPWL 10090 11751901 t miannu "PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276)" SIGNOR-250029 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT "down-regulates activity" phosphorylation Ser81 EPVVRRLsTQFTAAN 10090 BTO:0000944 11751901 t miannu "PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276)" SIGNOR-250492 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 PRKACA protein P17612 UNIPROT POLD3 protein Q15054 UNIPROT down-regulates phosphorylation Ser458 GKANRQVsITGFFQR 9606 22148433 t llicata "In this study, we identified s458, located in the pcna-interacting protein (pip-box) motif of p68, as a phosphorylation site for pka. Phosphomimetic mutation of s458 resulted in a decrease in p68 affinity for pcna as well as the processivity of pol _." SIGNOR-195203 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 PRKACA protein P17612 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Thr34 MIRRRRPtPAMLFRL 10604473 t miannu "DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ " SIGNOR-250031 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Ser178 TAHNKRIsTLTIEEG -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-250032 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 PRKACA protein P17612 UNIPROT PPP1R9B protein Q96SB3 UNIPROT "down-regulates activity" phosphorylation Ser94 SERGVRLsLPRASSL 9606 BTO:0000007 12417592 t miannu "Spinophilin is phosphorylated in vitro by protein kinase A (PKA). two major sites of phosphorylation, Ser-94 and Ser-177, that are located within the actin-binding domain of spinophilin. Phosphorylation of spinophilin by PKA modulated the association between spinophilin and the actin cytoskeleton. phosphorylation of spinophilin reduced the stoichiometry of the spinophilin-actin interaction. In contrast, the ability of spinophilin to bind to PP1 remained unchanged." SIGNOR-250035 PRKACA protein P17612 UNIPROT PPP2R5D protein Q14738 UNIPROT up-regulates phosphorylation Ser573 KVLLRRKsELPQDVY 9606 BTO:0000007;BTO:0000938 17301223 t gcesareni "Protein kinase a activates protein phosphatase 2a by phosphorylation of the b56delta subunit." SIGNOR-153218 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation S496 ATPQRSGSVSNYRSC 9606 BTO:0001949 27784766 t Luana "These data indicate a novel regulatory role of PKC to inhibit AMPKα1 in human cells. As PKC activation is associated with insulin resistance and obesity, PKC may underlie the reduced Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487. | AMPK activity reported in response to overnutrition in insulin-resistant metabolic and vascular tissues." SIGNOR-259865 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser486 DDEITEAKsGTATPQRS 10116 BTO:0002135 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256110 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser491 SSTPQRSCsAAGLHRPR 10116 BTO:0002135 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256112 PRKACA protein P17612 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation Ser173 DGEFLRTsCGSPNYA 9606 19942859 t gcesareni "Pka associates with and phosphorylates ampk?1 At ser-173 to impede threonine thr-172 phosphorylation and thus activation of ampk1 by lkb1 in response to lipolytic signals" SIGNOR-161860 PRKACA protein P17612 UNIPROT PRKAR2B protein P31323 UNIPROT up-regulates phosphorylation Ser114 NRFTRRAsVCAEAYN 9606 BTO:0000782 15187164 t gcesareni "Serine 114 phosphorylation is required for both nuclear localization and down-regulation of il-2 production by riibeta." SIGNOR-125545 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 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation 9606 BTO:0000776 19047375 t gcesareni "B2 adrenergic receptor stimulation induces the pka dependent phosphorylation of heptp and releases bound p38 mapk" SIGNOR-182522 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation Ser44 RLQERRGsNVALMLD 9606 10559944 t llicata "Here we show that cyclic-amp-dependent protein kinase (pka) phosphorylates serine residue 23 in the kim of heptp in vitro and in intact cells. This modification reduces binding of map kinases to the kim, an effect that is prevented by mutation of serine 23 to alanine." SIGNOR-72147 PRKACA protein P17612 UNIPROT PTPRR protein Q15256 UNIPROT "down-regulates activity" phosphorylation Ser339 GLQERRGsNVSLTLD 9534 BTO:0000298 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 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser233 VSSQHRYsTPHAFTF 9534 BTO:0004055 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 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser259 SQRQRSTsTPNVHMV 9534 BTO:0004055 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-250041 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser43 FGYQRRAsDDGKLTD 9534 BTO:0004055 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-250039 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t gcesareni "serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo.cAMP increased Raf-1 serine 259 phosphorylation in a PKA-dependent manner with kinetics that correlated with ERK deactivation." SIGNOR-86141 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser43 FGYQRRAsDDGKLTD 9606 11971957 t gcesareni "Serine 43 phosphorylation decreased the binding to ras in serum-starved but not in mitogen-stimulated cells. However, the kinase activity of a rafs43a mutant was fully inhibited by pka." SIGNOR-86145 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser621 PKINRSAsEPSLHRA 9606 11971957 t gcesareni "We have mapped all camp-induced phosphorylation sites in raf-1, showing that serines 43, 259, and 621 are phosphorylated by pka in vitro and induced by camp in vivo" SIGNOR-86137 PRKACA protein P17612 UNIPROT RAP1A protein P62834 UNIPROT "down-regulates activity" phosphorylation Ser180 KKKPKKKsCLLL 9534 BTO:0000298 9867809 t miannu "Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells." SIGNOR-250042 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 PRKACA protein P17612 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser490 KSPTRKKsGPFGSRR -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-250043 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 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 PRKACA protein P17612 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 9660950 t llicata "The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka)." SIGNOR-58972 PRKACA protein P17612 UNIPROT RET protein P07949 UNIPROT down-regulates phosphorylation Ser696 SSGARRPsLDSMENQ 9606 BTO:0000938 20682772 t llicata "Furthermore, we find that activation of protein kinase a (pka) by forskolin reduces the recruitment of shp2 to ret and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of ser(696), a known pka phosphorylation site in ret, enhances shp2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth." SIGNOR-167349 PRKACA protein P17612 UNIPROT RGS10 protein O43665 UNIPROT "down-regulates activity" phosphorylation Ser168 QTAAKRAsRIYNT 9606 BTO:0000007 11443111 t lperfetto "We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel." SIGNOR-109173 PRKACA protein P17612 UNIPROT RGS13 protein O14921 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr41 SFENLMATKYGPVVY BTO:0000007 20974683 t miannu "Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry." SIGNOR-259835 PRKACA protein P17612 UNIPROT RGS14 protein O43566 UNIPROT "up-regulates activity" phosphorylation Thr495 SATGKRQtCDIEGLV -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-250046 PRKACA protein P17612 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" phosphorylation Ser188 ARRGKKKsGCLVL 10090 BTO:0000944 12654918 t miannu "PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell." SIGNOR-250047 PRKACA protein P17612 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t miannu "Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII). Incubation of Rad with PKA decreases GTP binding by 60-70%, but this effect seems to be independent of phosphorylation, as it is observed with the Ser273-->Ala mutant of Rad containing a mutation at the site of PKA phosphorylation." SIGNOR-250048 PRKACA protein P17612 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Ser27 TSPTGRGsMAAPSLH 9606 11162439 t llicata "Serine 27, a human retinoid x receptor alpha residue, phosphorylated by protein kinase a is essential for cyclicamp-mediated downregulation of rxralpha function." SIGNOR-104954 PRKACA protein P17612 UNIPROT RYR1 protein P21817 UNIPROT "up-regulates activity" phosphorylation Ser2843 KKKTRKIsQSAQTYD -1 14532276 t miannu "PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure" SIGNOR-250078 PRKACA protein P17612 UNIPROT RYR2 protein Q92736 UNIPROT "up-regulates activity" phosphorylation Ser2808 YNRTRRIsQTSQVSV -1 14532276 t miannu "PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure" SIGNOR-250079 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT "down-regulates activity" phosphorylation Ser491 VPETKGKsFEEIAAE 9534 BTO:0004055 8626492 t miannu "GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity." SIGNOR-250049 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT "down-regulates activity" phosphorylation Ser503 AAEFQKKsGSAHRPK 9534 BTO:0004055 8626492 t miannu "GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity." SIGNOR-250050 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 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT "down-regulates activity" phosphorylation Ser505 EFQKKSGsAHRPKAA 9534 BTO:0004055 8626492 t miannu "GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity." SIGNOR-250051 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 PRKACA protein P17612 UNIPROT SNAPIN protein O95295 UNIPROT "up-regulates activity" phosphorylation Ser50 HVHAVREsQVELREQ 11283605 t miannu "PKA-phosphorylation of Snapin significantly increases its binding to synaptosomal-associated protein-25 (SNAP-25). Mutation of Snapin serine 50 to aspartic acid (S50D) mimics this effect of PKA phosphorylation" SIGNOR-250053 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser181 YQPRRRKsVKNGQAE 9606 15889150 t llicata "We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta." SIGNOR-137085 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser64 EPDLKKEsEEDKFPV 9606 15889150 t llicata "We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta." SIGNOR-137089 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 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 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 t llicata "Pka activated src both in vitro and in vivo by phosphorylating src on serine 17" SIGNOR-114277 PRKACA protein P17612 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser338 IEKRYRSsINDKIIE 9606 16381800 t llicata "Sterol regulatory element-binding protein 1 is negatively modulated by pka phosphorylation. ser338 of srebp-1a and ser314 of srebp-1c are pka phosphorylation sites." SIGNOR-143392 PRKACA protein P17612 UNIPROT SRF protein P11831 UNIPROT down-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 9606 BTO:0000887;BTO:0001260 19778940 t llicata "Our results indicate that phosphorylation of srf by pka inhibits smc-specific transcription we identified t159 as a phosphorylation site" SIGNOR-188177 PRKACA protein P17612 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation Ser119 YGPPSRRsENRVVVS 9606 22393468 t llicata "Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo" SIGNOR-196397 PRKACA protein P17612 UNIPROT STK11 protein Q15831 UNIPROT "up-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 10116 BTO:0002874 11297520 t miannu "Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth." SIGNOR-250055 PRKACA protein P17612 UNIPROT STK24 protein Q9Y6E0 UNIPROT unknown phosphorylation Thr18 ALNKRRAtLPHPGGS 9606 BTO:0000007 BTO:0000142;BTO:0000671 10644707 t llicata "Further experiments demonstrated that mst3b, but not mst3, was effectively phosphorylated by activation of cyclic amp-dependent protein kinase (pka) in both in vivo and in vitro assays. The mutation of thr-18 into ala in mst3b (t18a), a putative pka phosphorylation site that is absent in mst3, abolished its phosphorylation by pka." SIGNOR-74284 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000142 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 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000782;BTO:0001271 8125092 t gcesareni "Phosphorylation of either serine 16 or 63 is sufficient to inhibit stathmin in vitro. Phosphorylation at ser-63 reduces tubulin binding 10-fold and suppresses the mt polymerization inhibition activity." SIGNOR-36370 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser63 AAEERRKsHEAEVLK 9606 BTO:0000142 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-38322 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser63 AAEERRKsHEAEVLK 9606 BTO:0000782;BTO:0001271 8125092 t gcesareni "Phosphorylation of either serine 16 or 63 is sufficient to inhibit stathmin in vitro. Phosphorylation at ser-63 reduces tubulin binding 10-fold and suppresses the mt polymerization inhibition activity." SIGNOR-36374 PRKACA protein P17612 UNIPROT STMN2 protein Q93045 UNIPROT "down-regulates activity" phosphorylation Ser50 KQINKRAsGQAFELI 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-250056 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 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 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 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-200496 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 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-119099 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 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser346 RAPSRKDsLESDSST 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-172003 PRKACA protein P17612 UNIPROT SYN1 protein P17600 UNIPROT "down-regulates activity" phosphorylation Ser9 NYLRRRLsDSNFMAN -1 10571231 t miannu "Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I" SIGNOR-250058 PRKACA protein P17612 UNIPROT SYN2 protein Q92777 UNIPROT "down-regulates activity" phosphorylation Ser10 NFLRRRLsDSSFIAN -1 10571231 t miannu "Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I" SIGNOR-250059 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 BTO:0001271 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 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT up-regulates phosphorylation Ser172 NRVKRRPsPYEMEIT 9606 BTO:0001271 22310283 t llicata "The phosphorylation of serine 172 of tal1 specifically destabilizes tal1 interaction with histone demethylase lsd1 and, therefore, leads to the activation of the certain tal1 target genes in differentiated erythroid cells or t-cell leukemia." SIGNOR-195983 PRKACA protein P17612 UNIPROT TENT2 protein Q6PIY7 UNIPROT "down-regulates activity" phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 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 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 PRKACA protein P17612 UNIPROT TFAP2A protein P05549 UNIPROT up-regulates phosphorylation Ser239 AEVQRRLsPPECLNA 9606 10037142 t llicata "Recombinant ap-2 was phosphorylated in vitro by protein kinase a (pka) at ser239. Mutation of ser239 to ala abolished in vitro phosphorylation of ap-2 by pka, but not the dna binding activity of ap-2. Cotransfection studies showed that pka stimulated the effect of ap-2 on the apoe promoter, but not that of the s239a mutant." SIGNOR-64955 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 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 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates phosphorylation Ser23 PAPIRRRsSNYRAYA 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-134605 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates phosphorylation Ser24 APIRRRSsNYRAYAT 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-134609 PRKACA protein P17612 UNIPROT TPH1 protein P17752 UNIPROT "up-regulates activity" phosphorylation Ser58 RKSKRRNsEFEIFVD -1 9109552 t miannu "The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme." SIGNOR-250062 PRKACA protein P17612 UNIPROT TPH2 protein Q8IWU9 UNIPROT up-regulates phosphorylation Ser19 YWARRGFsLDSAVPE 9606 BTO:0000142 18339632 t llicata "We also demonstrate that phosphorylation of serine 19, a protein kinase a consensus site located in this n-terminal domain, results in increased tph2 stability and consequent increases in enzyme output in cell culture systems" SIGNOR-178018 PRKACA protein P17612 UNIPROT UBE3A protein Q05086 UNIPROT "down-regulates activity" phosphorylation Thr508 MYSERRItVLYSLVQ 10090 BTO:0000142 26255772 t gcesareni "These data suggest that PKA phosphorylation at T485 inhibits UBE3A ubiquitin ligase activity in cells." SIGNOR-236899 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 16197368 t llicata "We show that, in human platelets, vasp is phosphorylated by pkc on ser157, but not ser239, in response to phorbol ester stimulation, in a manner blocked by the pkc inhibitor bim i (bisindolylmaleimide i)." SIGNOR-140841 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Thr278 LARRRKAtQVGEKTP -1 8182057 t miannu "The vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cAMP-dependent- (cAK) and cGMP-dependent protein kinase (cGK) in human platelets and other cardiovascular cells.‚  three VASP phosphorylation sites are phosphorylated by cAK and cGK. Thr, Ser I, and Ser 2 correspond to Thr278, Ser157, Ser239 of the VASP protein, respectively" SIGNOR-250065 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT "up-regulates activity" phosphorylation Ser239 GAKLRKVsKQEEASG 9606 BTO:0000132 12576312 t miannu "PKA activation is indeed sufficient to induce phosphorylation of VASP Ser239 in platelets PKA plays a predominant role in the cGMP-induced phosphorylation of VASP and platelet inhibition in human platelets." SIGNOR-250063 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser25 PGTASRPsSSRSYVT -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-250066 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser39 TTSTRTYsLGSALRP -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-250067 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser47 LGSALRPsTSRSLYA -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-250070 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 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser66 GVYATRSsAVRLRSS -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-250068 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser7 sSSSYRRM -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-250071 PRKACA protein P17612 UNIPROT VTN protein P04004 UNIPROT unknown phosphorylation Ser397 NQNSRRPsRATWLSL -1 1706595 t miannu "Phosphorylation of vitronectin by protein kinase A is stoichiometric (approx. 1 mol/mol), that it is targeted to one site (Ser-378) at the C-terminal edge of the heparin-binding domain. gh the role of phosphorylation by PKA remains to be established, the identification of Ser-378 as the sole site for PKA action, and the proximity of the phosphorylation site to the point of cleavage that converts V75 into V65 10' focuses attention on a putative role for PKA in the modulation of this cleavage." SIGNOR-250072 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 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser393 KTCQRKFsRSDHLKT 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-53176 PRKACA protein P17612 UNIPROT YWHAZ protein P63104 UNIPROT up-regulates phosphorylation Ser58 VVGARRSsWRVVSSI 9606 16376338 t llicata "Phosphorylation by pka leads to modulation of 14-3-3zeta dimerization and affect its interaction with partner proteins. Substitution of ser58 to ala completely abolished phosphorylation of 14-3-3zeta by pka." SIGNOR-143373 PRKACB protein P22694 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." SIGNOR-81141 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 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." SIGNOR-81145 PRKACB protein P22694 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." SIGNOR-81149 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 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 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-163772 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 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-163776 PRKACB protein P22694 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./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-163780 PRKACB protein P22694 UNIPROT NGFR protein P08138 UNIPROT up-regulates phosphorylation Ser303 PEGEKLHsDSGISVD 9606 BTO:0000938 12682012 t llicata "Pka phosphorylates the p75 receptor and regulates its localization to lipid rafts. activation of camp?PKA Is required for translocation of p75ntr to lipid rafts, and for biochemical and biological activities of p75ntr, such as inactivation of rho and the neurite outgrowth." SIGNOR-99755 PRKACB protein P22694 UNIPROT TENT2 protein Q6PIY7 UNIPROT "down-regulates activity" phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 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 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 t gcesareni "Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death" SIGNOR-67400 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10230396 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-67392 PRKACG protein P22612 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-81153 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230396 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-67396 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 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-81157 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 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 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 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-163788 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 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-163792 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 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 PRKACG protein P22612 UNIPROT TENT2 protein Q6PIY7 UNIPROT "down-regulates activity" phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 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-259404 PRKAG1 protein P54619 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "form complex" binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 t lperfetto "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-139170 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 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 PRKAG3 protein Q9UGI9 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-139179 PRKAR1A protein P10644 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-258751 PRKAR1A protein P10644 UNIPROT PRKACB protein P22694 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-258755 PRKAR1B protein P31321 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-258753 PRKAR1B protein P31321 UNIPROT PRKACB protein P22694 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-258756 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 PRKAR2A protein P13861 UNIPROT PRKACB protein P22694 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-258757 PRKAR2B protein P31323 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-258754 PRKAR2B protein P31323 UNIPROT PRKACB protein P22694 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-258758 PRKAR2B protein P31323 UNIPROT PRKAR2B protein P31323 UNIPROT "down-regulates activity" phosphorylation Ser114 NRFTRRAsVCAEAYN 10090 BTO:0000944 15822905 t miannu "Ser114 (the autophosphorylation site) of human RII beta. Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A RII beta regulatory subunit to lose its ability to revert transformed fibroblasts." SIGNOR-250076 PRKCA protein P17252 UNIPROT ACO1 protein P21399 UNIPROT down-regulates phosphorylation Ser711 REFNSYGsRRGNDAV 9606 BTO:0000671 15636585 t gcesareni "Irp1 ser-711 is a phosphorylation site, critical for regulation of rna-binding and aconitase activities." SIGNOR-133188 PRKCA protein P17252 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY -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).‚ " SIGNOR-249223 PRKCA protein P17252 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)." SIGNOR-249225 PRKCA protein P17252 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 8810272 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-43744 PRKCA protein P17252 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-59229 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 16116087 t gcesareni "We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta." SIGNOR-139870 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 BTO:0000938 BTO:0000671 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 PRKCA protein P17252 UNIPROT ADD3 protein Q9UEY8 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser693 KKKFRTPsFLKKNKK -1 11895774 t lperfetto "Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. | Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. | The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin" SIGNOR-249143 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser396 RPWTRGGsLERSQSR 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248985 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser402 GSLERSQsRKDSLDD 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248986 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser406 RSQSRKDsLDDSGSC 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248987 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser410 RKDSLDDsGSCLSGS 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248988 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser412 DSLDDSGsCLSGSQR 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248989 PRKCA protein P17252 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-202780 PRKCA protein P17252 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser26 TPPSAYGsVKAYTNF 9606 BTO:0000452 2946940 t lperfetto "The protein-tyrosine kinase substrate p36 is also a substrate for protein kinase C in vitro and in vivo. | We present evidence suggesting that protein kinase C mediates phosphorylation of serine 25." SIGNOR-248892 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 PRKCA protein P17252 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000599 15730925 f irozzo "PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC." SIGNOR-256267 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr157 VLCVLATtDRRRRDL 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-155102 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 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser643 CFTPKGSsLKIEERA 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-36788 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 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser677 AIVSKIDsRLEQYTS 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-36796 PRKCA protein P17252 UNIPROT CASR protein P41180 UNIPROT down-regulates phosphorylation Thr888 FKVAARAtLRRSNVS 9606 21135065 t llicata "Casr(t888) is a protein kinase c (pkc) phosphorylation site in the receptor's intracellular domain that has previously been identified as a critical negative regulator of casr downstream signaling in vitro, thus, casr(t888) represents a functionally important, inhibitory phosphorylation site that contributes to the control of pth secretion." SIGNOR-170334 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser619 RELTNRHsLPFSLPS 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-249054 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser623 NRHSLPFsLPSQMEP 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-249055 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 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 PRKCA protein P17252 UNIPROT CD163 protein Q86VB7 UNIPROT unknown phosphorylation Ser1084 QRQRLAVsSRGENLV 9606 BTO:0000801 11298324 t lperfetto "Furthermore, we demonstrated that the cytoplasmic domains of CD163 variants are phosphorylated by PKC-alpha in vitro. Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines." SIGNOR-249082 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 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-249070 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 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t amattioni "Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation." SIGNOR-85175 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 PRKCA protein P17252 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates phosphorylation Ser153 SMTDFYHsKRRLIFS 9606 16055744 t lperfetto "Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase c-mediated phosphorylation of ser153" SIGNOR-139302 PRKCA protein P17252 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-197285 PRKCA protein P17252 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Thr141 RRDARGLtPLELALQ 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.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response" SIGNOR-197289 PRKCA protein P17252 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 15730925 f irozzo "PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC." SIGNOR-256660 PRKCA protein P17252 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser23 NDMKVRKsSTPEEVK 9606 BTO:0001271 22855535 t lperfetto "Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization" SIGNOR-198478 PRKCA protein P17252 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser24 DMKVRKSsTPEEVKK 9606 BTO:0001271 22855535 t lperfetto "Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization" SIGNOR-198482 PRKCA protein P17252 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser686 WTETKKQsFKQTGEF -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-248849 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 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 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 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-129264 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 PRKCA protein P17252 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-129272 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 ritonavir chemical CHEBI:45409 ChEBI CYP2B6 protein P20813 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000131 18285471 t Luana "These results show that ritonavir induces human CYP2B6 activity. " SIGNOR-257770 PRKCA protein P17252 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates phosphorylation Ser312 ASLKRSPsASSLSSM 9606 20519438 t lperfetto "Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively" SIGNOR-165857 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 PRKCA protein P17252 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates phosphorylation 9606 20577053 t gcesareni "The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex," SIGNOR-166368 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates phosphorylation Thr455 MRLGKRRtLFQTKNS 9606 17463002 t llicata "These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity." SIGNOR-154621 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates phosphorylation Ser462 TLFQTKNsVMRKLYG 9606 17463002 t llicata "These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity." SIGNOR-154617 PRKCA protein P17252 UNIPROT CYBA protein P13498 UNIPROT up-regulates phosphorylation T147 ERPQIGGTIKQPPSN -1 19948736 t Manara "Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding. | Threonine 147 of p22phox Is Phosphorylated by PKC-α and PKC-δ in Vitro" SIGNOR-260891 PRKCA protein P17252 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-249023 PRKCA protein P17252 UNIPROT DDX5 protein P17844 UNIPROT "down-regulates activity" phosphorylation Ser557 VSAGIQTsFRTGNPT -1 7525583 t lperfetto "We report that p68 is phosphorylated by protein kinase C in vitro and binds calmodulin in a Ca(2+)-dependent manner. Both phosphorylation and calmodulin binding inhibited p68 ATPase activity | In addition, a 20-amino acid peptide corresponding to residues 549-568 of p68 was phosphorylated in a Ca- and phospholipid-dependent manner hy PKC" SIGNOR-248896 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT "down-regulates activity" phosphorylation Ser66 MLTKQNNsFQRSKRR 9534 BTO:0000298 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 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT "down-regulates activity" phosphorylation Ser70 QNNSFQRsKRRYFKL 9534 BTO:0000298 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-249266 PRKCA protein P17252 UNIPROT DGKZ protein Q13574 UNIPROT unknown phosphorylation Ser454 SKKKKRAsFKRKSSK 9716136 t lperfetto "Two isoforms of protein kinase C, but not others, regulate the localization of DGK-zeta. |The PSD in MARCKS is phosphorylated by PKC, which suggested that DGK-zeta may also be a substrate for PKC, and that this couldregulate its intracellular location." SIGNOR-249010 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 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT unknown phosphorylation Ser138 KPRTIYSsYQLAALQ 10090 BTO:0000667 11343707 t lperfetto "Dlx3 is primarily phosphorylated by PKCalpha. By deletion and mutational analysis, we show that the serine residue S138, 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. | Since DNA binding may reveal only a part of Dlx3 protein function, we cannot rule out the influence of phosphorylation on other biological functions. Thus, the characterization of the full biological function of PKC phosphorylation of Dlx3 protein will require further studies." SIGNOR-249095 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT "up-regulates activity" phosphorylation Thr134 KKVRKPRtIYSSYQL -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-249097 PRKCA protein P17252 UNIPROT DNM1 protein Q05193 UNIPROT unknown phosphorylation Ser795 VPPARPGsRGPAPGP -1 10766777 t lperfetto "Phosphorylation of dynamin I on Ser-795 by protein kinase C blocks its association with phospholipids." SIGNOR-249039 PRKCA protein P17252 UNIPROT EDF1 protein O60869 UNIPROT "down-regulates activity" phosphorylation Thr91 GRQSKGLtQKDLATK 9606 BTO:0001949 10816571 t lperfetto "EDF-1 was phosphorylated in vitro by PKC in the presence of Ca2+ and phospholipids | This results shows that introduction of a single negative charge by phosphorylation at Thr-91 inhibited CaM-EDF-1 interactions." SIGNOR-249041 PRKCA protein P17252 UNIPROT EGFR protein P00533 UNIPROT up-regulates 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 NFIL3 protein Q16649 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 10090 BTO:0003104 10082541 f lperfetto "NFIL3 inhibits apoptosis without affecting Bcl-xL expression." SIGNOR-256653 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 PRKCA protein P17252 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates phosphorylation Ser234 QRAIPPRsIRGDQIA 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-180203 PRKCA protein P17252 UNIPROT EIF4E protein P06730 UNIPROT unknown phosphorylation Ser209 DTATKSGsTTKNRFV 10090 BTO:0000944 8662663 t lperfetto "Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins." SIGNOR-248945 PRKCA protein P17252 UNIPROT EIF6 protein P56537 UNIPROT unknown phosphorylation Ser235 QPSTIATsMRDSLID 9606 14654845 t llicata "Pkc stimulation led to eif6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eif6 impaired rack1/pkc-mediated translational rescue." SIGNOR-119600 PRKCA protein P17252 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 9341188 t miannu "Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation." SIGNOR-52850 PRKCA protein P17252 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000017 15647376 t lperfetto "Phosphorylation of ezrin is required for both conformational activation and for signaling to downstream events. The activating c-terminal threonine phosphorylation on t567 was first described to be downstream of the rho pathway (matsui et al., 1998). Additional studies have implicated protein kinase c (pkc)  in the phosphorylation of ezrin t567." SIGNOR-133223 PRKCA protein P17252 UNIPROT F11R protein Q9Y624 UNIPROT unknown phosphorylation Ser284 KVIYSQPsARSEGEF 9606 BTO:0000130;BTO:0000876 11027562 t gcesareni "We also demonstrated phosphorylation of ser 284, a putative pkc phosphorylation site, by immunoblotting with anti-phosphoserine-jam antibody in thrombin-stimulated platelets." SIGNOR-83037 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 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 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 t lperfetto "Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7." SIGNOR-248860 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -1 2155236 t lperfetto "Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7." SIGNOR-248862 PRKCA protein P17252 UNIPROT GFPT1 protein Q06210 UNIPROT "down-regulates activity" phosphorylation Ser205 AVGTRRGsPLLIGVR -1 10806197 t lperfetto "Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMP-dependent protein kinase at serine 205 blocks the enzyme activity." SIGNOR-249040 PRKCA protein P17252 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser368 QRPSSRAsSRASSRP 10116 BTO:0002931 10871288 t lperfetto "Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication." SIGNOR-249048 PRKCA protein P17252 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Ser262 SPAKDCGsQKYAYFN 9606 14702389 t gcesareni "Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes." SIGNOR-120907 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 PRKCA protein P17252 UNIPROT GJB1 protein P08034 UNIPROT "up-regulates activity" phosphorylation Ser233 NPPSRKGsGFGHRLS 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-248920 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -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-248960 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser72 QPRFIVYsYKYQHDD -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-248959 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 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 t gcesareni "Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling." SIGNOR-48677 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 PRKCA protein P17252 UNIPROT GRIA1 protein P42261 UNIPROT unknown phosphorylation Ser832 LIEFCYKsRSESKRM 9606 BTO:0000007 8663994 t lperfetto "In addition, protein kinase C specifically phosphorylates Ser-831 of GluR1 in HEK-293 cells and in cultured neurons." SIGNOR-248950 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser683 TKEFFRRsKIAVFDK -1 8848293 t lperfetto "Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG)." SIGNOR-248954 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser717 GVARVRKsKGKYAYL -1 8848293 t lperfetto "Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG)." SIGNOR-248955 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser880 YNVYGIEsVKI 9606 BTO:0000007 10501226 t lperfetto "Here, we show that the C terminus of GluR2 of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor is phosphorylated by protein kinase C and that serine-880 is the major phosphorylation site. This phosphorylation also occurs in human embryonic kidney (HEK) cells by addition of 12-O-tetradecanoylphorbol 13-acetate." SIGNOR-249022 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Thr850 EAKRMKLtFSEAIRN -1 10366608 t lperfetto "In addition, we identified threonine 830 as a potential PKC phosphorylation site." SIGNOR-249017 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni "Receptor internalization, altered;intracellular localization" SIGNOR-97554 PRKCA protein P17252 UNIPROT GRIN2A protein Q12879 UNIPROT unknown phosphorylation Ser1416 ASYCSRDsRGHNDVY 10116 BTO:0000601 11104776 t lperfetto "PKC-dependent phosphorylation of NR2A(Ser(1416)) as a key mechanism in inhibiting alphaCaMKII-binding and promoting dissociation of alphaCaMKII.NR2A complex." SIGNOR-249065 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 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 PRKCA protein P17252 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto "Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells." SIGNOR-249058 PRKCA protein P17252 UNIPROT GRM1 protein Q13255 UNIPROT "down-regulates activity" phosphorylation Thr695 GSKKKICtRKPRFMS 9606 BTO:0000007 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 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 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -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-249285 PRKCA protein P17252 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 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 PRKCA protein P17252 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto "Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka)." SIGNOR-188581 PRKCA protein P17252 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-249246 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 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-249252 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser109 KERRRTEsINSAFAE 9606 BTO:0000007 14636580 t lperfetto "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. " SIGNOR-249242 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Thr107 PKKERRRtESINSAF 9606 BTO:0000007 14636580 t lperfetto "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. " SIGNOR-249244 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 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 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates activity" phosphorylation Ser37 TASEHRKsSKPIMEK -1 9389649 t lperfetto "Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro." SIGNOR-248992 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates activity" phosphorylation Ser38 ASEHRKSsKPIMEKR -1 9389649 t lperfetto "Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro." SIGNOR-248993 PRKCA protein P17252 UNIPROT HLA-A protein P01892 UNIPROT unknown phosphorylation Ser359 SAQGSDVsLTACKV 2941417 t lperfetto "As shown in Fig. 6A, the HLA heavy chain was phosphorylated by kinase C. | The major site of in vivo phosphorylation of the HLA-B7 heavy chain was localized to Ser-335 which is conserved in all specificitie" SIGNOR-248891 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser21 KEEPKRRsARLSAKP 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-76282 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser25 KRRSARLsAKPPAKV 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-76286 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 PRKCA protein P17252 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates phosphorylation Ser29 QRRSARLsAKPAPPK 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-76324 PRKCA protein P17252 UNIPROT HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser95 RAVSREDsQRPGAHL 9606 7727389 t gcesareni "A survey of seven protein kinases showed that a1 was heavily phosphorylated by protein kinase c (pkc) and also was phosphorylated by casein kinase iiamino acid sequencing revealed that these sites were ser95, ser192, and ser199;phosphorylation at ser192 was more abundant than at ser95 and ser199. Phosphorylation by pkc inhibited the strand annealing activity of a1." SIGNOR-32291 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 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" fspada "The peptide p9-s396a/s398a (both ser396 and ser398 to alanines) was phosphorylated only slightly or not phosphorylated by these kinases. Thus both ser396 and ser398 can be phosphorylated by camk ii and pkc" SIGNOR-124352 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 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 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT "up-regulates activity" phosphorylation Thr63 LSSAWPGtLRSGMVP 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-107688 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Ser14 PFSCHYPsRLRRDPF 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-197940 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 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Ser268 WQRRQRKsRRTI 9606 BTO:0000782 2303462 t lperfetto "The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site." SIGNOR-22984 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Thr271 RQRKSRRtI 9606 BTO:0000782 2303462 t lperfetto "The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site." SIGNOR-22988 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1062 AVKTVNEsASLRERI -1 7926007 t lperfetto "Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites." SIGNOR-248905 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1064 KTVNESAsLRERIEF -1 7926007 t lperfetto "Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites." SIGNOR-248906 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Thr1362 YEEHIPYtHMNGGKK -1 8463287 t lperfetto "Therefore, the present study directly identifies threonine 1336 in the HIR as a phosphorylation site for insulin and PMA." SIGNOR-248933 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 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-128714 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 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 PRKCA protein P17252 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 16574739 t flangone "We show that pkcalpha is likely to be directly involved in ser24 phosphorylation...Using Ser24asp irs-1 mutants to mimic the phosphorylated residue, we demonstrate that the phosphorylation status of ser24 does play an important role in regulating phosphoinositide binding to, and the intracellular localization of, the irs1-ph domain, which can ultimately impinge on insulin-stimulated glucose uptake" SIGNOR-145398 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249121 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr760 LFKSATTtVMNPKFA 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249125 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 PRKCA protein P17252 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1494 TLTRDYNsLTRSEHS 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-124498 PRKCA protein P17252 UNIPROT ITPKB protein P27987 UNIPROT "down-regulates activity" -1 9374536 t lperfetto "However, when assayed in the presence of calcium/calmodulin, the activity of the B isoform was decreased following phosphorylation by either protein kinase." SIGNOR-248990 PRKCA protein P17252 UNIPROT KCNE1 protein P15382 UNIPROT "down-regulates activity" phosphorylation Ser102 VQARVLEsYRSCYVV -1 1553557 t lperfetto "Inhibition of the current was not seen in channels in which Ser103 was replaced by Ala, although other properties of the current were unchanged. These results indicate that inhibition of the potassium current results from direct phosphorylation of the channel subunit protein at Ser103." SIGNOR-248852 PRKCA protein P17252 UNIPROT KCNJ13 protein O60928 UNIPROT down-regulates phosphorylation Ser201 TRPSPLTsVRVSAVL 9606 18976636 t gcesareni "After pharmacological pkc activation, kir7.1 currents were strongly inhibited. Co-application of pkc inhibitors attenuated this effect. Inactivation of pkc consensus sites also strongly attenuated the effect with a single site ((201)s) being essential for almost the total pkc sensitivity." SIGNOR-181863 PRKCA protein P17252 UNIPROT KCNMA1 protein Q12791 UNIPROT up-regulates phosphorylation Ser1200 SHSSQSSsKKSSSVH 9606 BTO:0000887;BTO:0001260 19592459 t gcesareni "Results showed that mutating s1076 altered the effect of pkc activation on bk(ca) channels in hek-293 cells" SIGNOR-186755 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT "up-regulates activity" phosphorylation Ser551 CVMRFLVsKRKFKES 10029 BTO:0000246 12754513 t lperfetto "Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process." SIGNOR-249209 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT "up-regulates quantity" phosphorylation Ser558 SKRKFKEsLRPYDVM 10029 BTO:0000246 12754513 t lperfetto "Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process." SIGNOR-249210 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" phosphorylation Ser741 TKADKRRsVRIGSYI 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-248898 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" phosphorylation Ser746 RRSVRIGsYIERDVT 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-248899 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" phosphorylation Ser821 ARDIKNDsNYVVKGN 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-248897 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 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser741 TKADKRRsVRIGSYI 9606 7539802 t miannu "Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity" SIGNOR-28601 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser746 RRSVRIGsYIERDVT 9606 7539802 t miannu "Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity" SIGNOR-28605 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 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 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT unknown phosphorylation Ser525 NTWGCGNsLRTALIN -1 8477740 t lperfetto "An interphase-specific phosphorylation at Ser525 matching the PKC consensus sequence and of peptides phosphorylated by unknown kinases was determined." SIGNOR-248935 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT "up-regulates activity" phosphorylation Ser403 QRSRGRAsSHSSQTQ -1 7925482 t lperfetto "Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence." SIGNOR-248903 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT "up-regulates activity" phosphorylation Ser404 RSRGRASsHSSQTQG -1 7925482 t lperfetto "Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence." SIGNOR-248904 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4517 LYMGGHGsRHSLAST 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-126958 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4520 GGHGSRHsLASTDEK 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-127207 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 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Thr4460 GFQHQRMtNGAMNVE 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-127215 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser159 KKKKKRFsFKKSFKL -1 1560845 t gcesareni "Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin" SIGNOR-243192 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser163 KRFSFKKsFKLSGFS -1 1560845 t gcesareni "Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin" SIGNOR-249650 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser170 SFKLSGFsFKKNKKE -1 1560845 t gcesareni "Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin" SIGNOR-249670 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser101 AAPEAGAsPVEKEAP -1 8034575 t lperfetto "Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites." SIGNOR-248909 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser118 GEAAEPGsPTAAEGE -1 8034575 t lperfetto "Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | We conclude that the primary phosphorylation site is Ser116 |" SIGNOR-248907 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -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-248925 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL 9606 16116087 t llicata "The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms." SIGNOR-139906 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -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-248928 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9606 16116087 t llicata "The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms." SIGNOR-139910 PRKCA protein P17252 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-248931 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser46 VKVNGDAsPAAAESG -1 8034575 t lperfetto "Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites." SIGNOR-248908 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser81 AAGSGAAsPSAAEKG -1 8034575 t lperfetto "Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites." SIGNOR-248910 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser141 MASQKRPsQRHGSKY -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-248869 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 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -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-248871 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser249 GLSLSRFsWGAEGQR -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-248872 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser266 FGYGGRAsDYKSAHK -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-248873 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser285 VDAQGTLsKIFKLGG -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-248874 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -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-248875 PRKCA protein P17252 UNIPROT MET protein P08581 UNIPROT down-regulates phosphorylation Ser985 PHLDRLVsARSVSPT 9606 8294430 t fstefani "These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor." SIGNOR-37718 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser2 sSKRAKAK 9606 22136066 t lperfetto "Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity." SIGNOR-177940 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser3 sKRAKAKT 9606 22136066 t lperfetto "Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity" SIGNOR-192792 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Thr10 SKRAKAKtTKKRPQR 9606 22136066 t lperfetto "Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity" SIGNOR-191536 PRKCA protein P17252 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" phosphorylation Thr115 ADRRKAAtMRERRRL 9534 BTO:0001538 1335366 t lperfetto "FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains." SIGNOR-248845 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 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 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-89154 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 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-89158 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 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-89162 PRKCA protein P17252 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-89166 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 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-89170 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 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-89174 PRKCA protein P17252 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-89178 PRKCA protein P17252 UNIPROT NFATC1 protein O95644 UNIPROT "down-regulates activity" phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 BTO:0000007 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 PRKCA protein P17252 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 t miannu "Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress" SIGNOR-91826 PRKCA protein P17252 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Ser48 RQGGRTSsQRQRDPE 9606 BTO:0001130 11980664 t llicata "Phosphorylation of wild-type nkx3.1 decreased the apparent binding affinity of the protein for the consensus sequence by 3-fold relative to the nonphosphorylated protein (fig. 3) _ ." SIGNOR-86723 PRKCA protein P17252 UNIPROT NOS1 protein P29475 UNIPROT unknown -1 1375933 t lperfetto "We now report that NOS is stoichiometrically phosphorylated by cAMP dependent protein kinase, protein kinase C, and calcium/calmodulin-dependent protein kinase, with each kinase phosphorylating a different serine site on NOS." SIGNOR-248848 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 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser536 GRGSKRLsRSVTMRK 9606 24505490 t llicata "A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498." SIGNOR-204546 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser544 RSVTMRKsQRSSKGS 9606 24505490 t llicata "A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498." SIGNOR-204550 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Thr540 KRLSRSVtMRKSQRS 9606 24505490 t llicata "A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498." SIGNOR-204554 PRKCA protein P17252 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 BTO:0000007 20110267 t llicata "Phosphorylation of nadph oxidase activator 1 (noxa1) on serine 282 by map kinases and on serine 172 by protein kinase c and protein kinase a prevents nox1 hyperactivation." SIGNOR-163667 PRKCA protein P17252 UNIPROT NOXO1 protein Q8NFA2 UNIPROT up-regulates phosphorylation Thr346 AIQSRCCtVTRRALE 9606 23957209 t llicata "Phosphorylation of thr341 allows noxo1 to sufficiently interact with noxa1, an interaction that participates in nox1 activation." SIGNOR-202482 PRKCA protein P17252 UNIPROT NPHS1 protein O60500 UNIPROT "up-regulates activity" phosphorylation Thr1120 EYEESQWtGERDTQS 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-178695 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 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser145 VVCGDRAsGYHYNAL 9606 18755856 t llicata "Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154." SIGNOR-180537 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser164 CKGFFRRsITKNAVY 9606 18755856 t llicata "Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154." SIGNOR-180541 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 PRKCA protein P17252 UNIPROT OCLN protein Q16625 UNIPROT "up-regulates activity" phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 BTO:0000837 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-249105 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 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249089 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249092 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser312 SKSHRRTsLPCIPRE 9606 19261611 t gcesareni "Phosphorylation and activation of pde3a required the activation of pkc" SIGNOR-184448 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser428 IPKRLRRsLPPGLLR 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-184452 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 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser465 VRRDRSTsIKLQEAP 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-184460 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser492 MTLTKSRsFTSSYAI 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-184464 PRKCA protein P17252 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates phosphorylation Ser104 TKLTRIPsAKKYKDI 9606 BTO:0000149 15917297 t miannu "Pea-15 is phosphorylated on two ser residues, ser104 and ser116. Protein kinase c (pkc) phosphorylates ser104 / we report that phosphorylation of pea-15 blocks its interaction with erk1/2 in vitro and in vivo and that phosphorylation of both ser104 and ser116 is required for this effect." SIGNOR-137841 PRKCA protein P17252 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Thr475 TPLSSSNtIRRPRNY -1 1322130 t lperfetto "The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme." SIGNOR-248844 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 PRKCA protein P17252 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 BTO:0000876 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 PRKCA protein P17252 UNIPROT PLCB1 protein Q9NQ66 UNIPROT unknown phosphorylation Ser887 HSQPAPGsVKAPAKT 10090 BTO:0005065 11278470 t lperfetto ". Two-dimensional phosphopeptide mapping and site-directed mutagenesis demonstrated that PKC promoted phosphorylation of PLC beta1 at serine 887 in the nucleus of IGF-I-treated cells. Overexpression of either a PLC beta1 mutant in which the PKC phosphorylation site Ser(887) was replaced by alanine, or a dominant-negative PKC alpha, resulted in a sustained activation of nuclear PLC following IGF-I stimulation." SIGNOR-249081 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 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 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser2 sLKNEPRV 9606 BTO:0000142 10441128 t gcesareni "Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells." SIGNOR-69930 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser561 PRKFSKFsLYKQLHR 9606 BTO:0000142 10441128 t gcesareni "Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells." SIGNOR-69934 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Thr147 PIPTRRHtFRRQNVR 9606 BTO:0000142 10441128 t gcesareni "Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells." SIGNOR-69938 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Ser243 RWLVVKDsFLLYMCL 9606 15979581 t miannu "The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity" SIGNOR-138351 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr252 LLYMCLEtGAISFVQ 9606 15979581 t miannu "The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity" SIGNOR-138355 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser113 GQKFARKsTRRSIRL 9606 7559487 t miannu "Pleckstrin is a substrate for protein kinase c / a combination of phosphopeptide analysis and site-directed mutagenesis shows that three residues in the intervening sequence between the two pleckstrin ph domains become phosphorylated: ser113, thr114, and ser117. /these results suggest that the phosphorylation of at least two of the sites is required for maximal pleckstrin activity" SIGNOR-28880 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser117 ARKSTRRsIRLPETI 9606 7559487 t gcesareni "To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%." SIGNOR-28884 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser117 ARKSTRRsIRLPETI 9606 8615792 t gcesareni "To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%." SIGNOR-40048 PRKCA protein P17252 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates phosphorylation Thr38 QKRHARVtVKYDRRE 9606 BTO:0000938 BTO:0000887;BTO:0000142 12495628 t gcesareni "A biochemical circuit that involves pkc-mediated activation of cpi-17 modulates the distinct physiological processes of vascular contractility and cerebellar ltd." SIGNOR-96692 PRKCA protein P17252 UNIPROT PPP1R14A protein Q96A00 UNIPROT unknown phosphorylation Thr38 QKRHARVtVKYDRRE -1 15003508 t lperfetto "For that purpose, PKCa, e, l, and f were incubated with CPI-17 in the presence of 50 lM [c- 32P]ATP and kinase buffer. The results indicated that all PKC isoforms were able to phosphorylate CPI-17 in vitro (Table 1). PKCa phosphorylated CPI-17 to a similar extent to PKCe and to a much greater extent than f and l." SIGNOR-249259 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 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 PRKCA protein P17252 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 t llicata "These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748." SIGNOR-66666 PRKCA protein P17252 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 10197446 t llicata "These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748." SIGNOR-66670 PRKCA protein P17252 UNIPROT PRKG1 protein Q13976 UNIPROT up-regulates phosphorylation Thr59 THIGPRTtRAQGISA 9606 12609995 t gcesareni "Antibodies generated against phosphorylated threonine 58 were used to demonstrate phosphorylation in response to pma treatment of the cells with kinetics similar to vasodilator-stimulated phosphoprotein phosphorylation. A phospho-mimetic mutation at this site (t58e) generated a partially activated pkg that was more sensitive to cgmp levels. A phospho- mutation (t58a) revealed that this residue is important but not sufficient for pkg activation by pkc." SIGNOR-98803 PRKCA protein P17252 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 15730925 f irozzo "PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC." SIGNOR-256266 PRKCA protein P17252 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-249236 PRKCA protein P17252 UNIPROT PTGIR protein P43119 UNIPROT unknown phosphorylation Ser328 TPLSQLAsGRRDPRA 9606 BTO:0000007 9722557 t lperfetto "These results indicate that PKC-dependent phosphorylation is of critical importance to homologous regulation of hIP. Ser-328 is a primary site for PKC phosphorylation of hIP." SIGNOR-249011 PRKCA protein P17252 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates phosphorylation Ser39 FMRLRRLsTKYRTEK 9606 BTO:0000567 7520867 t miannu "Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435 / phosphorylation of ser39 in vitro decreases the activity of ptp-pest by reducing its affinity for substrate." SIGNOR-27300 PRKCA protein P17252 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates phosphorylation Ser435 KKLERNLsFEIKKVP 9606 BTO:0000567 7520867 t llicata "Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435. our results suggest that both pkc and pka are capable of phosphorylating, and therefore inhibiting, ptp-pest in vivo" SIGNOR-27304 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 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser497 ATVKSRWsGSQQVEQ 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-37844 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser499 VKSRWSGsQQVEQPT 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-97644 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 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 12551925 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-97648 PRKCA protein P17252 UNIPROT RALB protein P11234 UNIPROT unknown phosphorylation Ser198 KSSKNKKsFKERCCL 9606 BTO:0000763 20940393 t llicata "Here we test this hypothesis and show that ralb is phosphorylated at s198 by protein kinase c (pkc). this indicates phosphorylation of ralb is important for the development of lung metastasis in human bladder cancer cells." SIGNOR-168532 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 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 11910029 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-249147 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 9099669 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-248967 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser343 TVSKTETsQVAPA -1 11910029 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-249148 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 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Thr336 GDDEASAtVSKTETS -1 9099669 t lperfetto "Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343." SIGNOR-248969 PRKCA protein P17252 UNIPROT RORA protein P35398 UNIPROT unknown phosphorylation Ser35 ETPLNQEsARKSEPP 9606 20122401 t llicata "Wnt5a/pkcalpha-dependent phosphorylation on serine residue 35 of roralpha is crucial to link roralpha to wnt/beta-catenin signaling, which exerts inhibitory function of the expression of wnt/beta-catenin target genes." SIGNOR-163702 PRKCA protein P17252 UNIPROT RPL10 protein P27635 UNIPROT unknown -1 9016777 t lperfetto "QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun." SIGNOR-248957 PRKCA protein P17252 UNIPROT RPL10 protein P27635 UNIPROT unknown phosphorylation Ser168 GRQKIHIsKKWGFTK -1 9016777 t lperfetto "Moreover, QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun. " SIGNOR-248958 PRKCA protein P17252 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 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-97279 PRKCA protein P17252 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-249000 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 BTO:0002320 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-249002 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 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -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-249006 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 PRKCA protein P17252 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248973 PRKCA protein P17252 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248976 PRKCA protein P17252 UNIPROT SDC4 protein P31431 UNIPROT "up-regulates activity" phosphorylation Ser179 MKKKDEGsYDLGKKP 10116 BTO:0001176 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-249149 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT "down-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. | Thus, we have identified a new mechanism whereby serine phosphorylation of ShcA controls the ability of its phosphotyrosine-binding domain to bind PTP-PEST, which is responsible for the dephosphorylation and down-regulation of ShcA after insulin stimulation." SIGNOR-249150 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser161 ENLTQVGsILGNLKD 9606 BTO:0000132 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249227 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser23 ITDESLEsTRRILGL 9606 BTO:0000132 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249228 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Thr24 TDESLEStRRILGLA 9606 BTO:0000132 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249229 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Ser187 RIMEKADsNKTRIDE 9606 BTO:0000567 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 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 PRKCA protein P17252 UNIPROT SPAG1 protein Q07617 UNIPROT unknown phosphorylation Ser326 VERDLKNsEAASETQ -1 11517287 t lperfetto "In-vitro incubation with [_-32P]ATP showed that HSD-3.8 protein can be phosphorylated by PKC. The phosphate is probably linked to the serine residue presenting the sequence X LysXX SerX." SIGNOR-249109 PRKCA protein P17252 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Ser12 KSKPKDAsQRRRSLE -1 2996780 t lperfetto "We propose that protein kinase C is responsible for this modification based on the following evidence. First, the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and teleocidin, and synthetic diacylglycerol, known activators of protein kinase C in vivo, cause nearly complete phosphorylation of pp60src at serine 12. Second, among five purified serine/threonine-specific protein kinases tested, only protein kinase C phosphorylates pp60c-src and pp60v-src in vitro at serine 12. Third, purified protein kinase C phosphorylates a synthetic peptide corresponding to the N-terminal 20 amino acids of pp60c-src at serine 12. The physiological significance of this novel phosphorylation is discussed." SIGNOR-248893 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 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT down-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 9606 BTO:0000887;BTO:0001260 19778940 t llicata "In summary, the results from the present study indicate that phosphorylation of srf at t159 by pka inhibits smc-specific transcription by inhibiting srf binding to carg elements." SIGNOR-188181 PRKCA protein P17252 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249182 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser5 sSKKRKPK 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-126568 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 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "down-regulates activity" phosphorylation Ser166 LGARAKEsLDLRAHL -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249069 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "down-regulates activity" phosphorylation Ser23 PAPIRRRsSNYRAYA -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249066 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "down-regulates activity" phosphorylation Ser24 APIRRRSsNYRAYAT -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249067 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "down-regulates activity" phosphorylation Ser39 EPHAKKKsKISASRK -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249068 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 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-134613 PRKCA protein P17252 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-134617 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 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 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 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 BTO:0000671 15533987 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-130269 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1145 RDKRESDsERLKRTS 9606 15590641 t gcesareni "Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites." SIGNOR-132243 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1152 SERLKRTsQKVDLAL 9606 15590641 t gcesareni "Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites." SIGNOR-132247 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation S162 FDIVSRGSTADLDGL 9606 BTO:0000007 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-260886 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation S189 TDEEFREPST 9606 BTO:0000007 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 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation T175 GLLPFLLTHKKRLTD 9606 BTO:0000007 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-260882 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 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT "up-regulates activity" phosphorylation Ser654 YVEVFKNsDKEDDQE 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-149952 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1101 NAQNLMQsVKETVRE -1 11741957 t lperfetto "PKC Phosphorylates Serines 1033 and 1045 in Helix H5" SIGNOR-249128 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1113 VREAEAAsIKIRTDA -1 11741957 t lperfetto "PKC Phosphorylates Serines 1033 and 1045 in Helix H5" SIGNOR-249129 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser10 TRSVSSSsYRRMFGG -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-248877 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser22 FGGPGTAsRPSSSRS -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-248878 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 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser27 TASRPSSsRSYVTTS -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-248879 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 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser39 TTSTRTYsLGSALRP 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-248885 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser42 TRTYSLGsALRPSTS -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-248881 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser51 LRPSTSRsLYASSPG -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-248883 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser66 GVYATRSsAVRLRSS -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-248884 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser7 sSSSYRRM -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-248886 idelalisib chemical CHEBI:82701 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190813 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser9 STRSVSSsSYRRMFG -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-248876 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 PRKCB protein P05771 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-202784 PRKCB protein P05771 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser2 sTVHEILC -1 8898866 t lperfetto "A comparison of the phosphorylation patterns obtained identified Ser-II as the protein kinase C site responsible for regulating the annexin II-p11 interaction. Ser-II lies within the sequence mediating p11 binding, i.e. amino-acid residues 1 to 14 of annexin II, and phosphorylation at this site most likely leads to a direct spatial interference with p11 binding." SIGNOR-248956 PRKCB protein P05771 UNIPROT BTK protein Q06187 UNIPROT "down-regulates activity" phosphorylation Ser180 GSLKPGSsHRKTKKP 9606 BTO:0003076 11598012 t lperfetto "We provide direct evidence that PKCbeta acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCbeta results in a dramatic increase in B-cell receptor (BCR)-mediated Ca2+ signaling. We identified a highly conserved PKCbeta serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and FcepsilonRI-mediated signaling in B and mast cells, respectively. | This deductive analysis indicated that PKCbeta phosphorylates S180 in the region bisecting the Btk motif (BM) and the PRR of the TH domain." SIGNOR-249110 PRKCB protein P05771 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 t lperfetto "Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization" SIGNOR-151011 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 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 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-249073 PRKCB protein P05771 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-249075 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 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-129280 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 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 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 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 PRKCB protein P05771 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-129292 PRKCB protein P05771 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-129296 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 BTO:0000142 12486117 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-96632 PRKCB protein P05771 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-249024 PRKCB protein P05771 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-249026 PRKCB protein P05771 UNIPROT EIF4E protein P06730 UNIPROT unknown phosphorylation Ser209 DTATKSGsTTKNRFV 10090 BTO:0000944 8662663 t lperfetto "Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins." SIGNOR-248946 PRKCB protein P05771 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 9341188 t miannu "Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation." SIGNOR-52854 PRKCB protein P05771 UNIPROT EWSR1 protein Q01844 UNIPROT up-regulates phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 19076070 t lperfetto "Ews was reported to be phosphorylated in vitro by pkc (protein kinase c). The site of phosphorylation was not identified, but was suggested to be ser266 . The mutation of ser266 to alanine suppressed phosphorylation and binding to dna and reduced the transcriptional activity of the ews-fli1 fusion protein by 40%" SIGNOR-182786 PRKCB protein P05771 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser41 AATKIQAsFRGHITR -1 2140056 t lperfetto "We conclude that serine-41 is the protein kinase C phosphorylation site of neuromodulin and that phosphorylation of this amino acid residue blocks binding of calmodulin to neuromodulin." SIGNOR-248859 PRKCB protein P05771 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser368 QRPSSRAsSRASSRP 10116 BTO:0002931 10871288 t lperfetto "Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication." SIGNOR-249049 PRKCB protein P05771 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-249084 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 PRKCB protein P05771 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-249279 PRKCB protein P05771 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -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-249286 PRKCB protein P05771 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 11884598 t gcesareni "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-115718 PRKCB protein P05771 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-249247 PRKCB protein P05771 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 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-249253 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1200 ASSLHSVsSKSFRDF 9606 BTO:0000776 21482705 t llicata "We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane." SIGNOR-173383 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1203 LHSVSSKsFRDFLLE 9606 BTO:0000776 21482705 t llicata "We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane." SIGNOR-173387 PRKCB protein P05771 UNIPROT ILF3 protein Q12906 UNIPROT down-regulates phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 BTO:0000782 20870937 t llicata "In this study, we demonstrate that pma stimulation led to phosphorylation of nf90 at ser(647) via pkc_i. This phosphorylation was necessary for nuclear export of nf90 in response to pma and for il-2 mrna stabilization." SIGNOR-168173 PRKCB protein P05771 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249119 PRKCB protein P05771 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249122 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser15 SSYRGRKsGNKPPSK 9606 7993631 t gcesareni "We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type." SIGNOR-35622 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser15 SSYRGRKsGNKPPSK 9606 9649584 t gcesareni "This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation." SIGNOR-58498 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 7993631 t gcesareni "We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type." SIGNOR-35626 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 9649584 t gcesareni "This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation." SIGNOR-58502 PRKCB protein P05771 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates phosphorylation Ser146 MEPERRDsQDGSSYR 9606 BTO:0000150 12571245 t lperfetto "Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration" SIGNOR-97942 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser395 LKLSPSPsSRVTVSR -1 8034666 t lperfetto "Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo." SIGNOR-248911 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser405 VTVSRASsSRSVRTT 9606 BTO:0001271 8034666 t lperfetto "Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo." SIGNOR-248912 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -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-248923 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -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-248926 PRKCB protein P05771 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-248929 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 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 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-89186 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 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-89193 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 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-89197 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 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 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-89205 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 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-89209 PRKCB protein P05771 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-89213 PRKCB protein P05771 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 t miannu "Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress" SIGNOR-91830 PRKCB protein P05771 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-251630 PRKCB protein P05771 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-248914 PRKCB protein P05771 UNIPROT OCLN protein Q16625 UNIPROT "up-regulates activity" phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 BTO:0000837 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-249106 PRKCB protein P05771 UNIPROT ORAI1 protein Q96D31 UNIPROT down-regulates phosphorylation Ser27 GGSTTSGsRRSRRRS 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-166040 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 PRKCB protein P05771 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249090 PRKCB protein P05771 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249093 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT down-regulates phosphorylation Ser661 QNEFAGFsYTNPEFV 9606 10828076 t "The effect has been demonstrated using P05771-2" llicata "We found in preliminary studies that autophosphorylation at ser660 was enhanced in response to angiotensin ii and phorbol esters.2 this raises the possibility that initial translocation and activation of pkc result in further autophosphorylation, which then provides a further force for reverse translocation and signal termination." SIGNOR-77583 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT unknown phosphorylation Ser16 PPSEGEEsTVRFARK -1 2377895 t lperfetto "Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16" SIGNOR-248863 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT unknown phosphorylation Thr17 PSEGEEStVRFARKG -1 2377895 t lperfetto "Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16" SIGNOR-248868 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates 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 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 PRKCB protein P05771 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-249237 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser580 CAEMREDsARVYENV 9606 BTO:0000007 11781100 t lperfetto " In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta." SIGNOR-249136 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 BTO:0000007 11781100 t lperfetto " In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta." SIGNOR-249139 PRKCB protein P05771 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. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619." SIGNOR-37474 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 PRKCB protein P05771 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 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-97283 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 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 PRKCB protein P05771 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-249005 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -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-249007 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 PRKCB protein P05771 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248974 PRKCB protein P05771 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248977 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 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0001271 7637391 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-30353 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 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-50598 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0001271 7637391 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-30357 PRKCB protein P05771 UNIPROT STXBP1 protein P61764 UNIPROT "down-regulates activity" phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249186 PRKCB protein P05771 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249183 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" phosphorylation Ser466 SKASSRRsSFSMEEG 10090 BTO:0000968 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 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" phosphorylation Ser467 KASSRRSsFSMEEGD 10090 BTO:0000968 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-255316 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 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-134624 PRKCB protein P05771 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-134628 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 17010989 t lperfetto "Pkc-betaii sensitizes cardiac myofilaments to ca2+ by phosphorylating troponin i on threonine-144." SIGNOR-149957 PRKCB protein P05771 UNIPROT TOP2A protein P11388 UNIPROT "up-regulates activity" phosphorylation Ser29 EDAKKRLsVERIYQK 9606 BTO:0000567 12569090 t lperfetto "Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides." SIGNOR-249195 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser523 MEKEDYHsLYQSHL 9606 BTO:0000848 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 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser527 DYHSLYQsHL 9606 BTO:0000848 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-67870 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser713 KKKFRTPsFLKKSKK -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-248952 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 PRKCD protein Q05655 UNIPROT ADRA2A protein P08913 UNIPROT "up-regulates activity" phosphorylation Ser232 RRTRVPPsRRGPDAV 10029 BTO:0000246 11732925 t lperfetto "Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling." SIGNOR-249126 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser261 TGHGLRRsSKFCLKE -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-248854 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 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser345 ELLCLRRsSLKAYGN -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-248857 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser346 LLCLRRSsLKAYGNG -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-248856 PRKCD protein Q05655 UNIPROT BAG3 protein O95817 UNIPROT up-regulates phosphorylation Ser187 SSSSSSAsLPSSGRS 9606 23108398 t lperfetto "Pkc_-mediated phosphorylation of bag3 at ser187 site induces epithelial-mesenchymal transition and enhances invasiveness in thyroid cancer fro cells. we showed that bag3 was implicated in epithelial-mesenchymal transition (emt) procedure, and phosphorylation state at ser187 site had a critical role in emt regulation by bag3." SIGNOR-199316 PRKCD protein Q05655 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t lperfetto "In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation." SIGNOR-249108 PRKCD protein Q05655 UNIPROT BEST1 protein O76090 UNIPROT "down-regulates activity" phosphorylation S358 SAQFRRASFMGSTFN 9606 BTO:0000007 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 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 10636859 t gcesareni "Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation." SIGNOR-73967 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 12464600 t gcesareni "Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation." SIGNOR-96067 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 t gcesareni "Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation." SIGNOR-151015 PRKCD protein Q05655 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation S167 LFPSFIHSQKRNPQT 9935 BTO:0001141 24211614 t Manara "Endothelin-1 stimulates catalase activity through the PKCδ-mediated phosphorylation of serine 167." SIGNOR-260904 PRKCD protein Q05655 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates activity" phosphorylation T790 TRNDVAPTLMSVPRY 10029 BTO:0000246 27203386 t Manara "Phosphorylation of E-cadherin at threonine 790 by protein kinase Cδ reduces β-catenin binding and suppresses the function of E-cadherin." SIGNOR-260893 PRKCD protein Q05655 UNIPROT CHAT protein P28329 UNIPROT "up-regulates quantity" phosphorylation Ser558 VPTYESAsIRRFQEG 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-249271 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 PRKCD protein Q05655 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Ser171 EKVSRRLsRSKNEPR 9606 20335173 t lperfetto "A novel cross-talk in diacylglycerol signaling: the rac-gap beta2-chimaerin is negatively regulated by protein kinase cdelta-mediated phosphorylation. phosphorylation of beta2-chimaerin on ser(169) located in the sh2-c1 domain linker region via protein kinase cdelta, which retained beta2-chimaerin in the cytosol and prevented its c1 domain-mediated translocation to membranes" SIGNOR-164687 PRKCD protein Q05655 UNIPROT CREBBP protein Q92793 UNIPROT unknown phosphorylation Ser437 CLPLKNAsDKRNQQT 11463380 t lperfetto "This study demonstrates that transcriptional control of mitogen-responsive genes by AP-1 and Pit-1 response elements involves direct phosphorylation of CBP and that growth factor€“dependent phosphorylation of CBP within the GF box is indispensable for signaling via these sites. " SIGNOR-249104 PRKCD protein Q05655 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation S715 GYRQDDPSYRSFHSG 9606 BTO:0000007 25639486 t Manara "Moreover, protein kinase Cδ, which directly phosphorylates β-catenin at Ser715, is required for the TRIM33–β-catenin interaction. | Phosphorylation of β-catenin Ser715 is critical for TRIM33-induced β-catenin degradation" SIGNOR-260897 PRKCD protein Q05655 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" phosphorylation S405 KTQTPPVSPAPQPTE 10029 BTO:0000246 26490115 t Manara "Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosphorylation is dependent on PLCβ3-mediated PKCδ activation" SIGNOR-260889 PRKCD protein Q05655 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" phosphorylation S418 KTQTPPVSPAPQPTE 10029 BTO:0000246 26490115 t Manara "Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosp" SIGNOR-260890 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates activity" phosphorylation S324 LTSVSRGSSLKILSK 9606 BTO:0000007 10521508 t Manara "Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization." SIGNOR-260898 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates activity" phosphorylation S325 LTSVSRGSSLKILSK 9606 BTO:0000007 10521508 t Manara "Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization." SIGNOR-260899 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates activity" phosphorylation S338 LSKGKRGGHSSVSTES 9606 BTO:0000007 10521508 t Manara "Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization." SIGNOR-260900 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates activity" phosphorylation S339 LSKGKRGGHSSVSTES 9606 BTO:0000007 10521508 t Manara "Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization." SIGNOR-260901 PRKCD protein Q05655 UNIPROT CYBA protein P13498 UNIPROT up-regulates phosphorylation T147 ERPQIGGTIKQPPSN -1 19948736 t Manara "Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding. | Threonine 147 of p22phox Is Phosphorylated by PKC-α and PKC-δ in Vitro" SIGNOR-260892 PRKCD protein Q05655 UNIPROT CYTH1 protein Q15438 UNIPROT unknown phosphorylation Ser394 ARKKKVSsTKRH 9606 BTO:0001948 11438522 t lperfetto "We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1. " SIGNOR-249098 PRKCD protein Q05655 UNIPROT CYTH1 protein Q15438 UNIPROT unknown phosphorylation Thr395 RKKKVSStKRH 9606 BTO:0001948 11438522 t lperfetto "We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1. " SIGNOR-249099 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 BTO:0001130 10542228 t gcesareni "Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2." SIGNOR-71764 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 PRKCD protein Q05655 UNIPROT DAP3 protein P51398 UNIPROT up-regulates phosphorylation Thr237 ITRVRNAtDAVGIVL 9606 18227431 t amattioni "Dap3 is phosphorylated by protein kinase cdelta on thr237. Dap3 was originally identified as a pro-apoptotic protein. The mutation of the phosphorylation site thr237 to alanine reversed the cell death caused by the wild-type dap3" SIGNOR-160488 PRKCD protein Q05655 UNIPROT DBI protein P07108 UNIPROT up-regulates phosphorylation Thr42 ATVGDINtERPGMLD 9606 BTO:0000938 18194441 t gcesareni "Acyl coenzyme a-binding protein (acbp) is phosphorylated following protein kinase c activation." SIGNOR-160393 PRKCD protein Q05655 UNIPROT DNM1L protein O00429 UNIPROT up-regulates phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000567 17301055 t gcesareni "Drp1 was specifically phosphorylated in mitosis by cdk1/cyclin b on ser-585. Exogenous expression of unphosphorylated mutant drp1s585a led to reduced mitotic mitochondrial fragmentation." SIGNOR-153148 PRKCD protein Q05655 UNIPROT EEF1A1 protein P68104 UNIPROT unknown phosphorylation Thr432 AVRDMRQtVAVGVIK 7890750 t lperfetto "PKC delta phosphorylates eEF-1 alpha at Thr-431" SIGNOR-248902 PRKCD protein Q05655 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Thr678 RHIVRKRtLRRLLQE 10090 BTO:0001867 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 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 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 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 PRKCD protein Q05655 UNIPROT ENOX2 protein Q16206 UNIPROT up-regulates phosphorylation Ser504 ENLKEKEsCASRLCA 9606 22659163 t lperfetto "Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein." SIGNOR-197706 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 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 PRKCD protein Q05655 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates phosphorylation Thr312 TNGEFKMtDPDEVAR 9606 24058639 t miannu "After tgf-_ stimulation, fli1 phosphorylation by protein kinase c-_ induces disassembly of this transcription repressor complex and the acetylation of fli1 by pcaf, leading to the loss of fli1 dna binding. / phosphorylation of fli1 at threonine 312 decreases its interactions with p300 and hdac1" SIGNOR-202693 PRKCD protein Q05655 UNIPROT FSCN1 protein Q16658 UNIPROT "down-regulates activity" phosphorylation Ser39 KVNASASsLKKKQIW 9606 BTO:0000931 8647875 t lperfetto "Phosphorylation of human fascin inhibits its actin binding and bundling activities." SIGNOR-248944 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 PRKCD protein Q05655 UNIPROT G6PD protein P11413 UNIPROT up-regulates phosphorylation Thr236 NIACVILtFKEPFGT 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-167053 PRKCD protein Q05655 UNIPROT GNAZ protein P19086 UNIPROT unknown phosphorylation Ser27 DRHLRSEsQRQRREI 9606 BTO:0000007 8429024 t lperfetto "Gz alpha variants containing selected substitutions of alanine for serine residues were expressed in human kidney 293 cells, and the ability of each to be phosphorylated in response to phorbol 12-myristate 13-acetate was examined. A focus was placed on Ser25 and Ser27, the 2 serine residues within a sequence of Gz alpha used to obtain a phosphorylation-sensitive antibody. The results demonstrate that Ser27 is the primary site of phosphorylation. Conversion of Ser27 to an alanine resulted in a 65% decrease in incorporation of [32P] phosphate; conversion of Ser25 had no effect." SIGNOR-248932 PRKCD protein Q05655 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto "Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells." SIGNOR-249059 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 PRKCD protein Q05655 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -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-249287 PRKCD protein Q05655 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 11884598 t gcesareni "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-115722 PRKCD protein Q05655 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Thr46 PHRYRPGtVALREIR 9606 BTO:0000130 19363025 t gcesareni "We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation." SIGNOR-185144 PRKCD protein Q05655 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-249248 PRKCD protein Q05655 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 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-249254 PRKCD protein Q05655 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation S259 FPLRKTASEPNLKVR 9606 BTO:0001949 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 PRKCD protein Q05655 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation S498 RHRPLSRTQSSPLPQ 9606 BTO:0001949 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-260876 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 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser64 PRGRPKGsKNKGAAK 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-73610 PRKCD protein Q05655 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Ser302 GRGGRGGsRARNLPL 9606 10329716 t lperfetto "Ser302 is a major k protein site phosphorylated by pkcdelta in vitrothe ability of pkc_ to inducibly bind and phosphorylate k protein may serve not only to alter the activity of k protein itself, but k protein may also provide an avenue for pkc_ to engage in a cross-talk with other k protein molecular partners in response to specific changes in the extracellular environment" SIGNOR-67515 PRKCD protein Q05655 UNIPROT HNRNPK protein P61978 UNIPROT unknown phosphorylation S302 GRGGRGGSRARNLPL 9606 BTO:0000661 10329716 t Manara "We have shown that PKCδ binds and phosphorylates K protein. These observations broaden the range of K protein interactions. PKCδ targets Ser302, which is located in the middle of what appears to be a highly interactive KI domain" SIGNOR-260877 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 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 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 BTO:0000671 9335553 f gcesareni "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-52707 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000222 BTO:0000887;BTO:0001103 16611834 t gcesareni "Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta." SIGNOR-146105 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000671 15069075 t gcesareni "Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta." SIGNOR-123734 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15143153 t gcesareni "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-124737 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249120 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249124 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT "up-regulates activity" phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000782 11700305 t lperfetto "We identify catalytic domain fragments of protein kinase c (pkc) delta and pkcbetai/ii as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin cd18 chain. The sites phosphorylated in vitro were identified as ser-745 and thr-758. Pkc-mediated phosphorylation of cd18 after cell stimulation could lead to the recruitment of 14-3-3 proteins to the activated integrin, which may play a role in regulating its adhesive state or ability to signal." SIGNOR-111495 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000782 18550856 t gcesareni "In this study, we present evidence that pkc isoforms are the major protein kinases that phosphorylate the c terminus of the integrin cd18 chain in leukocytes. Ser-745 is identified as a novel phosphorylation site in the integrin cytoplasmic domain. Additionally, we show that a thr-758-phosphorylated integrin peptide can interact with 14-3-3 proteins in leukocyte lysates" SIGNOR-178897 PRKCD protein Q05655 UNIPROT ITGB7 protein P26010 UNIPROT unknown phosphorylation Thr783 PLYKSAItTTINPRF 10090 BTO:0001825 12682249 t lperfetto "Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784)." SIGNOR-249205 PRKCD protein Q05655 UNIPROT KCNJ1 protein P48048 UNIPROT "up-regulates activity" 9606 BTO:0000007 8621594 t lperfetto "To determine whether this channel is a substrate for PKA, ROMK tagged with the hemagglutinin epitope was transiently transfected into HEK293 cells. In vitro labeling of immunoprecipitated proteins from transfected cells showed that ROMK could be phosphorylated by PKA. | Taken together, these results provide strong evidence that direct phosphorylation of the channel polypeptide by PKA is involved in channel regulation and PKA-dependent phosphorylation is essential for ROMK channel activity." SIGNOR-248943 PRKCD protein Q05655 UNIPROT KLF5 protein Q13887 UNIPROT "up-regulates activity" phosphorylation Ser153 LRTGLYKsQRPCVTH 9606 BTO:0003038 12682370 t lperfetto "Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function. | Inhibition of protein kinase activity by H7 or calphostin C blocked both full-length and N-terminal fragment (amino acids 1-238) KLF5 activities. Mutation at a potential protein kinase C phosphorylation site within the CBP interaction domain of KLF5 reduces its transactivation function. Furthermore, using the GST pull-down approach, we showed that phosphorylation of KLF5 enhances its interaction with CBP. The results of the present study provide a mechanism for KLF5 transactivation function. | We found that KLF5€™s activity was reduced to half when the serine in the potential PKC phosphorylation site was mutated to alanine (Fig. 6B, S153A) Nonetheless, the S153A mutant still retains significant transactivation activity." SIGNOR-249206 PRKCD protein Q05655 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Thr1224 RYVPPSStDRSPYEK 9606 11877440 t gcesareni "We show that phosphorylation of muc1 by pkcdelta increases binding of muc1 and beta-catenin in vitro and in vivo. The functional significance of the muc1-pkcdelta interaction is further supported by the demonstration that mutation of the pkcdelta phosphorylation site abrogates muc1-mediated decreases in binding of beta-catenin to e-cadherin" SIGNOR-115501 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 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-150351 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 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-150355 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 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-89217 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 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-89221 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 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 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-89229 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 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-89233 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 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-89237 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 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 PRKCD protein Q05655 UNIPROT NCF4 protein Q15080 UNIPROT "up-regulates activity" phosphorylation Thr154 LRRLRPRtRKVKSVS 9606 BTO:0000738 9804763 t lperfetto "P40(phox) is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase. Implication of a protein kinase c-type kinase in the phosphorylation process." SIGNOR-249012 PRKCD protein Q05655 UNIPROT NFE2L2 protein Q16236 UNIPROT "up-regulates activity" phosphorylation Ser40 SREVFDFsQRRKEYE -1 12198130 t lperfetto "Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription." SIGNOR-249161 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 PRKCD protein Q05655 UNIPROT NR2F6 protein P10588 UNIPROT down-regulates phosphorylation Ser83 CKSFFKRsIRRNLSY 9606 BTO:0000782 18701084 t esanto "Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6." SIGNOR-180017 PRKCD protein Q05655 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-249063 PRKCD protein Q05655 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Ser360 ELKALLQsSASRKTQ 9606 BTO:0000938 21145366 t gcesareni "Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb" SIGNOR-170348 PRKCD protein Q05655 UNIPROT PEBP1 protein P30086 UNIPROT up-regulates phosphorylation Ser153 RGKFKVAsFRKKYEL 9606 14654844 t miannu "Here we show that the raf kinase inhibitor protein (rkip) is a physiological inhibitor of grk-2. After stimulation of gpcr, rkip dissociates from its known target, raf-1 (refs 6-8), to associate with grk-2 and block its activity. This switch is triggered by protein kinase c (pkc)-dependent phosphorylation of the rkip on serine 153." SIGNOR-119551 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 PRKCD protein Q05655 UNIPROT PLSCR1 protein O15162 UNIPROT up-regulates phosphorylation Thr161 CGPSRPFtLRIIDNM 9606 BTO:0000661 BTO:0000975 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 PRKCD protein Q05655 UNIPROT PLSCR3 protein Q9NRY6 UNIPROT up-regulates phosphorylation Thr21 PPPPYPVtPGYPEPA 9606 16267027 t gcesareni "Ad198-activated pkc-delta induces phosphorylation of mitochondrial pls3 at thr21;pls3 is a critical downstream effector of pkc-delta in ad198-induced apoptosis." SIGNOR-140759 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser302 TQRASRRsDSASSEP 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-185291 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 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser503 KENIFGEsRASTFCG 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-185299 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 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser299 NQVTQRAsRRSDSAS 9606 17603046 t gcesareni "Here, we demonstrate that pkcdelta undergoes in vitro autophosphorylation at three sites within its v3 region (s299, s302, s304), each of which is unique to this pkc isoform and evolutionarily conserved" SIGNOR-156523 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser645 LNEKARLsYSDKNLI 9606 15731106 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-134207 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 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 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 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 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" SIGNOR-66749 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr507 FGESRAStFCGTPDY 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. studies reported herein show that a t505a substitution reduces pkcdelta-thr(295) autophosphorylation" SIGNOR-185287 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 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-123449 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 PRKCD protein Q05655 UNIPROT PTPN22 protein Q9Y2R2 UNIPROT down-regulates phosphorylation Ser35 FLKLKRQsTKYKADK 9606 BTO:0000782 18056643 t llicata "We show that lyp is phosphorylated exclusively at ser-35 by pkc both in vitro and in vivo. our data establish a mechanism by which pkc could attenuate the cellular function of lyp, thereby augmenting t cell activation." SIGNOR-159591 PRKCD protein Q05655 UNIPROT PTPRA protein P18433 UNIPROT "up-regulates activity" phosphorylation Ser189 QAGSHSNsFRLSNGR 9606 BTO:0000017 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-249113 PRKCD protein Q05655 UNIPROT PTPRA protein P18433 UNIPROT "up-regulates activity" phosphorylation Ser213 PLLARSPsTNRKYPP 9606 BTO:0000017 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 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT "up-regulates activity" phosphorylation S6 MAVQISKKRKFVA 9606 BTO:0000007 19059439 t Manara "Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA" SIGNOR-260894 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT "up-regulates activity" phosphorylation T221 TPISEQKGGK 9606 BTO:0000007 19059439 t Manara "Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA" SIGNOR-260895 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 15950189 t lperfetto "It has been shown previously that ribosomal protein s3 (rps3)" SIGNOR-137967 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 19059439 t llicata "Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. pkc? Kinase assay then indicated that at least two residues, serine 6 and threonine 221, are phosphorylated by pkc?" SIGNOR-182619 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr221 KDEILPTtPISEQKG 9606 19059439 t gcesareni "Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. Phosphorylated rps3 was only detected in non-ribosomal rps3 and the repair endonuclease activity of rps3 was increased by its phosphorylation." SIGNOR-182623 PRKCD protein Q05655 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t gcesareni "Protein kinase c phosphorylates ribosomal protein s6 kinase betaii and regulates its subcellular localization." SIGNOR-97287 PRKCD protein Q05655 UNIPROT SDC4 protein P31431 UNIPROT down-regulates phosphorylation Ser179 MKKKDEGsYDLGKKP 9606 11916978 t gcesareni "Protein conformation;cell adhesion, induced;cell motility, inhibited;decreased rho a activation" SIGNOR-116265 PRKCD protein Q05655 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Ser28 LEEGASGsTPPEELP 9606 16963224 t llicata "Activated pkc delta was able to phosphorylate shca at ser29, as determined by mass spectrometry." SIGNOR-149402 PRKCD protein Q05655 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Ser139 EEWTRHGsFVNKPTR 9606 16963224 t "The effect has been demonstrated using P29353-2" gcesareni "Pkc delta phosphorylates p52shca at ser29 to regulate erk activation in response to h2o2." SIGNOR-149398 PRKCD protein Q05655 UNIPROT SLC29A1 protein Q99808 UNIPROT "up-regulates activity" phosphorylation S281 QPTNESHSIKAILKN 9606 25725289 t Manara "Phosphorylation of hENT1 by PKC has effects on both the function and subcellular trafficking of hENT1" SIGNOR-260888 PRKCD protein Q05655 UNIPROT SMPD1 protein P17405 UNIPROT up-regulates phosphorylation Ser508 DGNYSGSsHVVLDHE 9606 BTO:0000150 17303575 t lperfetto "Activation of acid sphingomyelinase by protein kinase cdelta-mediated phosphorylation. Phosphorylation of ser(508) proved to be an indispensable step for asmase activation and membrane translocation in response to pma" SIGNOR-153276 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 PRKCD protein Q05655 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 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-154791 PRKCD protein Q05655 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001253 16418226 t gcesareni "Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation." SIGNOR-143828 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 PRKCD protein Q05655 UNIPROT TBL1XR1 protein Q9BZK7 UNIPROT "up-regulates activity" phosphorylation S123 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 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 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 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates phosphorylation Ser23 PAPIRRRsSNYRAYA 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-178880 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates phosphorylation Ser24 APIRRRSsNYRAYAT 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-178884 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 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-163908 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 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-129304 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 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 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 PRKCE protein Q02156 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Ser779 PLDQYSPsFPDTRSS 9606 BTO:0000938 23564461 t lperfetto "Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiationour findings show that in addition to fgfr tyrosine phosphorylation, the phosphorylation of a conserved serine residue, ser(779), can quantitatively control ras/mapk signaling to promote specific cellular responses." SIGNOR-201671 PRKCE protein Q02156 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates phosphorylation Ser782 PLEQYSPsYPDTRSS 9606 BTO:0000938 23564461 t lperfetto "Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation" SIGNOR-201675 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 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 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser368 QRPSSRAsSRASSRP 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-144465 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser369 RPSSRASsRASSRPR 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-144469 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser373 RASSRASsRPRPDDL 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-144473 PRKCE protein Q02156 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-249281 PRKCE protein Q02156 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -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-249288 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 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-128718 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 PRKCE protein Q02156 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-158129 PRKCE protein Q02156 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 1374067 t lperfetto "In conclusion, we have shown that the PKCe catalytic fragment physically associates with and phosphorylates CK8/18 HT29 cells. The nature of this association and its physiological significance remain to be determined." SIGNOR-248847 PRKCE protein Q02156 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-251632 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 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr424 IREYPPItSDQQRQL 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-173639 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr438 LYKRNFDtGLQEYKS 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-173643 PRKCE protein Q02156 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-249064 PRKCE protein Q02156 UNIPROT PPP1R14A protein Q96A00 UNIPROT unknown phosphorylation Thr38 QKRHARVtVKYDRRE -1 15003508 t lperfetto "For that purpose, PKCa, e, l, and f were incubated with CPI-17 in the presence of 50 lM [c- 32P]ATP and kinase buffer. The results indicated that all PKC isoforms were able to phosphorylate CPI-17 in vitro (Table 1). PKCa phosphorylated CPI-17 to a similar extent to PKCe and to a much greater extent than f and l." SIGNOR-249258 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 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 t gcesareni "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. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin." SIGNOR-89411 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 9606 12058027 t miannu "In cells transfected with pkc? Or pkc? The phosphorylation of ser876 was markedly more pronounced than the phosphorylation of ser706/ser710 / the phosphorylation of ser706/ser710 in pkd2 reflects the activation of the kinase." SIGNOR-89415 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 12058027 t gcesareni "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. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin." SIGNOR-89419 PRKCE protein Q02156 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 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 PRKCE protein Q02156 UNIPROT SLC4A3 protein P48751 UNIPROT "up-regulates activity" phosphorylation Ser67 EKPSRSYsERDFEFH 9606 BTO:0000007 11739292 t lperfetto "We conclude that following Ang II stimulation of cells, PKCepsilon phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium." SIGNOR-249127 PRKCE protein Q02156 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001253 16418226 t gcesareni "Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation." SIGNOR-143832 PRKCE protein Q02156 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates phosphorylation Ser16 NSCPLSLsWGKRHSV 9606 16757566 t llicata "Here we show that tram is transiently phosphorylated by pkcepsilon on serine-16 our study provides a possible target for these molecules in lps signaling. Dag may activate pkc?, Leading to the phosphorylation and activation of tram." SIGNOR-146991 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser502 YFLQRRPsMKTLFVD 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-249230 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser502 YFLQRRPsMKTLFVD 9606 BTO:0000007 11884385 t lperfetto "Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP." SIGNOR-249141 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 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser801 VPLLREAsARDRQSA 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-249232 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser801 VPLLREAsARDRQSA 9606 BTO:0000007 11884385 t lperfetto "Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP." SIGNOR-249142 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser821 YLRQFSGsLKPEDAE 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-249233 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 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Thr705 WKLQRAItILDTEKS 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-249235 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 PRKCG protein P05129 UNIPROT APTX protein Q7Z2E3 UNIPROT up-regulates phosphorylation Thr125 AKNPGLEtHRKRKRS 9606 19561170 t llicata "We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx." SIGNOR-186409 PRKCG protein P05129 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-249074 PRKCG protein P05129 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-85183 PRKCG protein P05129 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-129316 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 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-129320 PRKCG protein P05129 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-129324 PRKCG protein P05129 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-129328 PRKCG protein P05129 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-129332 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 PRKCG protein P05129 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-249027 PRKCG protein P05129 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto "Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells." SIGNOR-249060 PRKCG protein P05129 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-249282 PRKCG protein P05129 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -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-249289 PRKCG protein P05129 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-249249 PRKCG protein P05129 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 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-249255 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr115 GTIAKSGtKAFMEAL 9606 24117238 t lperfetto "Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_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-202812 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 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 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 PRKCG protein P05129 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-251633 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 PRKCG protein P05129 UNIPROT OCLN protein Q16625 UNIPROT "up-regulates activity" phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 BTO:0000837 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 PRKCG protein P05129 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249094 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 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 PRKCG protein P05129 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." SIGNOR-37545 PRKCG protein P05129 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates 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-97295 PRKCG protein P05129 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248975 PRKCG protein P05129 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248978 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT "down-regulates activity" phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249187 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249184 PRKCG protein P05129 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 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-134632 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 PRKCG protein P05129 UNIPROT TOP2A protein P11388 UNIPROT "up-regulates activity" phosphorylation Ser29 EDAKKRLsVERIYQK 9606 BTO:0000567 12569090 t lperfetto "Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides." SIGNOR-249196 PRKCG protein P05129 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-248964 PRKCH protein P24723 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-202792 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249118 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto "Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |" SIGNOR-249123 PRKCH protein P24723 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-251634 PRKCH protein P24723 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 t llicata "These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748." SIGNOR-66730 PRKCH protein P24723 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 10197446 t llicata "These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748." SIGNOR-66734 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 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-89423 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 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 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-89431 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser580 CAEMREDsARVYENV 9606 BTO:0000007 11781100 t lperfetto " In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta" SIGNOR-249137 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 BTO:0000007 11781100 t lperfetto " In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta." SIGNOR-249140 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 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 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-172890 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 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 PRKCI protein P41743 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000195 18270268 t llicata "Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation." SIGNOR-160855 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 PRKCQ protein Q04759 UNIPROT FOSL1 protein P15407 UNIPROT "up-regulates activity" phosphorylation T227 LEPEALHTPTLMTTP 9606 BTO:0000093 27816489 t Manara "PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors." SIGNOR-260879 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 PRKCQ protein Q04759 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -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-249290 PRKCQ protein Q04759 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-249250 PRKCQ protein Q04759 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 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-249256 PRKCQ protein Q04759 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation 9606 23352416 t gcesareni "At the same time, ea causes pkc?-Mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence." SIGNOR-200576 PRKCQ protein Q04759 UNIPROT ICAM3 protein P32942 UNIPROT "up-regulates activity" phosphorylation Ser518 REHQRSGsYHVREES 9606 BTO:0000661 9268366 t lperfetto "Ser489 was a phosphorylation site in vitro for recombinant protein kinase Ctheta. Finally, treatment of Jurkat cells with chelerythrine chloride, a protein kinase C inhibitor, prevented ICAM-3-triggered spreading. " SIGNOR-248979 PRKCQ protein Q04759 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation S1101 GCRRRHSSETFSSTP 10090 BTO:0000165 15364919 t Manara "Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101)." SIGNOR-260906 PRKCQ protein Q04759 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 26431586 f lperfetto "It is known that the teta isoform of the PKC family promotes the fusion of myoblasts and regulates the expression of caveolin-3 and beta1D integrin [15]. Of note, it has also been demonstrated that PKCepsilon expression increases during insulin-induced myogenic differentiation of the C2C12 cells." SIGNOR-241525 PRKCQ protein Q04759 UNIPROT MSN protein P26038 UNIPROT unknown phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0001545 9856983 t lperfetto "By using mass spectroscopy and direct microsequencing of CNBr fragments of phospho-moesin, the phosphorylation site was identified as KYKT*LRQIR (where * indicates the phosphorylation site) (Thr558), which is conserved in the ERM family | Thus, PKC-theta is identified as a major kinase within cells with specificity for moesin and with activation under non-classical PKC conditions. It appears likely that this activity corresponds to a specific intracellular pathway controlling the function of moesin as well as other ERM proteins." SIGNOR-249013 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 PRKCQ protein Q04759 UNIPROT PKCtheta/Nfix complex SIGNOR-C121 SIGNOR "form complex" binding 10090 BTO:0000165 20178747 t llicata "In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A." SIGNOR-238019 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 PRKCQ protein Q04759 UNIPROT RASGRP3 protein Q8IV61 UNIPROT up-regulates phosphorylation Thr133 YDWMRRVtQRKKVSK 9606 BTO:0000776 15545601 t lperfetto "Activation of rasgrp3 by phosphorylation of thr-133 is required for b cell receptor-mediated ras activation. our data suggest that pkc, after being activated by diacylglycerol, phosphorylates rasgrp3, thereby contributing to its full activation." SIGNOR-130490 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 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 PRKCZ protein Q05513 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 16116087 t gcesareni "We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta." SIGNOR-139914 PRKCZ protein Q05513 UNIPROT AKT2 protein P31751 UNIPROT "up-regulates activity" phosphorylation Thr309 SDGATMKtFCGTPEY -1 9512493 t lperfetto "The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells." SIGNOR-248997 PRKCZ protein Q05513 UNIPROT AKT3 protein Q9Y243 UNIPROT "up-regulates activity" phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000007 9512493 t lperfetto "The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells." SIGNOR-248996 PRKCZ protein Q05513 UNIPROT AQP9 protein O43315 UNIPROT up-regulates phosphorylation Ser11 EGAEKGKsFKQRLVL 9606 BTO:0000130 21873454 t lperfetto "Wt-pkc_-mediated phosphorylation of wt aqp9 in vitro. In the experiments, substitution of ser11 to ala markedly inhibited phosphorylation. the s11a mutation in fibroblasts caused a smoother cell periphery with fewer aqp9-induced filopodia" SIGNOR-176278 PRKCZ protein Q05513 UNIPROT BAX protein Q07812 UNIPROT down-regulates phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 BTO:0000551 17525161 t lperfetto "Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184." SIGNOR-155111 PRKCZ protein Q05513 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser144 GDVGALEsLRGNADL 9606 16287866 t gcesareni "Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets ser144 is the atypical protein kinase c isoform zeta (pkczeta)." SIGNOR-141629 PRKCZ protein Q05513 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "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-129336 PRKCZ protein Q05513 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "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-129340 PRKCZ protein Q05513 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-249284 PRKCZ protein Q05513 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -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-249291 PRKCZ protein Q05513 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 14657655 t gcesareni "Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent." SIGNOR-119889 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 PRKCZ protein Q05513 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000007 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 PRKCZ protein Q05513 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 BTO:0000007 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-249016 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser307 TRRSRTEsITATSPA 10029 BTO:0001131 15069075 t lperfetto "Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results." SIGNOR-236760 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000671 15069075 t gcesareni "Thus, pkc-zeta might promote feedback ir/irs-1 complex formation and irs-1 tyrosine phosphorylation through phosphorylation of ser318." SIGNOR-123738 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 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 PRKCZ protein Q05513 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr564 RGTASRStFHGQPRE 9606 15084291 t lperfetto "Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells" SIGNOR-124221 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 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 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 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-89260 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 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-89264 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 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-89268 LFNG protein Q8NES3 UNIPROT JAG1 protein P78504 UNIPROT down-regulates binding 9606 BTO:0000007 15574878 t gcesareni "Although jagged1-induced signaling was suppressed by lfng and mfng" SIGNOR-131560 PRKCZ protein Q05513 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-89272 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 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-89284 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 PRKCZ protein Q05513 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-251637 PRKCZ protein Q05513 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Thr456 GRLTELRtFNHHHAE 9606 BTO:0000195 18668687 t "The effect has been demonstrated using Q96RI1-2" gcesareni "The effect of fic1 on fxr phosphorylation and nuclear localization and its effects on bsep promoter activity could be blocked with protein kinase c zeta (pkc zeta) inhibitors (pseudosubstrate or small interfering rna silencing). Recombinant pkc zeta directly phosphorylated immunoprecipitated fxr. The mutation of threonine 442 of fxr to alanine yielded a dominant negative protein," SIGNOR-179771 PRKCZ protein Q05513 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser827 REGFGRQsMSEKRTK 9606 12390250 t gcesareni "These results imply that serine 827 in the apkc binding site of par-3 is a target of apkc and that the regulated interaction between a protein kinase, apkc, and its substrate, par-3, plays an essential role in the establishment of cell polarity" SIGNOR-94523 PRKCZ protein Q05513 UNIPROT PPP1R14A protein Q96A00 UNIPROT unknown phosphorylation Thr38 QKRHARVtVKYDRRE -1 15003508 t lperfetto "For that purpose, PKCa, e, l, and f were incubated with CPI-17 in the presence of 50 lM [c- 32P]ATP and kinase buffer. The results indicated that all PKC isoforms were able to phosphorylate CPI-17 in vitro (Table 1). PKCa phosphorylated CPI-17 to a similar extent to PKCe and to a much greater extent than f and l." SIGNOR-249261 PRKCZ protein Q05513 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr560 TSEPVQLtPDDEDAI 9606 11141077 t gcesareni "Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylation" SIGNOR-85505 PRKCZ protein Q05513 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-249239 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 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 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser641 GKVYGKTsHLRAHLR 9606 19464346 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-185741 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser670 CGKRFTRsDELQRHK 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-160766 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr668 SYCGKRFtRSDELQR 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-160770 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 PRKCZ protein Q05513 UNIPROT YWHAB protein P31946 UNIPROT "down-regulates activity" phosphorylation Thr143 SGDNKQTtVSNSQQA 9534 BTO:0004055 10620507 t lperfetto "Our results with the 14-3-3 mutants indirectly imply a new phosphorylation site, 130Ser (and to a lesser extent 141Thr), in 14-3-3b that regulates the association}dissociation of 14-3-3b and PKC-f." SIGNOR-249035 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 PRKD1 protein Q15139 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 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-163920 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 PRKD1 protein Q15139 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 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-163928 PRKD1 protein Q15139 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates phosphorylation Ser1981 ASLGRRAsFHLECLK 9606 22100296 t gcesareni "Both the expression of a dominant-negative mutant of pkd and the mutation of serine 1884 but not serine 1930, putative targets of pkd, strongly reduced l-type calcium currents and single channel activity without affecting the channel's expression at the plasma membrane. Our results suggest that serine 1884 is essential for the regulation of hcav1.2 by pkd." SIGNOR-177481 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 PRKD1 protein Q15139 UNIPROT CERT1 protein Q9Y5P4 UNIPROT down-regulates phosphorylation Ser132 SSLRRHGsMVSLVSG 9606 17591919 t lperfetto "In this study, we identify cert as a novel in vivo pkd substrate. Phosphorylation on serine 132 by pkd decreases the affinity of cert toward its lipid target phosphatidylinositol 4-phosphate at golgi membranes and reduces ceramide transfer activity" SIGNOR-156500 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr112 EGMQIPStQFDAAHP 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-183384 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 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser298 EKLAKHEsQQDYSKG 9606 20363754 t lperfetto "Pkd phosphorylates cortactin in vitro and in vivo at serine 298 thereby generating a 14-3-3 binding motif. In vitro, a phosphorylation-deficient cortactin-s298a protein accelerated vca-arp-cortactin-mediated synergistic actin polymerization and showed reduced f-actin binding" SIGNOR-164756 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser348 EAVTSKTsNIRANFE 9606 BTO:0000150 19038333 t lperfetto "Here we have investigated the possible role of pkd as a cortactin kinase. Using a mass spectrometric approach, we found that pkd phosphorylates cortactin on ser 298 examination of cortactin phosphorylation kinetics revealed that ser 298 serves as a priming site for subsequent phosphorylation of ser 348" SIGNOR-182502 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 22865920 t lperfetto "When phosphorylated by camk/pkd, class iia hdacs bind 14-3-3 chaperone proteins, which facilitates their nuclear export, thereby relieving hdac-mediated transcriptional repression." SIGNOR-198662 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 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 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-132898 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 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18617643 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-179430 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 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-132902 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 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 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 PRKD1 protein Q15139 UNIPROT OSBP protein P22059 UNIPROT down-regulates phosphorylation Ser240 TALQRSLsELESLKL 9606 21285358 t gcesareni "Pkd attenuates the function of both cert and osbp by phosphorylation at their respective ser(132) and ser(240) residues (phosphorylation inhibition)" SIGNOR-171756 PRKD1 protein Q15139 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-148876 PRKD1 protein Q15139 UNIPROT PIP4K2A protein P48426 UNIPROT down-regulates phosphorylation Thr376 KAAHAAKtVKHGAGA 9606 16563698 t lperfetto "We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases." SIGNOR-145370 PRKD1 protein Q15139 UNIPROT PKD2 protein Q13563 UNIPROT "up-regulates activity" phosphorylation Ser801 SSLPRPMSSRSFPRS 9606 BTO:0000007 20881056 t miannu "Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. Phosphorylation at this site was significantly increased in response to serum and epidermal growth factor stimulation.We confirmed previous studies showing that PC2 mediated Ca2+ release from the ER can be stimulated by ATP.Phosphorylation at Ser801 seems to be permissive for this activity without altering the subcellular localization nor homophilic and heterophilic (with PC1) interactions of wild-type PC2." SIGNOR-259829 PRKD1 protein Q15139 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates phosphorylation Thr38 QKRHARVtVKYDRRE 9606 BTO:0000142 15003508 t llicata "Cpi-17 is phosphorylated by several kinases on thr-38 in vitro, which increases the inhibitory potency of cpi-17 on pp1 by 1000-fold using affinity chromatography and western blot analysis, we found interaction with all pkc isotypes and casein kinase i isoforms, ckialpha and cki. By contrast, rock and pkn did not associate with cpi-17, suggesting that pkc may be the relevant kinase that phosphorylates thr-38 in vivo." SIGNOR-123226 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser738 ARIIGEKsFRRSVVG -1 10867018 t lperfetto "The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot" SIGNOR-249046 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser742 GEKSFRRsVVGTPAY -1 10867018 t lperfetto "The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot" SIGNOR-249047 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 19029298 t llicata "We show that pkd1-ser916 autophosphorylation does not necessarily correlate with pkd1 activity. Rather, autophosphorylation at ser916 is required for subsequent autophosphorylation at ser748." SIGNOR-182480 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 BTO:0000776 10473617 t llicata "Activation of the serine kinase protein kinase d (pkd)/pkcmicro is controlled by the phosphorylation of two serine residues within its activation loop via a pkc-dependent signaling cascade. In this study we have identified the c-terminal serine 916 residue as an in vivo phosphorylation site within active pkd/pkcmu. moreover, using different mutants of pkd/pkcmu, we show that serine 916 is not trans-phosphorylated by an upstream kinase but is rather an autophosphorylation event that occurs following activation of pkd/pkcmu." SIGNOR-70525 PRKD1 protein Q15139 UNIPROT PTRH2 protein Q9Y3E5 UNIPROT up-regulates phosphorylation Ser5 sLVMEYLA 9606 18703509 t lperfetto "Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1" SIGNOR-180085 PRKD1 protein Q15139 UNIPROT PTRH2 protein Q9Y3E5 UNIPROT up-regulates phosphorylation Ser87 GKVAAQCsHAAVSAY 9606 18703509 t lperfetto "Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1" SIGNOR-180089 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT down-regulates phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 t gcesareni "Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation." SIGNOR-113960 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT unknown phosphorylation Ser292 QLLRRESsVGYRVPA 9606 21209314 t llicata "Here, we report the identification of serine 292 in rin1 as an in vivo pkd phosphorylation site. we demonstrate that phosphorylation at serine 292 controls rin1-mediated inhibition of cell migration by modulating the activation of abl kinases." SIGNOR-170877 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT unknown phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 t llicata "Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation." SIGNOR-113964 PRKD1 protein Q15139 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 BTO:0000150 22276203 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. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba." SIGNOR-195531 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 21525957 t gcesareni "Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1." SIGNOR-173437 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 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-186467 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 PRKD1 protein Q15139 UNIPROT TLR5 protein O60602 UNIPROT up-regulates phosphorylation Ser805 YQLMKHQsIRGFVQK 9606 BTO:0002181 17442957 t lperfetto "Pkd phosphorylated the tlr5-derived target peptide in vitro, and phosphorylation of the putative target serine 805 in hek 293t cell-derived tlr5 was identified by mass spectrometry. These results demonstrate that both pkd1 and pkd2 are required for inflammatory responses following tlr2, tlr4, or tlr5 activation, although pkd1 is more strongly involved" SIGNOR-154473 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 PRKD2 protein Q9BZL6 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 11062248 t gcesareni "The addition of phorbol 12,13-dibutyrate in the presence of dioleoylphosphatidylserine stimulated the autophosphorylation of pkd2 in a synergistic fashion.In addition, we could identify the c-terminal ser(876) residue as an in vivo phosphorylation site within pkd2. Phosphorylation of ser(876) of pkd2 correlated with the activation status of the kinase." SIGNOR-83834 PRKD2 protein Q9BZL6 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 21525957 t gcesareni "Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1." SIGNOR-173441 PRKD3 protein O94806 UNIPROT GIT1 protein Q9Y2X7 UNIPROT unknown phosphorylation Ser46 RSLGRHIsIVKHLRH 9606 22893698 t lperfetto "We propose that phosphorylation of git1 on serine 46 by pkd3 represents a molecular switch by which git1 localization, paxillin trafficking, and cellular protrusive activity are regulated." SIGNOR-191839 PRKDC protein P78527 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 t gcesareni "DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform" SIGNOR-252431 PRKDC protein P78527 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 t gcesareni "DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform" SIGNOR-252447 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 PRKDC protein P78527 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 15668230 t gcesareni "We have found that dna-pk is the major constituent of an activity present in extracts of mammalian cells that phosphorylates chk2. Our results suggest that hypophosphorylated chk2 can be phosphorylated at thr68 by dna-pk in vitro." SIGNOR-133384 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser503 NDEITDEsLENFPSS 9606 16874298 t lperfetto "Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin" SIGNOR-148327 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 9606 16600297 t lperfetto "Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin" SIGNOR-145837 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser645 NLSTNADsQSSSDFE 9606 16600297 t lperfetto "Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin" SIGNOR-145841 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT "up-regulates activity" phosphorylation Thr143 ALKHVKEtQPPETVQ -1 BTO:0000567 24485452 t "In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents" SIGNOR-253557 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr5 tQTQDQPM 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-248887 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 PRKDC protein P78527 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates phosphorylation Thr135 GGGSTSDtQEDILDE 9606 11867762 t lperfetto "Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis" SIGNOR-115331 PRKDC protein P78527 UNIPROT JUN protein P05412 UNIPROT unknown phosphorylation Ser249 LSPIDMEsQERIKAE -1 8464713 t lperfetto "Here, we show that the DNA-PK modifies c-Jun in vitro and that serine residue 249 (Ser-249) is required for phosphorylation to occur. This residue corresponds to one of three sites of c-Jun that are phosphorylated in vivo and which negatively regulate c-Jun DNA binding in vitro. However, we find that phosphorylation of c-Jun by the DNA-PK does not interfere with DNA binding, indicating that phosphorylation at other sites is required for this effect." SIGNOR-248934 PRKDC protein P78527 UNIPROT Ku70/Ku80/DNA-PK complex SIGNOR-C107 SIGNOR "form complex" binding 9606 BTO:0002419 17308091 t miannu "complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established" SIGNOR-226026 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 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Ser672 CVMSGTDsQPKPDLE 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-125873 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Thr650 HLKAPNLtNVNKISN 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-125877 PRKDC protein P78527 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT unknown phosphorylation Ser245 PHTSNSAsLQGIDSQ 9606 18644470 t lperfetto "Here, we have identified two major in vitro dna-pk phosphorylation sites in the c-terminal region of xlf, serines 245 and 251. We show that these represent the major phosphorylation sites in xlf in vivo and that serine 245 is phosphorylated in vivo by dna-pk, while serine 251 is phosphorylated by ataxia-telangiectasia mutated (atm)." SIGNOR-179532 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 PRKDC protein P78527 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr11 EEQYYAAtQLYKDPC 10090 BTO:0002284 16166097 t miannu "The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome." SIGNOR-225542 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser114 EETRTPEsQPDTPPG 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-176016 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 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 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Ser2624 QTRTQEGsLSARWPV -1 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-249156 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Ser3205 TPLPEDNsMNVDQDG 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-249157 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2609 LTPMFVEtQASQGTL 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-249154 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2620 QGTLQTRtQEGSLSA -1 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-249158 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 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 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Ser2056 VQSYSYSsQDPRPAT 9606 17189255 t llicata "Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, in addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair." SIGNOR-151445 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 t gcesareni "Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster." SIGNOR-151449 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser13 FESYGSSsYGGAGGY -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248982 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser23 GAGGYTQsPGGFGSP -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248983 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser29 QSPGGFGsPAPSQAE -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248984 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR -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-248971 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 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 PRKDC protein P78527 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-121869 PRKDC protein P78527 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser435 LTVLNAFsQAPSTMQ -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-248921 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 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 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 PRKDC protein P78527 UNIPROT USF1 protein P22415 UNIPROT up-regulates phosphorylation 9606 19303849 t miannu "Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation." SIGNOR-184849 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 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser467 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-203741 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 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-72712 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 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-18237 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser737 EPLERRLsLVPDSEQ 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-72716 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser737 EPLERRLsLVPDSEQ 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-18241 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser768 LQARRRQsVLNLMTH 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-72720 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser768 LQARRRQsVLNLMTH 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-18245 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 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 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-18249 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 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-72728 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 PRKG1 protein Q13976 UNIPROT CREB1 protein P16220 UNIPROT unknown phosphorylation Ser133 EILSRRPsYRKILND -1 11175347 t lperfetto "G-kinase phosphorylated GST-CREB, albeit less efficiently than A-kinase, but GST was not phosphorylated by either kinase (Figure 5a). GST-CREB purified from bacteria was similarly phosphorylated by G-kinase, whereas GST-CREB containing a serine 133 to alanine mutation was not (Figure 5b). These results demonstrate that G-kinase can directly phosphorylate CREB on serine 133." SIGNOR-249076 PRKG1 protein Q13976 UNIPROT CRIP2 protein P52943 UNIPROT unknown phosphorylation Ser104 RAEERKAsGPPKGPS 9534 BTO:0000298 10681529 t lperfetto " Cyclic GMP kinase I phosphorylated CRP2 at Ser-104, because the mutation to Ala completely prevented the in vivo phosphorylation." SIGNOR-249038 PRKG1 protein Q13976 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 9606 BTO:0000887;BTO:0001260 15051728 t lperfetto "Pkgi also directly phosphorylates fhod1, and studies with wild-type and mutant fhod1-derived peptides identify ser-1131 in the fhod1 c terminus as the unique pkgi phosphorylation site in fhod1. phosphorylation of three conserved residues within the dad domain activates fhod1 while binding to rac regulates fhod1 subcellular localization" SIGNOR-123646 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 t "Translocation from Endosome to Lysosome" fspada "Ser396 and ser398 are also potential phosphorylation sites for capk, cgmp-dependent protein kinase, and camk ii. Elevation of intracellular camp content has been shown to attenuate histamine-induced accumulation of ip in c6 glioma cells (peakman and hill, 1994) and in ddt1 mf-2 smooth muscle cells (sipma et al., 1995" SIGNOR-66019 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 PRKG1 protein Q13976 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 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 "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-186784 PRKG1 protein Q13976 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 "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-186788 PRKG1 protein Q13976 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-186792 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 PRKG1 protein Q13976 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates phosphorylation Ser146 MEPERRDsQDGSSYR 9606 BTO:0000150 12571245 t lperfetto "Studies with human lasp mutants identified serine 146 as a specific phosphorylation site for cgk and cak in vivo. Lasp is an actin-binding protein, and the phospho-lasp-mimicking mutant s146d showed reduced binding affinity for f-actin in cosedimentation experiments." SIGNOR-97946 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 PRKG1 protein Q13976 UNIPROT PLCB3 protein Q01970 UNIPROT "down-regulates activity" phosphorylation Ser26 VETLRRGsKFIKWDE 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-249079 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 PRKG1 protein Q13976 UNIPROT RGS2 protein P41220 UNIPROT "up-regulates activity" phosphorylation Ser64 KPKTGKKsKQQAFIK -1 14608379 t lperfetto "Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. " SIGNOR-249241 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 PRKG1 protein Q13976 UNIPROT SF1 protein Q15637 UNIPROT "down-regulates activity" phosphorylation Ser20 PSKKRKRsRWNQDTM 10116 BTO:0000947 10449420 t lperfetto "PKG phosphorylates SF1 at Ser20, which inhibits the SF1-U2AF65 interaction leading to a block of pre-spliceosome assembly. Mutation of Ser20 to Ala or Thr also inhibits the interaction with U2AF65, indicating that Ser20 is essential for binding." SIGNOR-249018 PRKG1 protein Q13976 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates phosphorylation Thr276 SIWKGVKtSGKVVWV 9606 BTO:0000567 17913921 t gcesareni "These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5." SIGNOR-158186 MAPK3 protein P27361 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni "Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity." SIGNOR-48355 PRKG1 protein Q13976 UNIPROT SRF protein P11831 UNIPROT down-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 9606 BTO:0000887;BTO:0001260 19778940 t gcesareni "This residue conforms to a highly conserved consensus camp-dependent protein kinase (pka) site, and in vitro and in vivo labeling studies demonstrated that it was phosphorylated by pka. Results from gel shift and chromatin immunoprecipitation assays demonstrated that t159 phosphorylation inhibited srf binding to smc-specific carg elements." SIGNOR-188185 PRKG1 protein Q13976 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates phosphorylation Ser23 PAPIRRRsSNYRAYA 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-134640 PRKG1 protein Q13976 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates phosphorylation Ser24 APIRRRSsNYRAYAT 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-134644 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507-3 UNIPROT down-regulates phosphorylation Thr11 SPSLRRMtVMREKGR 9606 BTO:0000007 16331690 t "The effect has been demonstrated using Q13507-3" llicata "The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263." SIGNOR-142957 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation 9606 BTO:0000007 16331690 t "The effect has been demonstrated using Q13507-3" llicata "The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263." SIGNOR-142964 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 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-142953 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 BTO:0000007 14983059 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-122978 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser263 KNDYRKLsMQCKDFV 9606 BTO:0000007 16331690 t "The effect has been demonstrated using Q13507-3" llicata "The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263." SIGNOR-142961 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Ser157 EHIERRVsNAGGPPA 9606 14679200 t lperfetto "Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of rhoa and is inhibited by cgmp-dependent protein kinase phosphorylationg-kinase phosphorylation of vasp on ser(239) at the carboxyl-terminal end of the g-actin binding site, with some contribution by phosphorylation of ser(157)" SIGNOR-120347 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Ser239 GAKLRKVsKQEEASG 9606 14679200 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. G-kinase phosphorylation of vasp on ser(239) at the carboxyl-terminal end of the g-actin binding site, with some contribution by phosphorylation of ser(157)" SIGNOR-120351 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 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 "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-186796 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 PRKG2 protein Q13237 UNIPROT LASP1 protein Q14847 UNIPROT unknown phosphorylation Ser146 MEPERRDsQDGSSYR 9606 BTO:0000132 12571245 t lperfetto "Recombinant human LASP was phosphorylated by cGMP- and cAMP-dependent protein kinase (cAK) in vitro. Cotransfection of PtK-2 cells with LASP and cGK confirmed phosphorylation of LASP in vivo. Studies with human LASP mutants identified serine 146 as a specific phosphorylation site for cGK and cAK in vivo. LASP is an actin-binding protein, and the phospho-LASP-mimicking mutant S146D showed reduced binding affinity for F-actin in cosedimentation experiments." SIGNOR-249197 PRKG2 protein Q13237 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-249078 PRKG2 protein Q13237 UNIPROT PLCB3 protein Q01970 UNIPROT "down-regulates activity" phosphorylation Ser26 VETLRRGsKFIKWDE 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-249080 PRKG2 protein Q13237 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-71751 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT "down-regulates activity" ubiquitination 10090 16862145 t gcesareni "Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15." SIGNOR-243282 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT up-regulates ubiquitination 9606 BTO:0000938 BTO:0000142 16862145 t gcesareni "Treatment of cells with egf stimulates parkin binding to both eps15 and the egfr and promotes parkin-mediated ubiquitination of eps15" SIGNOR-148218 PRKN protein O60260 UNIPROT GPR37 protein O15354 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-249706 PRKN protein O60260 UNIPROT RANBP2 protein P49792 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 16332688 t irozzo "Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkin-mediated ubiquitination and proteasomal pathways. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2." SIGNOR-259116 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 PRLHR protein P49683 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-257280 PRLHR protein P49683 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-257198 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Ser252 MEGYRAPsRQDVYGP -1 12885254 t "GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro" SIGNOR-251234 PRLHR protein P49683 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-256694 PRLHR protein P49683 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-256837 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 PRLHR protein P49683 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-257089 PRL protein P01236 UNIPROT KRT14 protein P02533 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251902 PRL protein P01236 UNIPROT KRT15 protein P19012 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251904 PRL protein P01236 UNIPROT KRT19 protein P08727 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251905 PRMT1 protein Q99873 UNIPROT TAF15 protein Q92804 UNIPROT up-regulates methylation 9606 19124016 t miannu "The methylation of taf15 by prmt1 is required for the ability of taf15 to positively regulate the expression of the studied endogenous taf15-target genes." SIGNOR-183137 PRMT5 protein O14744 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates activity" methylation Arg140 KPEPLSArRGDCPTL 9606 BTO:0000007 22269951 t lperfetto "Hoxa9 methylation by prmt5 is essential for endothelial cell expression of leukocyte adhesion molecules. / prmt5 is a critical coactivator component in a newly defined, hoxa9-containing transcription complex./ Hoxa9 is methylated on arg140 by prmt5." SIGNOR-195526 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 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 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 profenamine chemical CHEBI:313639 ChEBI MAPK10 protein P53779 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000142 19261605 t "Inhibitor of p38;ATP binding pocket" gcesareni "Indazole-based inhibitors exemplified by sr-3737 were potent inhibitors of both jnk3 (ic50 12 nm)." SIGNOR-184443 progesterone smallmolecule CHEBI:17026 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" 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-258705 PROK1 protein P58294 UNIPROT PROKR1 protein Q8TCW9 UNIPROT up-regulates binding 9606 BTO:0000975 12054613 t gcesareni "The present study demonstrates that eg-vegf/prokineticin 1 and a peptide closely related to eg-vegf, prokineticin 2, are cognate ligands of two orphan g-protein-coupled receptors designated zaq (=eg-vegf/pk-r1) and i5e (=eg-vegf/pk-r2)" SIGNOR-89084 PROK2 protein Q9HC23 UNIPROT PROKR2 protein Q8NFJ6 UNIPROT up-regulates binding 9606 12024206 t gcesareni "We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2)" SIGNOR-87919 "Prolactin-releasing peptide-20" smallmolecule CHEBI:80301 ChEBI PRLHR protein P49683 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-257566 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 "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 propranolol chemical CHEBI:8499 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 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-258614 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 "prostaglandin D2(1-)" smallmolecule CHEBI:57406 ChEBI PTGDR protein Q13258 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-257568 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0000725 23645839 f apalma "Prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion" SIGNOR-255685 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER1 protein P34995 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-257569 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER2 protein P43116 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-257570 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER3 protein P43115 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-257571 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER4 protein P35408 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-257572 "prostaglandin F2alpha" smallmolecule CHEBI:15553 ChEBI Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates "transcriptional regulation" 9606 BTO:0001103 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 "prostaglandin F2alpha" smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 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-255360 "prostaglandin F2alpha" smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 3308494 f apalma "The results suggest a role for prostanoids in the regulation of both human myoblast proliferation and differentiation" SIGNOR-255362 protein A0A3G5BIY8 UNIPROT DDX5 protein P17844 UNIPROT "up-regulates activity" binding 9606 BTO:0000018 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 protriptyline chemical CHEBI:8597 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 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 protriptyline chemical CHEBI:8597 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 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 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 PROX1 protein Q92786 UNIPROT HIF1A protein Q16665 UNIPROT "up-regulates quantity by stabilization" 9606 27476001 f miannu "PROX1 is important to maintain HIF1Œ± protein stability by inhibiting the proteasome activity after DAB2IP loss, since our immunoprecipitation data showed that knocking-down PROX1 could enhance the protein‚Äìprotein interaction between HIF1Œ± and ubiquitin in DAB2IP-deficient LAPC-4 and RWPE-1 KD cells. we found that knocking-down PROX1 could decrease HIF1Œ± protein stability, because HIF1Œ± protein degradation was significantly blocked by MG132 treatment in LAPC-4 and RWPE-1 KD cells" SIGNOR-254766 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 PROX1 protein Q92786 UNIPROT RORC protein P51449 UNIPROT down-regulates 23723244 f azuccotti "In this study, we identify Prospero-related homeobox 1 (Prox1) as a novel co-repressor of the retinoic acid-related orphan receptors, RORgamma and RORalpha. Prox1 interacts directly with RORgamma and RORalpha and negatively regulates their transcriptional activity." SIGNOR-254507 PRPF4B protein Q13523 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr417 ISVDGLStPVVLSPG 9606 BTO:0000142;BTO:0000763 10799319 t lperfetto "Activated hprp4 phosphorylates residue thr-417 on elk-1 resulting in elk-1 activation." SIGNOR-77135 PRPF4B protein Q13523 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates phosphorylation 9606 17513757 t flangone "Using yeast two-hybrid screening of a human thymus cdna library, prp4, a serine/threonine protein kinase, was identified as a klf13-binding protein...coexpression of prp4 and klf13 increases nuclear localization of klf13 and ccl5 transcription." SIGNOR-154951 PRRX1 protein P54821 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-221890 PRRX1 protein P54821 UNIPROT MAFG protein O15525 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-221961 PRRX1 protein P54821 UNIPROT MAFK protein O60675 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-221932 PRRX1 protein P54821 UNIPROT MAF protein O75444 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-221893 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 PRSS21 protein Q9Y6M0 UNIPROT RAD21 protein O60216 UNIPROT up-regulates cleavage 9606 11875078 t miannu "Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation." SIGNOR-115426 PRTN3 protein P24158 UNIPROT AGT protein P01019 UNIPROT "up-regulates activity" cleavage Phe41 DRVYIHPFHLVIHNE -1 11747312 t miannu "Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen." SIGNOR-256314 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 PSEN1 protein P49768 UNIPROT g-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-209705 PSEN1 protein P49768 UNIPROT g-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10497236 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." lperfetto "Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains." SIGNOR-217746 PSEN1 protein P49768 UNIPROT g-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10593990 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." lperfetto "Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains." SIGNOR-217743 PSEN1 protein P49768 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates cleavage 9606 SIGNOR-C98 10593990 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." gcesareni "Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains." SIGNOR-72886 PSEN1 protein P49768 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 9606 SIGNOR-C98 10593990 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." gcesareni "Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains." SIGNOR-254308 PSENEN protein Q9NZ42 UNIPROT g-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-209708 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 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 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 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 PSPC1 protein Q8WXF1 UNIPROT "LMX1B/SFPQ/PSPC1 complex" complex SIGNOR-C106 SIGNOR "form complex" binding 10090 BTO:0000669 23308148 t miannu "LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo." SIGNOR-223973 PSPN protein O60542 UNIPROT GFRA4 protein Q9GZZ7 UNIPROT up-regulates binding 9606 BTO:0000938 11116144 t gcesareni "Glial cell line-derived neurotrophic factor (gdnf) family ligands signal through receptor complex consisting of a glycosylphosphatidylinositol-linked gdnf family receptor (gfr) alpha subunit and the transmembrane receptor tyrosine kinase ret." SIGNOR-85162 PTAFR protein P25105 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-257436 PTAFR protein P25105 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-257061 PTAFR protein P25105 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-257174 PTAFR protein P25105 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-256932 PTAFR protein P25105 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-257262 PTAFR protein P25105 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-257387 PTAFR protein P25105 UNIPROT GNAS protein Q5JWF2 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-256789 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 PTBP2 protein Q9UKA9 UNIPROT HNRNPH1 protein P31943 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-261269 PTCD3 protein Q96EY7 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding Q9Y2Q9 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-261437 PTCH1 protein Q13635 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates binding 9606 BTO:0000007 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 PTCH1 protein Q13635 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR "form complex" binding 10090 21664576 t lperfetto "Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands." SIGNOR-209602 PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT "down-regulates activity" binding 9606 14556242 t lperfetto "In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other." SIGNOR-118609 PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT "down-regulates activity" binding 9606 BTO:0001757;BTO:0001298 12192414 t lperfetto "We show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity." SIGNOR-91709 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 PTCRA protein Q6ISU1 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 1717999 t lperfetto "Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains" SIGNOR-134325 P-TEFb complex SIGNOR-C238 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001545 19516275 f miannu "Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits the positive transcription elongation factor b (P-TEFb), which is a key RNA polymerase II (Pol II) transcriptional regulator. In transfected cells, mutated NPM1 associated with, and sequestered, HEXIM1 in cytoplasm, resulting in higher transcription of RNA pol II target genes, among which were some positive regulators of cell-cycle progression such as cyclin D1 and anti-apoptotic proteins such as Mcl-1" SIGNOR-260137 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 P-TEFb complex SIGNOR-C238 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 19516275 f miannu "Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits the positive transcription elongation factor b (P-TEFb), which is a key RNA polymerase II (Pol II) transcriptional regulator. In transfected cells, mutated NPM1 associated with, and sequestered, HEXIM1 in cytoplasm, resulting in higher transcription of RNA pol II target genes, among which were some positive regulators of cell-cycle progression such as cyclin D1 and anti-apoptotic proteins such as Mcl-1" SIGNOR-260136 PTEN protein P60484 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." SIGNOR-228145 PTEN protein P60484 UNIPROT ABTB1 protein Q969K4 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 PTEN protein P60484 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" 9606 BTO:0001271 20596030 f lperfetto "Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib." SIGNOR-252638 PTEN protein P60484 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" 9606 BTO:0001332 19903340 f lperfetto "PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression" SIGNOR-189105 PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0001271 20596030 f lperfetto "Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib." SIGNOR-166478 PTEN protein P60484 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "down-regulates activity" dephosphorylation 9606 BTO:0001544 31374292 t miannu "PTEN targets the protein phosphatase activity of BCR-ABL. PTEN has the same function as PTP1B, which can regulate BCR-ABL dephosphorylation [13]. However, whether PTEN can mediate BCR-ABL dephosphorylation remains unknown. We found that under-expression of PTEN significantly upregulated phosphorylation level of BCR-ABL. In order to verify the mechanisms, co-IP assays were applied, demonstrating the ways in which PTEN and BCR-ABL interact with each other." SIGNOR-260080 PTEN protein P60484 UNIPROT CREB1 protein P16220 UNIPROT "down-regulates activity" dephosphorylation Ser133 EILSRRPsYRKILND 10090 BTO:0002572 21385900 t "Our study demonstrates that PTEN can dephosphorylate CREB at Ser133 and that PTEN protein phosphatase activity is required for CREB dephosphoryation.|Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth." SIGNOR-248543 PTEN protein P60484 UNIPROT EGR2 protein P11161 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-260049 PTEN protein P60484 UNIPROT GLI1 protein P08151 UNIPROT down-regulates 9606 17157787 f "PTEN is a suppressor of RAS-AKT function" gcesareni "Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code" SIGNOR-151134 PTEN protein P60484 UNIPROT GLI1 protein P08151 UNIPROT down-regulates 9606 17845852 f "PTEN is a suppressor of RAS-AKT function" gcesareni "Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code" SIGNOR-157776 PTEN protein P60484 UNIPROT HCLS1 protein P14317 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 PTEN protein P60484 UNIPROT NDRG1 protein Q92597 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-260054 PTEN protein P60484 UNIPROT NFIL3 protein Q16649 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-260055 PTEN protein P60484 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "down-regulates activity" 9606 BTO:0000938 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-252725 PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT "down-regulates activity" 9606 BTO:0000938 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-209856 PTEN protein P60484 UNIPROT PIK3CB protein P42338 UNIPROT "down-regulates activity" 9606 BTO:0000938 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 PTEN protein P60484 UNIPROT PINK1 protein Q9BXM7 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 BTO:0000007 22413754 t miannu "Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites" SIGNOR-248546 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 BTO:0000007 22413754 t miannu "Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites" SIGNOR-248545 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 PTEN protein P60484 UNIPROT SH2B2 protein O14492 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-260051 PTEN protein P60484 UNIPROT STAT5A protein P42229 UNIPROT down-regulates dephosphorylation 9606 BTO:0001271 20596030 t miannu "The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib." SIGNOR-166481 PTGDR protein Q13258 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-256898 PTGDR protein Q13258 UNIPROT GNAS protein Q5JWF2 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-256755 PTGER1 protein P34995 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-257278 PTGER1 protein P34995 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-257194 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 PTGER1 protein P34995 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000586 17251915 t gcesareni "Ep1 is a galfaq-coupled receptor that promotes calcium mobilization and pkc activation, whereas ep2 and ep4, which have a more prominent role in colon cancer, are coupled to galfas and stimulate camp accumulation" SIGNOR-152802 PTGER1 protein P34995 UNIPROT GNAS protein Q5JWF2 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-256811 PTGER2 protein P43116 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 BTO:0000586 17251915 f gcesareni "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)." SIGNOR-152805 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 PTGER2 protein P43116 UNIPROT GNAS protein P63092 UNIPROT up-regulates binding 9606 16293724 t gcesareni "Pge2 receptors are coupled to the g protein gs, which causes accumulation of cyclic adenosine monophosphate (camp) and activates protein kinase a (pka), we confirmed that pge2 treatment or transfection of cells with the active catalytic subunit of pka also stimulated the activity of a camp-responsive-elementdriven reporter gene (cre-luc)." SIGNOR-141597 PTGER2 protein P43116 UNIPROT GNAS protein Q5JWF2 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-256756 PTGER3 protein P43115 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-257203 PTGER3 protein P43115 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-256716 PTGER3 protein P43115 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-256859 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 PTGER3 protein P43115 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-257111 PTGER3 protein P43115 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 BTO:0000938 12038972 t gcesareni "Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)" SIGNOR-88195 PTGER4 protein P35408 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-257032 PTGER4 protein P35408 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-256903 PTGER4 protein P35408 UNIPROT GNAS protein Q5JWF2 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-256760 PTGES protein O14684 UNIPROT "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 21983014 t "The mPGES-1, one of three PGE2 synthases, is barely basally expressed, but is inducible by different stimuli and frequently co-expressed with COX-2. COX-2, mPGES-1 and PGE2 are enhanced during pain, inflammatory processes and in several cancer cells" SIGNOR-254263 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 PTGFR protein P43088 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-257082 PTGFR protein P43088 UNIPROT GNAS protein Q5JWF2 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-256810 PTGIR protein P43119 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-256949 PTGIR protein P43119 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-257078 PTGIR protein P43119 UNIPROT GNAS protein Q5JWF2 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-256806 PTGS2 protein P35354 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 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 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-141783 PTGS2 protein P35354 UNIPROT IL4 protein P05112 UNIPROT up-regulates 9606 22225874 t FFerrentino "Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression" SIGNOR-255967 PTGS2 protein P35354 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 20219869 t apalma "Furthermore, COX-2 inhibition reduced MyoD expression in regenerating muscle, suggesting a role for COX-2 in modulating muscle differentiation, as well as growth" SIGNOR-256214 PTGS2 protein P35354 UNIPROT Prostacycline smallmolecule CID:159 PUBCHEM up-regulates "small molecule catalysis" 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-113300 PTGS2 protein P35354 UNIPROT "prostaglandin D2" smallmolecule CHEBI:15555 ChEBI up-regulates "small molecule catalysis" 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 PTGS2 protein P35354 UNIPROT "prostaglandin F2alpha" smallmolecule CHEBI:15553 ChEBI up-regulates "small molecule catalysis" 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-113291 PTGS2 protein P35354 UNIPROT "prostaglandin F2alpha" smallmolecule CHEBI:15553 ChEBI up-regulates "small molecule catalysis" 9606 BTO:0001103 20219869 t apalma "NSAIDs are strong inhibitors of cycloxygenases (COX), and thereby impair the metabolism of arachidonic acid that is necessary for the synthesis of prostaglandins" SIGNOR-255359 PTH1R protein Q03431 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt." SIGNOR-199533 PTH2 protein Q96A98 UNIPROT PTH2R protein P49190 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671 11861531 t gcesareni "Subsequent efforts led to the isolation and definition of the primary structure of a novel peptide, referred to as tip39, from bovine hypothalamus and the synthetic peptide was shown to efficiently activate human, rat, and zebrafish pth2 receptors" SIGNOR-115124 PTH protein P01270 UNIPROT PTH2R protein P49190 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671 11861531 t gcesareni "Pth was shown to efficiently activate the human type 2 pth receptor (pth2 receptor)" SIGNOR-115104 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 18483407 t gcesareni "We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657." SIGNOR-178648 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 19934023 t gcesareni "We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657." SIGNOR-161824 PTK2B protein Q14289 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15105428 t llicata "Overexpression of pyk2 alone led to its spontaneous activation and tyrosine phosphorylation, resulting in activation of stat5b, indicated by the reporter gfp-stat5b. These effects were completely dependent upon tyr(402), the autophosphorylation site of pyk2, which allows recruitment of src family members for further activating phosphorylations at other sites on pyk2." SIGNOR-124339 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 PTK2B protein Q14289 UNIPROT SNCA protein P37840 UNIPROT unknown phosphorylation Tyr125 VDPDNEAyEMPSEEG 9534 BTO:0000298 12096713 t lperfetto "The present report demonstrates that the protein tyrosine kinase Pyk2/RAFTK is involved in cell stress-induced tyrosine phosphorylation of alpha S. Hyperosmotic stress induced tyrosine phosphorylation of alpha S via Pyk2/RAFTK at tyrosine residue 125." SIGNOR-249151 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 PTK2 protein Q05397 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates phosphorylation Tyr12 DSQQTNDyMQPEEDW 9606 23454549 t lperfetto "Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin ." SIGNOR-192126 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 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr4 yHAANQSY 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-192199 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT up-regulates phosphorylation Tyr265 MTYVSSFyHAFSGAQ 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-192191 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194340 PTK2 protein Q05397 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Tyr664 EGGWMEDyDYVHLQG 11604500 t lperfetto "FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD." SIGNOR-249111 PTK2 protein Q05397 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Tyr666 GWMEDYDyVHLQGKE 11604500 t lperfetto "FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD." SIGNOR-249112 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 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 PTK2 protein Q05397 UNIPROT PIK3R1 protein P27986 UNIPROT 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-53979 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 10816598 t miannu "Fak autophosphorylation site, tyr397. / extracellular matrix (ecm)-induced autophosphorylation of fak on tyr397 creates a high affinity binding site for the sh2 domain of c-src, and mutation (tyr to phe) of this residue inhibits association" SIGNOR-77434 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 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 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-133837 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 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-27879 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 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-133845 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 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-133849 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" binding 9606 15688067 t 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-257732 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" phosphorylation Tyr118 VGEEEHVySFPNKQK 9606 15688067 t miannu "Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites." SIGNOR-28243 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" phosphorylation Tyr31 FLSEETPySYPTGNH 9606 15688067 t miannu "Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites." SIGNOR-28247 PTK2 protein Q05397 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 21454698 t llicata "Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed." SIGNOR-173009 PTK2 protein Q05397 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-139146 PTK2 protein Q05397 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Y317 ELFDDPSYVNVQNLD 9606 9566877 t Luana " In vitro, FAK directly phosphorylated Shc Tyr-317 to promote Grb2 binding. FAK can associate and directly phosphorylate Shc at Tyr-317 to promote Grb2 binding and low-level signaling to ERK2." SIGNOR-259854 PTK2 protein Q05397 UNIPROT TLN1 protein Q9Y490 UNIPROT "up-regulates activity" binding 9606 15688067 t 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-257731 PTK2 protein Q05397 UNIPROT TRIO protein O75962 UNIPROT "up-regulates activity" phosphorylation Tyr2796 KDNFDSFySEVAELG 9534 BTO:0000298 12551902 t lperfetto "A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity." SIGNOR-249188 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 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 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-252622 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR 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-138437 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 PTK6 protein Q13882 UNIPROT ARHGAP5 protein Q13017 UNIPROT up-regulates phosphorylation Tyr1109 KGYSDEIyVVPDDSQ 9606 BTO:0000150 18829532 t lperfetto "Breast tumor kinase phosphorylates p190rhogap to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Brk phosphorylates p190 at the y(1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120rasgap (p120). As a consequence, brk stimulates p190 and attenuates p120 functions, leading to rhoa inactivation and ras activation, respectively." SIGNOR-181452 PTK6 protein Q13882 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 BTO:0001130 22084245 t lperfetto "Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro" SIGNOR-177242 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr440 GAYREHPyGRY 9606 BTO:0000567 16179349 t lperfetto "We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. |Tyrosine 440 was identified as a principal modulator of Sam68 localization and this site was phosphorylated in response to EGF treatment in human breast tumor cell lines." SIGNOR-249294 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 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10913193 t gcesareni "Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle" SIGNOR-80020 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT "up-regulates activity" phosphorylation Tyr447 RLSSFTSyENPT 9606 BTO:0000007 12121988 t lperfetto "Mutation of a C-terminal tyrosine (Tyr-447) increases enzyme activity and SH2 domain accessibility, consistent with a role for this residue in autoinhibition. | These results suggest that the Y447F and W44A mutations disrupt the normal intramolecular regulation of Brk and increase the catalytic activity of Brk." SIGNOR-249152 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT up-regulates phosphorylation Tyr342 RLIKEDVyLSHDHNI 9606 BTO:0000150 12121988 t miannu "Autophosphorylation increases enzyme activity of wild-type brk but not of a y342a mutant form of brk." SIGNOR-90604 PTK6 protein Q13882 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr250 PFLLDEDyEKVLGYV 9606 19393627 t lperfetto "Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates the signaling pathways downstream of them. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by Brk, using a series of STAP-2 YF mutants and anti-phospho-STAP-2 Tyr250 antibody. Furthermore, overexpression of the STAP-2 Y250F mutant protein affected Brk-mediated STAT3 activation." SIGNOR-247067 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 PTK6 protein Q13882 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000150 17997837 t llicata "Phosphospecific antibodies, mutational analysis, and in vitro kinase assays demonstrated that brk specifically mediated stat5b phosphorylation at the activating tyrosine, y699." SIGNOR-159066 PTK7 protein Q13308 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 23151663 t gcesareni "Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt." SIGNOR-199536 PTMA protein P06454 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 BTO:0000567 12522243 t "PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation." SIGNOR-259079 PTN protein P21246 UNIPROT ALK protein Q9UM73 UNIPROT up-regulates binding 9606 BTO:0000785 11278720 t gcesareni "We conclude from this series of experiments that ptn specifically binds to the alk orphan receptor as a high affinity ligand at least in part via the putative ligand binding domain described above." SIGNOR-106411 PTP4A1 protein Q93096 UNIPROT CDK2 protein P24941 UNIPROT up-regulates 9606 14643450 f gcesareni "Cells overexpressing either prl-1 or prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity and significantly lower p21cip1/waf1 protein levels" SIGNOR-119418 PTP4A2 protein Q12974 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation 9606 14643450 t amattioni "Cells overexpressing prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity" SIGNOR-119478 PTP4A3 protein O75365 UNIPROT EZR protein P15311 UNIPROT "down-regulates activity" dephosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0001109 18078820 t "Here we report the identification of Ezrin as a specific and direct cellular substrate of PRL-3. In HCT116 colon cancer cell line, Ezrin was identified among the cellular proteins whose phosphorylation level decreased upon ectopic over-expression of wtPRL-3 but not of catalytically inactive PRL-3 mutants. Although PRL-3 over-expression in HCT116 cells appeared to affect Ezrin phosphorylation status at both tyrosine residues and Thr567, suppression of the endogenous protein by RNA interference pointed to Ezrin-Thr567 as the residue primarily affected by PRL-3 action." SIGNOR-248342 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT "down-regulates activity" dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000586 19115206 t "the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431" SIGNOR-248341 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT "down-regulates activity" dephosphorylation Ser74 TVNQSLLsPLVLEVD 9606 BTO:0000586 19115206 t "the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431|The site-specific phosphorylation of keratins induces the disassembly of these filaments, and the balance between their phosphorylation and dephosphorylation controls the continuous exchange of intermediate filament subunits between a soluble pool and polymerized filaments" SIGNOR-248340 PTPN11 protein Q06124 UNIPROT CTNNA1 protein P35221 UNIPROT down-regulates dephosphorylation Tyr148 LADMADVyKLLVQLK 9606 16767162 t gcesareni "Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals." SIGNOR-147075 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 12582165 t lperfetto "Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not" SIGNOR-236424 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 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT "down-regulates activity" dephosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000782;BTO:0000776 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-236258 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT "down-regulates activity" dephosphorylation Tyr627 KGDKQVEyLDLDLDS 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-248674 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 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000782;BTO:0000776 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-236262 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000782;BTO:0000776 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 PTPN11 protein Q06124 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates dephosphorylation Tyr614 KSTGSVDyLALDFQP 9606 15170389 t gcesareni "Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2." SIGNOR-124958 PTPN11 protein Q06124 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates dephosphorylation 9606 BTO:0001271 19022774 t fspada "We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions." SIGNOR-182475 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 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr1179 GLENGLNyIDLDLVK 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-74856 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 7515062 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-27024 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 7515062 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-27028 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 14522994 t "We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association" SIGNOR-248665 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 PTPN11 protein Q06124 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates dephosphorylation 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-184604 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 PTPN11 protein Q06124 UNIPROT NRAS protein P01111 UNIPROT "up-regulates activity" dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t miannu "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-255754 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 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 PTPN11 protein Q06124 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-248669 PTPN11 protein Q06124 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation Tyr577 YMEDSTYyKASKGKL 9606 16920701 t gcesareni "Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner." SIGNOR-148926 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 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 PTPN11 protein Q06124 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" dephosphorylation Tyr701 DGPKGTGyIKTELIS 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-248672 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" dephosphorylation 10090 BTO:0004055 11163214 t gcesareni "Several experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity: c-Abl was hyperphosphorylated in PTP-PEST-deficient cells; disruption of the c-Abl-PSTPIP1-PEST-type PTP ternary complex by overexpression of PSTPIP1 mutants increased c-Abl phosphotyrosine content" SIGNOR-246222 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" dephosphorylation Tyr393 RLMTGDTyTAHAGAK 9534 BTO:0004055 11163214 t lperfetto "Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated." SIGNOR-235568 PTPN12 protein Q05209 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11432829 t gcesareni "Ptp-pest is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway." SIGNOR-109032 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr286 EELAMDVyDEVDRRE 9606 16317044 t fspada "Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest." SIGNOR-142711 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr392 QDNDQPDyDSVASDE 9606 16317044 t fspada "Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest." SIGNOR-142715 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr592 NSTPESDyDNTPNDM 9606 16317044 t fspada "Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest." SIGNOR-142719 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation -1 8454633 t gcesareni "Intrinsic activity was demonstrated in vitro against a variety of phosphotyrosine-containing substrates including BIRK, the autophosphorylated cytoplasmic kinase domain of the insulin receptor beta subunit." SIGNOR-39155 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-39147 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation "Tyr1185; Tyr1190" FGMTRDIyETDYYRK;DIYETDYyRKGGKGL -1 10734133 t gcesareni "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 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 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-75898 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 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 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-75902 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 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-75906 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 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-39159 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0003892 11731619 t "PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site" SIGNOR-248657 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 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT "down-regulates activity" dephosphorylation Tyr402 CSIESDIyAEIPDET 10116 11337490 t "Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation|CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity." SIGNOR-248662 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT "down-regulates activity" dephosphorylation Tyr579 RYIEDEDyYKASVTR 9606 BTO:0000887;BTO:0001260 11337490 t lperfetto "Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-pest-mediated dephosphorylation. / dephosphorylation of tyr402 and tyr579/580 by ptp-pest" SIGNOR-107502 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT "down-regulates activity" dephosphorylation Tyr580 YIEDEDYyKASVTRL 10116 11337490 t "Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation|CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity." SIGNOR-248664 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE 10090 BTO:0000944 19595712 t "We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis." SIGNOR-248661 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 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 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t gcesareni "The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions." SIGNOR-44361 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t gcesareni "The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions." SIGNOR-44862 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 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT "down-regulates activity" dephosphorylation Tyr291 AETSKLIyDFIEDQG 10090 14707117 t "mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities|WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST" SIGNOR-248660 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates dephosphorylation 9606 11711533 t gcesareni "Furthermore, we demonstrate that pstpip serves as a scaffold protein between ptp-pest and wasp and allows ptp-pest to dephosphorylate wasp. This finding suggests a possible mechanism for ptp-pest to directly modulate actin remodeling through the pstpip-wasp interaction." SIGNOR-111688 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 14707117 t gcesareni "Furthermore, we demonstrate that pstpip serves as a scaffold protein between ptp-pest and wasp and allows ptp-pest to dephosphorylate wasp. This finding suggests a possible mechanism for ptp-pest to directly modulate actin remodeling through the pstpip-wasp interaction." SIGNOR-121136 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-132551 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 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-132559 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 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 PTPN13 protein Q12923 UNIPROT STK25 protein O00506 UNIPROT "down-regulates activity" dephosphorylation 9606 17657516 t "To investigate dephosphorylation of CCM3 by FAP-1, phosphorylated GST-CCM3 was incubated with cdFAP-1, and reactions were analyzed by autoradiography. Again, GST-STK25 phosphorylated GST-CCM3 and possessed autophosphorylation activity. cdFAP-1 of 0.005 U were sufficient to dephosphorylate GST-CCM3 as well as the kinase GST-STK25.|More recently, the Golgi matrix protein GM130 was shown to function as a scaffold protein for STK25 and to activate STK25 through stimulation of autophosphorylation." SIGNOR-248711 PTPN13 protein Q12923 UNIPROT TRIP6 protein Q15654 UNIPROT "down-regulates activity" dephosphorylation Tyr55 PLPSEQCyQAPGGPE 10090 BTO:0002572 17591779 t "PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration.|Here we further demonstrate that a switch from c-Src-mediated phosphorylation to PTPL1/Fas-associated phosphatase-1-dependent dephosphorylation serves as an inhibitory feedback control mechanism of TRIP6 function in LPA-induced cell migration. PTPL1 dephosphorylates phosphotyrosine 55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells." SIGNOR-248713 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 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 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9606 16291744 t gcesareni "Here we report that protein-tyrosine phosphatase 1b (ptp 1b) is an ?-Actinin phosphatase." SIGNOR-141634 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 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 PTPN1 protein P18031 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR down-regulates dephosphorylation 9606 phosphorylation:Tyr177 9566916 t gcesareni "We have observed association and dephosphorylation of p210 bcr-abl, but not v-abl, by ptp1b in vivo." SIGNOR-56822 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 PTPN1 protein P18031 UNIPROT CAV1 protein Q03135 UNIPROT unknown dephosphorylation Tyr14 VDSEGHLyTVPIREQ -1 16388599 t "The scaffolding protein caveolin-1 is also a participant in these pathways and is specifically phosphorylated on tyrosine 14, when these pathways are activated. Here, we provide evidence that PTP1B can efficiently catalyze the removal of the phosphoryl group from phosphocaveolin-1." SIGNOR-248430 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 PTPN1 protein P18031 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" dephosphorylation Tyr1016 DVVDADEyLIPQQGF -1 8621392 t "We have shown previously that amino acid residues flanking the phosphotyrosine are important for efficient PTP1 catalysis (Table 1 and Refs. 9, 10, and 17). For example, the kcat/Km value for the undecapeptide, EGFR988-989 (epidermal growth factor autophosphorylation site Tyr992, residues 988-998) (Asp-Ala-Asp-Glu-pTyr-Leu-Ile-Pro-Gln-Gln-Gly) is 3220-fold higher than that of phosphotyrosine (Table 1). We further demonstrated that a minimum of six amino acid residues are required for the most efficient PTP1 binding and catalysis." SIGNOR-248407 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr534 NFLMDNAyFCEADAK 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-248420 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr566 SLNQEDIyITTESLT 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-248421 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10090 BTO:0000944 11579209 t lperfetto "Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor." SIGNOR-235495 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 BTO:0000007 16582879 t "Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR" SIGNOR-248408 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 10090 BTO:0000944 11579209 t lperfetto "Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor." SIGNOR-235499 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 16582879 t "Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR" SIGNOR-248409 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10090 BTO:0000944 11579209 t lperfetto "Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor." SIGNOR-235503 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 BTO:0000007 16582879 t "Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR" SIGNOR-248410 PTPN1 protein P18031 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation -1 10660596 t lperfetto "Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein." SIGNOR-74852 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000007 11970898 t "Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner" SIGNOR-248404 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 BTO:0000007 11970898 t "Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner" SIGNOR-248405 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 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 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-134955 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 15780598 t lperfetto "JAK2 and STAT3 are dephosphorylated by PTP1B in vitro" SIGNOR-133852 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT "down-regulates activity" dephosphorylation 9606 12857726 t "Using a pharmacological inhibitor, we provide evidence that PTP1B activation and LAT dephosphorylation processes were required for irreversible platelet aggregation.|In collagen-stimulated platelets, the signaling complexes recruited by tyrosine-phosphorylated LAT are essential for PLCgamma2 activation" SIGNOR-248403 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 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1235 DMYDKEYySVHNKTG 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-248412 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 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 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-181323 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 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-145145 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 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 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr1009 LDTSSVLyTAVQPNE -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-248416 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 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 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 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 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr716 RPPSAELySNALPVG 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179072 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr751 SKDESVDyVPMLDMK 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179076 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 PTPN1 protein P18031 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates dephosphorylation 9606 11350745 t gcesareni "Dephosphorylation of tyrosine residues by ptp1b, a protein tyrosine phosphatase, reduced the enhanced pkcdelta activity." SIGNOR-107754 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 PTPN1 protein P18031 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 16291744 t gcesareni "We show that coexpression of wild-type alpha-actinin and ptp 1b causes dephosphorylation at tyr-397 in fak." SIGNOR-141637 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates activity" dephosphorylation Tyr152 ISEDIKSyYTVRQLE -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-248424 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates activity" dephosphorylation Tyr153 SEDIKSYyTVRQLEL -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-248425 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 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2110 FGLARDIyKNDYYRK 9606 17416557 t gcesareni "In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products." SIGNOR-154199 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2114 RDIYKNDyYRKRGEG 9606 17416557 t gcesareni "In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products." SIGNOR-154203 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2115 DIYKNDYyRKRGEGL 9606 17416557 t gcesareni "In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products." SIGNOR-154207 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 BTO:0000007 11007774 t gcesareni "Incubation of the inactivated c-Src with PTP1B results in a dose-dependent reactivation of c-Src tyrosine kinase activity. Incubation of c-Src with 2 or 10 g of PTP1B results in partial or full restoration of c-Src kinase activity, respectively. The activation is accompanied by dephosphorylation of c-Src, both of Tyr-419 and of Tyr-530" SIGNOR-245299 PTPN1 protein P18031 UNIPROT STAM2 protein O75886 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Tyr291 KSEPEPVyIDEDKMD 9606 20504764 t "Together, the results presented here demonstrate that PTP1B can influence RTK signaling in a previously unrecognized manner. We show that PTP1B directly targets STAM2, part of the ESCRT-0 endosomal sorting complex, and we provide the first evidence that tyrosine phosphorylation affects STAM localization and function. This regulatory mechanism could impact signaling downstream of numerous cell surface receptors that are ubiquitinated and recognized by this conserved sorting machinery." SIGNOR-248406 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT "down-regulates activity" dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9534 BTO:0004055 10993888 t "A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b" SIGNOR-248429 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 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000007 17197020 t llicata "In HEK293 cells, transfected with the Ca2+ channel protein TRPV6, Ca2+ influx is increased and TRPV6 is tyrosine phosphorylated following addition of the tyrosine phosphatase inhibitor|PTP1B interacts with the N-terminal domain of TRPV6 within a region of amino acids 1-191 as shown by co-immunoprecipitation, bimolecular fluorescence complementation and the yeast 2-hybrid system. Point mutation of both tyrosines 161 and 162 in the TRPV6 protein abolishes the DMHV-effect on Ca2+ influx and tyrosine phosphorylation by Src. Single mutations of Y161 or Y162 shows that each of both tyrosines alone is sufficient for the DMHV-effect. 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." SIGNOR-248433 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 PTPN1 protein P18031 UNIPROT TYK2 protein P29597 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-134564 PTPN21 protein Q16825 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 15143158 t "Dephosphorylation of Y527 was more pronounced in cells expressing PTPD1 at each time point tested. PTPD1C1108S drastically inhibited Y527 dephosphorylation|Activation of src requires dephosphorylation of src residue Y527. This promotes displacement of the SH2 domain from this residue and subsequent autophosphorylation of residue Y416 within the activation loop" SIGNOR-248725 PTPN21 protein Q16825 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 15143158 t gcesareni "Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling." SIGNOR-124774 PTPN22 protein Q9Y2R2 UNIPROT CBL protein P22681 UNIPROT down-regulates dephosphorylation Ser798 SDISNASsSFGWLSL 9606 BTO:0000782 10068674 t amattioni "The tyrosine phosphatase lyp1 was found to be constitutively associated with the proto-oncogene c-cbl in thymocytes and t cells. Overexpression of lyp1 reduces cbl tyrosine phosphorylation. It is known that cbl is heavily tyrosine phosphorylated after tcr stimulation and can associate with the syk and zap tyrosine kinases, negatively regulating their activities. Tyrosine phosphatases keep cbl in a basally dephosphorylated state." SIGNOR-65405 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000007 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-248837 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 16461343 t amattioni "T cell signaling is negatively regulated by the activity of protein-tyrosine phosphatases. Native ptpn22 dephosphorylated tcrzeta in vitro and in cells." SIGNOR-144337 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT "down-regulates activity" dephosphorylation Tyr394 RLIEDNEyTAREGAK 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-248836 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 PTPN2 protein P17706 UNIPROT AKT1 protein P31749 UNIPROT 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-252640 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 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 15592458 t gcesareni "Here, we report that the 45-kda variant of the protein tyrosine phosphatase tcptp (tc45) can recognize delta egfr as a cellular substrate" SIGNOR-132316 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 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 PTPN2 protein P17706 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000782 22080863 t lperfetto "Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks" SIGNOR-177113 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 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr487 SLSNIDFyAQVSDIT 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-248392 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr534 NFLMDNAyFCEADAK 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-248393 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr566 SLNQEDIyITTESLT 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-248394 PTPN2 protein P17706 UNIPROT GJA1 protein P17302 UNIPROT up-regulates dephosphorylation Tyr247 VKGKSDPyHATSGAL 9606 BTO:0000671 24849651 t lperfetto "Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43." SIGNOR-205097 PTPN2 protein P17706 UNIPROT GJA1 protein P17302 UNIPROT up-regulates dephosphorylation Tyr265 KDCGSQKyAYFNGCS 9606 BTO:0000671 24849651 t lperfetto "Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43." SIGNOR-205101 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 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-248385 PTPN2 protein P17706 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-75910 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 PTPN2 protein P17706 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-75918 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1373652 t gcesareni "The question of whether protein tyrosine phosphatases (ptpases) dephosphorylate a multiply phosphorylated peptide in a random or ordered manner was investigated using the synthetic triphosphotyrosyl peptide trdiy(p)etdy(p)y(p)rk, corresponding to the major sites of autophosphorylation of the insulin receptor, as a substrate for four purified ptpases." SIGNOR-18018 PTPN2 protein P17706 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-75922 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 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-134620 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1034 AIETDKEyYTVKDDR 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-248395 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 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 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 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 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1214 VCDPKFHyDNTAGIS 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-248401 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 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 PTPN2 protein P17706 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-248387 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1235 DMYDKEYySVHNKTG 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-248388 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t gcesareni "We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met." SIGNOR-181331 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t gcesareni "We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met." SIGNOR-181335 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 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-248390 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 PTPN2 protein P17706 UNIPROT SHC1 protein P29353 UNIPROT "down-regulates activity" dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 9488479 t llicata "However, TC45 inhibited the EGF-induced association of p52Shc with Grb2, which was attributed to the ability of the PTP to recognize specifically p52Shc phosphorylated on Y239. These results indicate that TC45 recognizes not only selected substrates in a cellular context but also specific sites within substrates and thus may regulate discrete signaling events." SIGNOR-248397 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 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-133279 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 12138178 t "Upon interferon (IFN) stimulation, Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to DNA to activate transcription. The activity of Stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (PTP). We have now purified a Stat1 PTP activity from HeLa cell nuclear extract and identified it as TC45, the nuclear isoform of the T-cell PTP (TC-PTP)." SIGNOR-248402 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT down-regulates dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 12138178 t miannu "Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to dna to activate transcription. The activity of stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (ptp). We have now purified a stat1 ptp activity from hela cell nuclear extract and identified it as tc45, the nuclear isoform of the t-cell ptp (tc-ptp). Tc45 can dephosphorylate stat1 both in vitro and in vivo." SIGNOR-90814 PTPN2 protein P17706 UNIPROT STAT5A protein P42229 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-133547 PTPN2 protein P17706 UNIPROT WASL protein O00401 UNIPROT down-regulates dephosphorylation Tyr256 RETSKVIyDFIEKTG 9606 BTO:0000782 16293614 t gcesareni "Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42" SIGNOR-141652 PTPN3 protein P26045 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr534 NFLMDNAyFCEADAK 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-248459 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT "down-regulates activity" dephosphorylation Tyr796 GGTGGSVyTEDNDDD 9606 BTO:0000007 10364224 t "Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs." SIGNOR-248460 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT "down-regulates activity" dephosphorylation Tyr805 EDNDDDLyG 9606 BTO:0000007 10364224 t "Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs." SIGNOR-248461 PTPN5 protein P54829 UNIPROT BAK1 protein Q16611 UNIPROT "up-regulates activity" dephosphorylation Tyr108 QPTAENAyEYFTKIA 9606 20959805 t "In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation." SIGNOR-248542 PTPN5 protein P54829 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000938 BTO:0000671 11983687 t lperfetto "Wild-type step(61) dephosphorylates fyn at tyr(420) but not at tyr(531). These results suggest that step regulates the activity of fyn by specifically dephosphorylating the regulatory tyr(420) and may be one mechanism by which fyn activity is decreased within psds." SIGNOR-86791 PTPN5 protein P54829 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 BTO:0000938 23932588 t "A study conducted by Zhang et al. showed that STEP is significantly less efficient than PTPSL and HePTP at dephosphorylating p38a." gcesareni "First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a." SIGNOR-194829 PTPN6 protein P29350 UNIPROT ACTG1 protein P63261 UNIPROT down-regulates dephosphorylation Tyr218 DIKEKLCyVALDFEQ 9606 BTO:0000776 12646642 t gcesareni "Our data suggest that shp-1 plays a pivotal role in reorganization of cytoskeletal architecture inducing actin dephosphorylation. These results clearly demonstrate the direct interaction of shp-1 with actin" SIGNOR-99565 PTPN6 protein P29350 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" dephosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 18086677 t "Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis." SIGNOR-248477 PTPN6 protein P29350 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" dephosphorylation Tyr448 TILTEVNyEVSNKDD 9606 18086677 t "Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis." SIGNOR-248478 PTPN6 protein P29350 UNIPROT CD72 protein P21854 UNIPROT down-regulates dephosphorylation 9606 BTO:0000776 9740800 t gcesareni "Our work clearly identifies cd72 as both an shp-1 binding protein (figure 1,figure 2) and a direct substrate for shp-1 in vivo (figure 3). As tyrosine phosphorylation of cd72 strongly correlates with the ability of the bcr to deliver growth-inhibitory/apoptosis-inducing signals (figure 4), our results suggest that shp-1-catalyzed dephosphorylation of cd72 may antagonize these signals." SIGNOR-60155 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 9162089 t gcesareni "However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2." SIGNOR-48561 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 PTPN6 protein P29350 UNIPROT IL2RB protein P14784 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 9520455 t gcesareni "We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3." SIGNOR-55989 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 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 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 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 PTPN6 protein P29350 UNIPROT JAK1 protein P23458 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 t gcesareni "We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation." SIGNOR-119197 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 PTPN6 protein P29350 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates dephosphorylation 9606 BTO:0000142 12361947 t gcesareni "Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1." SIGNOR-94007 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18377662 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-248474 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 18377662 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-248475 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 PTPN6 protein P29350 UNIPROT KIT protein P10721 UNIPROT down-regulates binding 9606 9528781 t miannu "Shp-1 binds and negatively modulates the c-kit receptor by interaction with tyrosine 569 in the c-kit juxtamembrane domain." SIGNOR-56104 PTPN6 protein P29350 UNIPROT LCK protein P06239 UNIPROT "down-regulates activity" dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 BTO:0000007 11294838 t lperfetto "We demonstrate that shp-1 dephosphorylates the lymphoid-specific src family kinase lck at tyr-394. Because phosphorylation of tyr-394 activates lck, the fact that shp-1 specifically dephosphorylates this site suggests that shp-1 is a negative regulator of lck." SIGNOR-106604 PTPN6 protein P29350 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t "SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397" SIGNOR-248471 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 PTPN6 protein P29350 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates binding 9606 14551136 t gcesareni "All together, our results indicate that shp-1 inhibits prlr and epor signaling by recruitment and targeting of socs-1 to jak2, highlighting a new mechanism of shp-1 regulation of cytokine-receptor signaling." SIGNOR-118572 PTPN6 protein P29350 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 9261115 t "To determine whether the COOH-terminal or other phosphotyrosine residues within Src are subject to dephosphorylation by SHP-1, the effects of this phosphatase on Src tyrosine phosphorylation were initially examined using CNBr cleavage analysis. As illustrated in Fig.1 A, CNBr treatment of32P-labeled human Src has been shown previously to yield phosphorylated cleavage fragments of about 31, 9.7, and 4.7 kDa, which, respectively, contain the Src NH2-terminal region encompassing the major sites for serine phosphorylation on Src, Ser-12 and Ser-17 (31-kDa fragment), the inhibitory tyrosine phosphorylation site, Tyr-530 (4.7-kDa fragment), and a key site for autophosphorylation on activated Src, Tyr-419" SIGNOR-248473 PTPN6 protein P29350 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-248472 PTPN6 protein P29350 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation 9606 18508557 t gcesareni "Stat3 may also be a substrate of shp1" SIGNOR-178699 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 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 PTPN6 protein P29350 UNIPROT TYK2 protein P29597 UNIPROT down-regulates 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 f lperfetto "We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation" SIGNOR-119200 PTPN6 protein P29350 UNIPROT ZAP70 protein P43403 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-70237 PTPN7 protein P35236 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation Tyr182 TDDEMTGyVATRWYR 9606 BTO:0000661 10206983 t "In Jurkat cells, LC-PTP suppressed the ERK and p38 mitogen-activated protein kinase cascades" SIGNOR-248485 PTPN7 protein P35236 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 BTO:0000776 19047375 t gcesareni "Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation" SIGNOR-182525 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 10702794 t "HePTP efficiently dephosphorylated active ERK2 on the tyrosine residue in the activation loop in vitro. Together, these data identify ERK2 as a specific and direct target of HePTP and are consistent with a model in which HePTP negatively regulates ERK2 activity as part of a feedback mechanism" SIGNOR-248484 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 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 10415025 t fstefani "Lc-ptp dephosphorylated erk2 in vitro. the complex formation of lc-ptp with erk is the essential mechanism for the suppression. Taken collectively, these results indicate that lc-ptp suppresses mitogen-activated protein kinase directly in vivo." SIGNOR-69448 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 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 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-146668 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 PTPRA protein P18433 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" dephosphorylation Tyr531 FTATEPQyQPGENL 10090 BTO:0000255 9535845 t "In a coexpression system, PTPalpha effected a dose-dependent tyrosine dephosphorylation and activation of p59(fyn), where maximal dephosphorylation correlated with a 5-fold increase in kinase activity.|the increased p59fyn catalytic activity and SH2 availability for binding are consistent with a PTPα-mediated dephosphorylation of the C-terminal Tyr-531 of p59fyn." SIGNOR-248435 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 PTPRA protein P18433 UNIPROT KCNB1 protein Q14721 UNIPROT down-regulates dephosphorylation 9606 16870705 t gcesareni "Ptpalpha inhibits kv channels more strongly than ptpepsilon;this correlates with constitutive association of ptpalpha with kv2.1, driven by membranal localization of ptpalpha." SIGNOR-148301 PTPRA protein P18433 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t "We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI" SIGNOR-248436 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 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 PTPRA protein P18433 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-248437 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 BTO:0000938 7691597 t gcesareni "Endogenous pp60c-src kinase activity is enhanced in the rptp alpha-transfected cells, which may be due to direct dephosphorylation of the regulatory tyr residue at position 527 in pp60c-src by rptp alpha." SIGNOR-32014 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 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t gcesareni "Identification of tyrosine phosphatases that dephosphorylate the insulin receptor." SIGNOR-75989 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni "Identification of tyrosine phosphatases that dephosphorylate the insulin receptor." SIGNOR-75993 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni "Identification of tyrosine phosphatases that dephosphorylate the insulin receptor." SIGNOR-75997 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni "Identification of tyrosine phosphatases that dephosphorylate the insulin receptor." SIGNOR-76001 PTPRB protein P23467 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 19136612 t "VE-PTP/VEGFR2 complex formation resumes with time, leading to dephosphorylation and deactivation of VEGFR2 (right). B) In VE-PTP-deficient cells, such as after siRNA treatment, VEGFR2 activation (middle) is exaggerated, leading to increased phosphorylation at the Y951 and Y1175 phosphorylation sites" SIGNOR-248441 PTPRB protein P23467 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 21454675 t fstefani "Expression of rptp-beta inhibits both mek1/2 and erk1/2 phosphorylation." SIGNOR-173000 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 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 16101282 t gcesareni "Ptp1b and shp-2 are bound to the c-met receptor to control its activity. Although the binding of ptp1b increases when there is a decrease in c-met activation and acts as a negative regulator of the receptor, the increased binding and phosphorylation of shp-2 coincide with maximal stimulation of c-met, acting as a positive regulator." SIGNOR-139560 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 BTO:0000007 21454675 t gcesareni "Receptor-type protein tyrosine phosphatase beta (rptp-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (hgfr/met) function." SIGNOR-173004 PTPRC protein P08575 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 11909961 t "On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction." SIGNOR-248352 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1034 AIETDKEyYTVKDDR 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-248355 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1035 IETDKEYyTVKDDRD 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-248356 PTPRC protein P08575 UNIPROT JAK1 protein P23458 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-87154 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 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation 9606 24252238 t miannu "Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates." SIGNOR-255679 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 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 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-248349 PTPRC protein P08575 UNIPROT JAK3 protein P52333 UNIPROT "down-regulates activity" dephosphorylation 10090 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling" SIGNOR-248359 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 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 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT "down-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 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" dephosphorylation Tyr505 FTATEGQyQPQP 10090 BTO:0000782 17719247 t "CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity." SIGNOR-259933 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr397 RVIEDNEyTAREGAK 10090 BTO:0000776 10415030 t "CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)" SIGNOR-248353 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr508 YTATEGQyQQQP 10090 BTO:0000776 10415030 t "CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)" SIGNOR-248354 PTPRC protein P08575 UNIPROT SKAP1 protein Q86WV1 UNIPROT "up-regulates activity" dephosphorylation Tyr232 EEEKEETyDDIDGFD 9606 BTO:0000661 11909961 t "Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity. Furthermore, overexpression of SKAP55-Y232F also caused the tyrosine hyperphosphorylation of Fyn with a decreased kinase activity. Thus, SKAP55 is an essential adapter to couple CD45 with the Src family kinases for dephosphorylation and, thus, positively regulates TCR signaling." SIGNOR-248360 PTPRC protein P08575 UNIPROT TYK2 protein P29597 UNIPROT "down-regulates activity" dephosphorylation Tyr1054 AVPEGHEyYRVREDG 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-248357 PTPRC protein P08575 UNIPROT TYK2 protein P29597 UNIPROT "down-regulates activity" dephosphorylation Tyr1055 VPEGHEYyRVREDGD 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-248358 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 19478061 t "Transfection of wild-type PTPRD resulted in the specific dephosphorylation of STAT3 at tyrosine 705, a residue that must be phosphorylated for STAT3 to be active" SIGNOR-248442 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000551;BTO:0000527 BTO:0000142 19478061 t miannu "Transfection of wild-type ptprd resulted in the specific dephosphorylation of stat3 at tyrosine 705, a residue that must be phosphorylated for stat3 to be active" SIGNOR-185933 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-248444 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-248445 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 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr999 YASSNPEyLSASDVF 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-248443 PTPRE protein P23469 UNIPROT KCNB1 protein Q14721 UNIPROT "down-regulates activity" dephosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000007 10921884 t "Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon" SIGNOR-248450 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0000007 12754301 t llicata "The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop" SIGNOR-248448 PTPRE protein P23469 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 9534 BTO:0004055 15522235 t llicata "PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src." SIGNOR-238074 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 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 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-76009 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-16239 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 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-76013 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-16243 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t lperfetto "Many cellular receptors signal via tyrosine phosphorylation. The tyrosine kinases required for this activity are often recruited upon ligand bindingAlternatively, receptors themselves have kinase activity, like insulin receptors. In either case, the receptors are returned to their original state through the activity of protein-tyrosine phosphatases (PTPs)The major candidate PTPs previously implicated in IRK dephosphorylation are PTP-1b and LAR." SIGNOR-76017 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 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-16247 PTPRF protein P10586 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 11121408 t gcesareni "Here we show that lar reduces the constitutive tyrosine autophosphorylation and kinase activity of ret-men2a but not ret-men2b, accompanying a significant decrease of phosphorylation of phospholipase cgamma, akt, and erk1/2." SIGNOR-85166 PTPRF protein P10586 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 11121408 t gcesareni "Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b" SIGNOR-85170 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 PTPRG protein P23470 UNIPROT BLNK protein Q8WV28 UNIPROT "up-regulates activity" dephosphorylation Tyr84 EHSDSEMyVMPAEEN -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-254692 PTPRG protein P23470 UNIPROT BMX protein P51813 UNIPROT "down-regulates activity" dephosphorylation Tyr40 LTKTNLSyYEYDKMK -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-254693 PTPRG protein P23470 UNIPROT BTK protein Q06187 UNIPROT "down-regulates activity" dephosphorylation Tyr223 LKKVVALyDYMPMNA -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-254694 PTPRG protein P23470 UNIPROT CDK2 protein P24941 UNIPROT "down-regulates activity" dephosphorylation Tyr15 EKIGEGTyGVVYKAR -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-254695 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 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 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 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 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" dephosphorylation Tyr1172 ISLDNPDyQQDFFPK -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-254700 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 PTPRG protein P23470 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" dephosphorylation Tyr1474 GSSNGHVyEKLSSIE -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-254702 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" dephosphorylation Tyr1089 RDIYETDyYRKGGKG -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-254704 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" dephosphorylation Tyr1090 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 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" dephosphorylation Tyr999 YASSNPEyLSASDVF -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-254703 PTPRG protein P23470 UNIPROT ITGAL protein P20701 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000876 25624455 f miannu "PTPRG activation inhibits chemoattractantinduced 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-254736 PTPRG protein P23470 UNIPROT ITGB1 protein P05556 UNIPROT "down-regulates activity" dephosphorylation Tyr783 DTGENPIyKSAVTTV -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-254706 PTPRG protein P23470 UNIPROT ITGB2 protein P05107 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000876 25624455 f miannu "PTPRG activation inhibits chemoattractantinduced 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 PTPRG protein P23470 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1054 FGLARDIyKDPDYVR -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-254707 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 PTPRG protein P23470 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1003 VSNESVDyRATFPED -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-254712 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" dephosphorylation Tyr742 KQADTTQyVPMLERK -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-254713 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" dephosphorylation Tyr754 ERKEVSKySDIQRSL -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-254714 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr577 YMEDSTYyKASKGKL -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-254718 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr861 PIGNQHIyQPVGKPD -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-254720 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 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" dephosphorylation Tyr576 RYMEDSTyYKASKGK -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-254719 PTPRG protein P23470 UNIPROT PTPRG protein P23470 UNIPROT "down-regulates activity" binding 9606 BTO:0000876 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 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" dephosphorylation -1 25624455 t miannu "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-254722 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" dephosphorylation Tyr118 VGEEEHVySFPNKQK -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-254721 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 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 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK -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-254725 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL -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-254726 PTPRG protein P23470 UNIPROT STAT2 protein P52630 UNIPROT "up-regulates activity" dephosphorylation Tyr690 NLQERRKyLKHRLIV -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-254728 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 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 PTPRG protein P23470 UNIPROT VCL protein P18206 UNIPROT "down-regulates activity" dephosphorylation Tyr822 KSFLDSGyRILGAVA -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-254731 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-76080 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 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-76084 PTPRJ protein Q12913 UNIPROT CBL protein P22681 UNIPROT "down-regulates activity" 9606 19836242 f "Because c-CBL’s activation is achieved via tyrosine phosphorylation, we tested the effect of DEP-1 on modification of a major site of phosphorylation, namely tyro- sine 731. Upon DEP-1 overexpression, c-CBL displayed reduced phosphorylation on this site compared to control cells (Figure 7B). This result offers a mechanism by which DEP-1 affects EGFR trafficking: by dephosphorylating EGFR, and possibly also SRC family kinases involved in phosphoryla- tion of c-CBL [31, 32], DEP-1 reduces activation of c-CBL and its recruitment to the activated EGFR, hence inhibiting subsequent receptor internalization and degradation." SIGNOR-248839 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Tyr1092 TFLPVPEyINQSVPK 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-248698 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 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-21295 PTPRJ protein Q12913 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-76092 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 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-21303 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 BTO:0000782 10734133 t gcesareni "Ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase." SIGNOR-76096 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 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-76100 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 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-21307 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1054 FGLARDIyKDPDYVR 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-248709 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 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 18936167 t gcesareni "The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2." SIGNOR-181672 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 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 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Tyr204 HTGFLTEyVATRWYR -1 19494114 t "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-248707 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 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 PTPRJ protein Q12913 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 12062403 t "Primary sequence determinants responsible for site-selective dephosphorylation of the PDGF beta-receptor by the receptor-like protein tyrosine phosphatase DEP-1|DEP-1 dephosphorylation of original and chimeric phospho-peptides spanning the preferred pY1021" SIGNOR-248704 PTPRJ protein Q12913 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates dephosphorylation 9606 18348712 t gcesareni "As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors." SIGNOR-252727 PTPRJ protein Q12913 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates dephosphorylation 9606 18348712 t gcesareni "As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors." SIGNOR-178049 PTPRJ protein Q12913 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11259588 t miannu "Cd148 can dephosphorylate lat and plc?1 In vitro. / plc?1 Undergoes inducible tyrosine phosphorylation following tcr stimulation (46), and this phosphorylation is required to stimulate its catalytic activity" SIGNOR-105790 PTPRJ protein Q12913 UNIPROT PLCG1 protein P19174 UNIPROT unknown dephosphorylation 9606 11259588 t "Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation" SIGNOR-248706 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT "down-regulates activity" dephosphorylation Tyr1062 TWIENKLyGMSDPNW 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-248700 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 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 16778204 t gcesareni "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). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret" SIGNOR-147161 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 16778204 t gcesareni "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). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret" SIGNOR-147165 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 10116 15735685 t "The rat tyrosine phosphatase eta increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue" SIGNOR-248705 PTPRK protein Q15262 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT "up-regulates activity" dephosphorylation 9606 BTO:0003009 31934854 t "We show that PTPRK acts via the transmembrane E3 ubiquitin ligase ZNRF3, a negative regulator of Wnt signaling promoting Wnt receptor degradation, which is also expressed in the organizer." SIGNOR-260110 PTPRR protein Q15256 UNIPROT MAPK7 protein Q13164 UNIPROT "down-regulates activity" dephosphorylation Tyr221 HQYFMTEyVATRWYR 9534 BTO:0004055 12042304 t "in this study we concentrated on whether and how PTP-SL, a kinase-interacting motif-containing PTP, might be involved in the down-regulation of the ERK5 signal|Whereas inactivation of ERK5 by PTP-SL monitored in vitro is most probably simply due to the dephosphorylation of tyrosine 220 in the activating TEY motif" SIGNOR-248721 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 PTPRR protein Q15256 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001616 17360477 t "Here, we report identification of signal transducer and activator of transcription 3 (STAT3) as a substrate of PTPRT. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position." SIGNOR-248719 PTPRZ1 protein P23471 UNIPROT ALK protein Q9UM73 UNIPROT down-regulates dephosphorylation 9606 BTO:0000785 17681947 t gcesareni "Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation." SIGNOR-157227 PTPRZ1 protein P23471 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT "down-regulates activity" dephosphorylation Tyr1105 RNEEENIySVPHDST 10090 BTO:0000601 16513268 t "Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP| Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo." SIGNOR-248451 PTTG1 protein O95997 UNIPROT LGALS1 protein P09382 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002428 19351864 f miannu "PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR." SIGNOR-255068 PTTG1 protein O95997 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR "up-regulates activity" 10090 BTO:0000093 22002306 f "Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling" SIGNOR-256535 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 PTTG1 protein O95997 UNIPROT TIMP2 protein P16035 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0002429 19351864 f miannu "Suppressing PTTG expression by siRNA decreased cell motility in both PTTG-HA/EC9706 and KYSE150 cells. By using mass spectrometric analysis, we identified that PTTG up-regulated S100A4 and galectin-1 secretion and down-regulated tissue inhibitor of metalloproteinase-2 secretion to the culture media." SIGNOR-255069 PTX3 protein P26022 UNIPROT CFH protein P08603 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 19050261 t miannu "Our findings identify PTX3 as a unique FH ligand in that it can bind both of the two hot-spots of FH, namely SCR7 and SCR19-20 and indicate that PTX3 participates in the localization of functionally active FH. PTX3 binds FH without interfering with its complement inhibitory function. Therefore PTX3 may contribute to focusing FH regulatory action, prevent excessive complement activation, and thus exert an important function in the control of inflammation in response to tissue injury." SIGNOR-252140 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 PURB protein Q96QR8 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-253901 purmorphamine chemical CHEBI:63053 ChEBI SMO protein Q99835 UNIPROT up-regulates binding 9606 17419683 t gcesareni "The activity of smo toward gi was stimulated severalfold with the synthetic agonist purmorphamine and inhibited almost completely by cyclopamine and other antagonists of shh." SIGNOR-154282 putrescine smallmolecule CHEBI:17148 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000452 BTO:0001103 14617280 f apalma "Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism" SIGNOR-255551 PVR protein P15151 UNIPROT CD226 protein Q15762 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 30591568 t lperfetto "We focused on receptor-ligand interactions between CAFs and NK cell and found that cell-surface poliovirus receptor (PVR/CD155), a ligand of activating NK receptor DNAM-1, was downregulated in the CAFs compared with NEFs. |Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12)." SIGNOR-261424 PVR protein P15151 UNIPROT TIGIT protein Q495A1 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 30591568 t lperfetto "Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12)." SIGNOR-261425 PXN protein P49023 UNIPROT ILK protein Q13418 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11304546 t gcesareni "Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events." SIGNOR-106824 PYCARD protein Q9ULZ3 UNIPROT "AIM2 inflammasome" complex SIGNOR-C222 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-256401 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 PYCARD protein Q9ULZ3 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-256408 PYCARD protein Q9ULZ3 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-256411 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 Pyridostigmine chemical CHEBI:8665 ChEBI BCHE protein P06276 UNIPROT "down-regulates activity" "chemical inhibition" -1 20627738 t Luana "The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors " SIGNOR-257880 "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 PYY protein P10082 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 7592911 t gcesareni "Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid." SIGNOR-29767 PYY protein P10082 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 t esanto "Maml3 forms complexes in vivo with icn and csl and functiosn as transcriptional coactivators for notch signaling." SIGNOR-114749 QOCYWLABLBUJOR-UHFFFAOYSA-N chemical CID:53299324 PUBCHEM SLC6A3 protein Q01959 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-257796 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 Quadazocine chemical CID:115077 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-258418 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 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 quetiapine chemical CHEBI:8707 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-258842 quetiapine chemical CHEBI:8707 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-258535 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 quetiapine chemical CHEBI:8707 ChEBI HTR2A protein P28223 UNIPROT "up-regulates activity" "chemical activation" 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-258532 quizartinib smallmolecule CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 19754199 t "Compound 7 (AC220) (quizartinib) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models." SIGNOR-255666 quizartinib smallmolecule CHEBI:90217 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-258270 QYDAFJUKVGVEKO-PKOVDKIBSA-N smallmolecule CID:16132339 PUBCHEM MRGPRX1 protein Q96LB2 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-257543 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 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 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 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-258273 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 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-259793 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 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-258274 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 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206364 (R)-5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin chemical CID:11957727 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-258867 RAB10 protein P61026 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22" SIGNOR-260618 RAB14 protein P61106 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22" SIGNOR-260619 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 RAB1A protein P62820 UNIPROT ULK1 protein O75385 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 27334615 t Sara "C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation" SIGNOR-261299 RAB1A protein P62820 UNIPROT USO1 protein O60763 UNIPROT "up-regulates activity" binding -1 10903204 t Giulio "Here, the tethering factor p115 was shown to be a Rab1 effector that binds directly to activated Rab1." SIGNOR-261287 RAB21 protein Q9UL25 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22" SIGNOR-260620 RAB22A protein Q9UL26 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR "up-regulates activity" relocalization 9606 30404817 t lperfetto "Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis." SIGNOR-260696 RAB22A protein Q9UL26 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22" SIGNOR-260621 RAB23 protein Q9ULC3 UNIPROT GLI3 protein P10071 UNIPROT down-regulates 9606 16364285 f gcesareni "Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization." SIGNOR-143160 RAB23 protein Q9ULC3 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates 9606 16364285 f gcesareni "Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization." SIGNOR-143163 RAB2A protein P61019 UNIPROT PRKCI protein P41743 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 14570876 t Sara "Rab2 Binds to the PKCι/λ Regulatory Domain and Inhibits PKCι/λ-dependent GAPDH Phosphorylation" SIGNOR-261301 RAB2A protein P61019 UNIPROT TRIP11 protein Q15643 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 25473115 t Sara "Vesicle-associated Rab2 then mediates attachment to the Rab2 binding site within the central coiled-coil region of GMAP-210, bringing the vesicle into closer proximity to the target membrane. GMAP-210 function in vivo is dependent upon its ability to tether membranes, which is mediated exclusively by the amino-terminal ALPS motif. Binding to Rab2 is also important for GMAP-210 function, although it is dispensable for tethering per se." SIGNOR-261300 RAB32 protein Q13637 UNIPROT "AP-1 complex" complex SIGNOR-C248 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-260700 RAB32 protein Q13637 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-260698 RAB32 protein Q13637 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-260695 RAB33B protein Q9H082 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates binding 9606 18448665 t gcesareni "Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation." SIGNOR-178542 RAB38 protein P57729 UNIPROT "AP-1 complex" complex SIGNOR-C248 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-260701 RAB4A protein P20338 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22" SIGNOR-260617 RAB4A protein P20338 UNIPROT RUFY1 protein Q96T51 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 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 RAB5A protein P20339 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22" SIGNOR-260616 RAB5A protein P20339 UNIPROT PIK3R4 protein Q99570 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-260708 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 RAB7A protein P51149 UNIPROT NTRK1 protein P04629 UNIPROT "down-regulates activity" phosphorylation 10116 BTO:0001009 16306406 f 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 RAB7A protein P51149 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" BTO:0001131 14617358 t Sara "The p150 adapter protein is in a complex with rab7. The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7" SIGNOR-261302 RAB7A protein P51149 UNIPROT PSMA7 protein O14818 UNIPROT "up-regulates activity" binding 10036 BTO:0000120 14998988 t Sara "Rab7 Forms a Complex with the Proteasome -Subunit XAPC. In this study the proteasome alpha-subunit XAPC7 (also known as PSMA7, RC6-1, and HSPC in mammals) was identified to interact specifically with Rab7 and was recruited to multivesicular late endosomes through this interaction." SIGNOR-261303 RAB7A protein P51149 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 10116 BTO:0000968 16040606 t Sara "Rab7-Rac1 interaction may mediate late endosomal transport between microtubules and microfilaments" SIGNOR-261304 RAB8A protein P61006 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 18694559 f miannu "CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110" SIGNOR-252148 RAB9A protein P51151 UNIPROT GCC2 protein Q8IWJ2 UNIPROT "up-regulates activity" 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-253087 RAB9A protein P51151 UNIPROT PLIN3 protein O60664 UNIPROT "up-regulates activity" 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-253089 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 RABEP1 protein Q15276 UNIPROT RAB5A protein P20339 UNIPROT up-regulates binding 9606 11452015 t miannu "We have previously shown that rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of rabex-5, a rab5 nucleotide exchange factor, and the effector rabaptin-5." SIGNOR-109352 RABEP1 protein Q15276 UNIPROT RABGEF1 protein Q9UJ41 UNIPROT up-regulates binding 9606 11452015 t miannu "We show that rabaptin-5 increases the exchange activity of rabex-5 on rab5." SIGNOR-109395 RABEPK protein Q7Z6M1 UNIPROT IGF2R protein P11717 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-253090 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 RABGEF1 protein Q9UJ41 UNIPROT RAB5A protein P20339 UNIPROT up-regulates binding 9606 11452015 t miannu "We have previously shown that rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of rabex-5, a rab5 nucleotide exchange factor, and the effector rabaptin-5." SIGNOR-109398 RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates binding 9606 11130076 t gcesareni "Here we demonstrate that irsp53, a substrate for insulin receptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex." SIGNOR-85302 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" 9606 23151663 f 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-199539 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 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 17251915 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-152808 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 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 RAC1 protein P63000 UNIPROT PAK2 protein Q13177 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-248250 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 RAC1 protein P63000 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 "BTO:0003009; BTO:0000018" 22549160 f irozzo "The small GTPase Rac1 regulates many cellular processes, including cytoskeletal reorganization, cell migration, proliferation, and survival. We found that silencing of Rac1 expression decreases NSCLC migration and proliferation [.]" SIGNOR-259088 RAC1 protein P63000 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR "up-regulates activity" 23290138 f "Simone Vumbaca" "This result strongly supports the assertion that Wnt7a and FN stimulate PCP signaling to drive the symmetric expansion of satellite stem cells during regenerative myogenesis." SIGNOR-255648 RAC1 protein P63000 UNIPROT ROCK1 protein Q13464 UNIPROT "up-regulates activity" binding 9606 27571105 t areggio "Although there are other activators of PCP, Wnt5a can activate the PCP pathway by forming a complex with Fzd and Ror2 receptors, activating DVL, which in turn activates Rho-family small GTPases, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK)" SIGNOR-258972 RAC1 protein P63000 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-98938 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 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 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 RACK1 protein P63244 UNIPROT TRPM6 protein Q9BX84 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18258429 t Manara "We identified RACK1 as the first TRPM6-associated protein and demonstrated that RACK1 inhibits TRPM6 channel activity depending on the phosphorylation state T1851 in the α-kinase domain." SIGNOR-260921 RAD18 protein Q9NS91 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination 9606 19706603 t gcesareni "Rad5 interacts with the e3 ligase rad18, which is initially required to monoubiquitinate pcna" SIGNOR-187705 RAD1 protein O60671 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 t gcesareni "The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner" SIGNOR-179379 RAD21 protein O60216 UNIPROT APOB protein P04114 UNIPROT "down-regulates quantity" "transcriptional repression" 9606 BTO:0000007 25575569 t "The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector." SIGNOR-259974 RAD21 protein O60216 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 BTO:0000511 20711430 f "Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice" SIGNOR-259975 RAD21 protein O60216 UNIPROT ERG protein P11308 UNIPROT "down-regulates activity" relocalization 9606 BTO:0001545 26607380 t miannu "Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity." SIGNOR-261515 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 24321385 t miannu "We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells" SIGNOR-259973 RAD23B protein P54727 UNIPROT PAX3 protein P23760 UNIPROT "down-regulates activity" binding -1 17662948 t llicata "Monoubiquitinated Pax3 was shuttled to the intrinsic proteasomal protein S5a by interacting specifically with the ubiquitin-binding protein Rad23B." SIGNOR-237667 RAD23B protein P54727 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 16401726 f 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-261062 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 RAD50 protein Q92878 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 21763684 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-175053 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 RAD50 protein Q92878 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-251506 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 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 RAD51 protein Q06609 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27660832 f lperfetto "Rad51 is a key component of homologous recombination (HR) to repair DNA double-strand breaks and it forms Rad51 recombinase filaments of broken single-stranded DNA to promote HR. In addition to its role in DNA repair and cell cycle progression, Rad51 contributes to the reprogramming process during the generation of induced pluripotent stem cells" SIGNOR-251508 RAD52 protein P43351 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27649245 f lperfetto "Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans| in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. |These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals." SIGNOR-251507 RAD9A protein Q99638 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 t gcesareni "The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner" SIGNOR-179382 (R)-adrenaline smallmolecule CHEBI:28918 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-258458 (R)-adrenaline smallmolecule CHEBI:28918 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-258459 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRB2 protein P07550 UNIPROT up-regulates binding 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 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS1 protein O95835 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-199196 (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 RAE1 protein P78406 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 20498086 f miannu "The export of mRNAs is a multistep process, involving the packaging of mRNAs into messenger ribonucleoprotein particles (mRNPs), their transport through nuclear pore complexes, and mRNP remodeling events prior to translation. Ribonucleic acid export 1 (Rae1) and Nup98 are evolutionarily conserved mRNA export factors that are targeted by the vesicular stomatitis virus matrix protein to inhibit host cell nuclear export. these data suggest that the Rae1*Nup98 complex directly binds to the mRNP at several stages of the mRNA export pathway." SIGNOR-260871 RAE1 protein P78406 UNIPROT NUP98 protein P52948 UNIPROT "up-regulates activity" binding 9606 16036565 t miannu "Nup98 is a major interacting partner of Rae1 and known to beinvolved in mRNA export." SIGNOR-260868 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 17535812 t lperfetto "The activation of several major anti-apoptotic signaling pathways correlates with an increase in the phosphorylation of bad on ser-112, ser-136, and ser-155. These phosphorylation events result in bad inactivation through sequestration by 14-3-3 proteins" SIGNOR-155293 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 15849194 t "Ser112 corresponds to EIRSRHSsYPAGTED" lperfetto "Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD|Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112." SIGNOR-81165 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000975 10359597 t lperfetto "Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." SIGNOR-235987 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000975 10359597 t lperfetto "Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 ras activation leads to raf and subsequently mek activation. Phospholipide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." SIGNOR-235991 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser218;Ser222 VSGQLIDsMANSFVG;LIDSMANsFVGTRSY 9606 8157000 t "Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases." gcesareni "To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1." SIGNOR-36553 RAF1 protein P04049 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 11427728 t gcesareni "Raf-1 interacts with the proapoptotic, stress-activated protein kinase ask1 (apoptosis signal-regulating kinase 1) in vitro and in vivo." SIGNOR-109023 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000975 11018021 t lperfetto "The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins." SIGNOR-244945 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 t "Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases." lperfetto "The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins." SIGNOR-244952 RAF1 protein P04049 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Thr268 PNVHMVStTLPVDSR -1 8349614 t lperfetto "Furthermore, we find that Thr268 is the predominant Raf-1 residue phosphorylated in in vitro autokinase assays." SIGNOR-248917 RAF1 protein P04049 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" phosphorylation Ser621 PKINRSAsEPSLHRA 9534 BTO:0004055 19595761 t lperfetto "We show that phosphorylation of s621 turns over rapidly and is enriched in the activated pool of endogenous raf-1. The phosphorylation on this site can be mediated by raf-1 itself but also by other kinase(s)" SIGNOR-235770 RAF1 protein P04049 UNIPROT STK3 protein Q13188 UNIPROT down-regulates binding 9606 15618521 t gcesareni "Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2)" SIGNOR-132824 RAG2 protein P55895 UNIPROT MTOR protein P42345 UNIPROT up-regulates relocalization 9606 22790199 t 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-198245 RAGAC complex SIGNOR-C113 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" relocalization 9606 20381137 t gcesareni "The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb" SIGNOR-228158 RAGAC complex SIGNOR-C113 SIGNOR MTOR protein P42345 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto "The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb" SIGNOR-228657 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT "up-regulates activity" phosphorylation Thr451 PIPKALGtPVLTPPT 10090 BTO:0000944 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-248003 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT "up-regulates activity" phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 BTO:0000944 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-249665 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr451 PIPKALGtPVLTPPT 10090 BTO:0000944 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-252984 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 BTO:0000944 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-252985 RALBP1 protein Q15311 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-260513 RALGDS protein Q12967 UNIPROT RIN1 protein Q13671 UNIPROT "up-regulates activity" binding 9606 10545207 t miannu "Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors." SIGNOR-220923 RALGDS protein Q12967 UNIPROT RIT1 protein Q92963 UNIPROT "up-regulates activity" binding 9606 10545207 t miannu "Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors." SIGNOR-220859 raloxifene chemical CHEBI:8772 ChEBI ESR1 protein P03372 UNIPROT "down-regulates activity" "chemical inhibition" -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-258582 Raltegravir chemical CID:54671008 PUBCHEM 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-258162 ramipril chemical CHEBI:8774 ChEBI ACE protein P12821 UNIPROT "down-regulates activity" "chemical inhibition" -1 6097265 t miannu "2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl] - (1S,3S,5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (Hoe 498) is a new, very effective and long lasting, nonsulfhydryl angiotensin I converting enzyme inhibitor." SIGNOR-258400 ramucirumab antibody DB05578 DRUGBANK KDR protein P35968 UNIPROT "down-regulates activity" binding 9606 28395526 t miannu "Ramucirumab (Cyramza), an anti-angionenic agent was approved in 2014 for treatment of several malignancies, including second-line treatment of patients with NSCLC with disease progression on or after platinum-based chemotherapy. Ramucirumab, an anti-VEGFR2 agent, combined with docetaxel, was FDA-approved for NSCLC patients." SIGNOR-259901 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 RANBP2 protein P49792 UNIPROT BICD2 protein Q8TD16 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000567 20386726 t irozzo "We show that the dynein/dynactin adaptor BICD2 is specifically recruited to the NPC in G2phase through a direct interaction with the NPC componentRanBP2." SIGNOR-259122 RANBP2 protein P49792 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0002932 28882106 t irozzo "RanBP2 can increase the sumoylation of p27kip1. In our study, the target protein p27kip1 mainly acts as a tumor-suppressor gene in the nucleus, RanBP2 and SUMO1 act as oncogenes by promoting the nuclear-cytoplasmic translocation and debilitate the G1-arrest brought by p27kip1 accumulation in the nucleus." SIGNOR-259115 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" relocalization 9606 20704570 t lperfetto "Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses" SIGNOR-232107 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates relocalization 9606 19289081 t gcesareni "Ranbp3 directly recognizes dephosphorylated smad2/3, which results from the activity of nuclear smad phosphatases, and mediates nuclear export of smad2/3 in a ran-dependent manner" SIGNOR-184608 RANBP9 protein Q96S59 UNIPROT DYRK1B protein Q9Y463 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 14500717 t llicata "Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met adaptor Ran-binding protein M." SIGNOR-238008 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 RAN protein P62826 UNIPROT XPOT protein O43592 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 9660920 t miannu "The first step in export appears to be the formation of a trimeric tRNA/exportin-t/RanGTP complex. tRNA and RanGTP bind to exportin-t in a highly cooperative manner: tRNA increases the affinity of exportin-t for RanGTP apparently 300-fold (Figure 5A); conversely, RanGTP has to increase the affinity of exportin-t for tRNA by the same factor. 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" SIGNOR-261392 RAP1A protein P62834 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "up-regulates activity" binding 10090 BTO:0003104 12808052 t lperfetto "The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity." SIGNOR-253362 RAP1B protein P61224 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "up-regulates activity" binding 10090 BTO:0003104 12808052 t lperfetto "The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity." SIGNOR-253363 RAP1GDS1 protein P52306 UNIPROT CDC42 protein P60953 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-171412 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 RAP1GDS1 protein P52306 UNIPROT RAC1 protein P63000 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-171418 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 RAP1GDS1 protein P52306 UNIPROT RAP1A protein P62834 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-171482 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 RAP1GDS1 protein P52306 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc" SIGNOR-171347 RAP1GDS1 protein P52306 UNIPROT RHOB protein P62745 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-171615 RAP1GDS1 protein P52306 UNIPROT RHOC protein P08134 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc" SIGNOR-171399 RAPGEF5 protein Q92565 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-183732 RAPGEF5 protein Q92565 UNIPROT KRAS protein P01116 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-183735 RAPGEF5 protein Q92565 UNIPROT NRAS protein P01111 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-183738 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 RAPGEF6 protein Q8TEU7 UNIPROT NRAS protein P01111 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-183799 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 RARA protein P10276 UNIPROT RXRG protein P48443 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-16466 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 RARA protein P10276 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-133231 RARB protein P10826 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-16519 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 RARB protein P10826 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-133234 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 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 RARG protein P13631 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t lperfetto "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-133237 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 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 10394594 t lperfetto "The Ras protein sits at the center of a many-tiered cascade of molecular interactions. Most of the proteins along this cascade are activated by phosphorylation, but Ras uses a bound guanine nucleotide to toggle between its “on” and “off” states. Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off,” and a collection of GTPase-activating proteins (GAPs) speed up the processthe complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved." SIGNOR-68990 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 9219684 t gcesareni "The three-dimensional structure of the complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms." SIGNOR-49477 RASGEF1A protein Q8N9B8 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183823 RASGEF1A protein Q8N9B8 UNIPROT KRAS protein P01116 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-183826 RASGEF1A protein Q8N9B8 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183829 RASGEF1B protein Q0VAM2 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183832 RASGEF1B protein Q0VAM2 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183835 RASGEF1B protein Q0VAM2 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-161481 RASGEF1C protein Q8N431 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-161505 RASGEF1C protein Q8N431 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-161508 RASGEF1C protein Q8N431 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-161511 RASGRF2 protein O14827 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-260575 RASSF1 protein Q9NS23 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002552 12024041 f Luana "RASSF1A expression dramatically inhibits native cyclin D1 accumulation | Regulation of cyclin D1 accumulation by RASSF1A is independent of the cyclin D1 promoter and likely occurs through inhibition of mRNA translation." SIGNOR-259455 RASSF1 protein Q9NS23 UNIPROT STK3 protein Q13188 UNIPROT "up-regulates activity" binding 9606 22195963 t lperfetto "Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating K-Ras-RASSF1A€“MST2 complex, as reported here." SIGNOR-249588 RASSF1 protein Q9NS23 UNIPROT STK3 protein Q13188 UNIPROT up-regulates binding 9606 21808241 t "Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage" milica "Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization." SIGNOR-175790 RASSF1 protein Q9NS23 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 21808241 t "Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage" milica "Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization." SIGNOR-175793 RASSF1 protein Q9NS23 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 22683405 t "Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage" gcesareni "Rassf1a and mst1 co-exist as a complex localizing at microtubules throughout the cell cycle, of which the rassf1a mst1 interaction is stimulatory to the mst1 kinase activity." SIGNOR-197744 RASSF5 protein Q8WWW0 UNIPROT KRAS protein P01116 UNIPROT "up-regulates activity" binding 9606 22195963 t lperfetto "NORE1A can bind K-Ras.GTP through its RA domain and regulate the proapoptotic activity of MST1/2 kinases" SIGNOR-249586 RASSF5 protein Q8WWW0 UNIPROT RASSF1 protein Q9NS23 UNIPROT "up-regulates activity" binding 9606 22195963 t lperfetto "NORE1A can heterodimerize with RASSF1A and, thus, mediate K-Ras regulation of RASSF1A" SIGNOR-249587 RASSF6 protein Q6ZTQ3 UNIPROT STK3 protein Q13188 UNIPROT down-regulates binding 9606 22830020 t gcesareni "When rassf 6 is bound to mst2, rassf 6 inhibits mst2 activity, thus, inhibiting its role in the hippo pathway." SIGNOR-198463 rauwolscine chemical CHEBI:48562 ChEBI HTR2B protein P41595 UNIPROT "down-regulates activity" "chemical inhibition" 10036 BTO:0000452 9459568 t miannu "These studies display the usefulness of [3H]rauwolscine as an antagonist radioligand for the cloned human 5-HT2B receptor. The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor" SIGNOR-258690 RB1CC1 protein Q8TDY2 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR "form complex" binding 9606 23863160 t lperfetto "In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation." SIGNOR-209887 RB1 protein P06400 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8242749 t gcesareni "A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition." SIGNOR-37139 RB1 protein P06400 UNIPROT ANP32A protein P39687 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 phosphorylation:Thr826 LPTPTKMtPRSRILV 15716273 t "We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation." SIGNOR-259083 RB1 protein P06400 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 21524151 f lperfetto "Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time." SIGNOR-245486 RB1 protein P06400 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates activity" binding 9606 8255752 t amattioni "E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery" SIGNOR-37305 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 RB1 protein P06400 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR down-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-245483 RB1 protein P06400 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates 9606 14560017 f gcesareni "We find that active rb mediates histone deacetylation on cyclin a, cdc2, topoisomerase iialfa, and thymidylate synthase promoters. We also demonstrate that this deacetylation is hdac dependent, since the hdac inhibitor trichostatin a (tsa) prevented histone deacetylation at each promoter." SIGNOR-118839 RB1 protein P06400 UNIPROT TRIP11 protein Q15643 UNIPROT down-regulates binding 9606 9256431 t miannu "The wild-type rb is able to interact with the rb-binding domain of trip230 / rb represses trip230-mediated activation of tr-regulated transcription." SIGNOR-50266 RBBP4 protein Q09028 UNIPROT PRC2 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-241906 RBBP5 protein Q15291 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-204825 RBBP8 protein Q99708 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-198473 RBBP8 protein Q99708 UNIPROT SPEN protein Q96T58 UNIPROT down-regulates binding 9606 16287852 t gcesareni "We identify the ctip and ctbp corepressors as novel components of the human rbp-jk/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain." SIGNOR-141616 RBCK1 protein Q9BYM8 UNIPROT BACH1 protein O14867 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000944 17682061 t miannu "HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process." SIGNOR-236971 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 RBL2 protein Q08999 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 BTO:0000165 10801445 f gcesareni "Furthermore, muscle cells overexpressing p130 had reduced levels of the muscle-promoting factor MyoD. In addition, p130 repressed the transactivation capacity of MyoD, an effect abolished by co-transfection of pRb" SIGNOR-241943 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 RBM10 protein P98175 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001938 30403180 f irozzo "In this study, we report that RBM10 acts as a tumor suppressor in osteosarcoma via the inhibition of cell growth, cell migration and invasion and the induction of cell apoptosis by inhibiting Bcl-2, activating caspase-3, and producing TNF-α. We also found that RBM10 overexpression significantly inhibited the expression of Bcl-2 and induced the expression of caspase-3" SIGNOR-259151 RBM10 protein P98175 UNIPROT CASP3 protein P42574 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001938 30403180 f irozzo "In this study, we report that RBM10 acts as a tumor suppressor in osteosarcoma via the inhibition of cell growth, cell migration and invasion and the induction of cell apoptosis by inhibiting Bcl-2, activating caspase-3, and producing TNF-α. We also found that RBM10 overexpression significantly inhibited the expression of Bcl-2 and induced the expression of caspase-3" SIGNOR-259152 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 RBM10 protein P98175 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001938 30403180 f irozzo "These data indicated that RBM10 overexpression induced osteosarcoma cell apoptosis via promoting the production of TNF-α that appear to act as an autocrine factor regulating osteosarcoma programmed cell death." SIGNOR-259153 RBM15 protein Q96T37 UNIPROT RBM15/NXF1 complex SIGNOR-C67 SIGNOR "form complex" binding 9606 17001072 t miannu "Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression." SIGNOR-149883 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 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11486031 t lperfetto "Using this inducible system, we show that Notchic activates transcription of the cyclin D1 gene with rapid kinetics." SIGNOR-209753 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000667 15866158 t "Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J_ protein to the p21 promoter." SIGNOR-252033 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR DUSP1 protein P28562 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0001103 17158101 f Andrea "Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis" SIGNOR-255744 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 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HEY1 protein Q9Y5J3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 21193018 t lperfetto "Activated NICD-RBP-Jk complex displaces co-repressors and recruits coactivator (co-A) mediating the transcription of target genes such as Hes-1 (hairy enhancer of split), cyclin D, Hey-1 (hairy/enhancer-of-split related with YRPW motif) and others [1213]." SIGNOR-170854 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000165 10066785 t lperfetto "Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis" SIGNOR-219359 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR NRARP protein Q7Z6K4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222;BTO:0000782 11783997 t gcesareni "These observations demonstrate that the nrarp gene is an evolutionarily conserved transcriptional target of the notch signaling pathway." SIGNOR-113786 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 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR PAX7 protein P23759 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001103 22493066 f svumbaca "Both binding sites were enriched by more than 5-fold in the ChIP assay with RBP-Jk antibody, suggesting that RBP-Jk occupies these sequences in the Pax7 promoter region." SIGNOR-255365 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates 10090 BTO:0002314 22045613 f gcesareni "Notch signaling is active in quiescent SCs. SC-specific deletion of recombining binding protein-J (RBP-J), a nuclear factor required for Notch signaling, resulted in the depletion of the SC pool and muscles that lacked any ability to regenerate in response to injury." SIGNOR-244004 RBPJ protein Q06330 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000667 15866158 t "Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J_ protein to the p21 promoter." SIGNOR-252032 RBPJ protein Q06330 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11432830 f gcesareni "The rbp-jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated notch1 through rbp-jkappa-dependent transcription." SIGNOR-109042 RBPJ protein Q06330 UNIPROT CIR1 protein Q86X95 UNIPROT up-regulates binding 9606 9874765 t amattioni "In the mechanism of cbf1-mediated repression, cbf1 binds to a unique corepressor cir. Targeting of cir to cbf1 is an important component of repression. Cir binds to histone deacetylase and to sap30 and serves as a linker between cbf1 and the histone deacetylase complex." SIGNOR-62932 RBPJ protein Q06330 UNIPROT GTF2A2 protein P52657 UNIPROT up-regulates binding 9606 9620850 t "Inhibits transcription" gcesareni "Rbp interacts with two transcriptional coactivators: dtafii110, a subunit of tfiid, and tfiia to repress transcription. The domain of dtafii110 targeted by rbp is the same domain that interacts with tfiia" SIGNOR-57832 RBPJ protein Q06330 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" binding 9606 BTO:0000938 10520600 t gcesareni "These results indicate that the two Hes genes are essential effectors for the Notch pathway and that neuronal differentiation is controlled by the pathway Notch-Hes1/Hes5-|Mash1." SIGNOR-71168 RBPJ protein Q06330 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000165 10066785 t gcesareni "ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA" SIGNOR-243178 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 RBPJ protein Q06330 UNIPROT MAML3 protein Q96JK9 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-176200 RBPJ protein Q06330 UNIPROT NFKB2 protein Q00653 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 9528780 f gcesareni "Rbp-jkappa is a strong transcriptional repressor of nf-kappab2. Moreover, this repression can be overcome by activated notch-1." SIGNOR-56100 RBPJ protein Q06330 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates "transcriptional repression" 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 RBPJ protein Q06330 UNIPROT PAX7 protein P23759 UNIPROT up-regulates binding 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 22493066 t gcesareni "Nicd regulates pax7 through interaction with rbp-j, which binds to two consensus sites upstream of the pax7 gene." SIGNOR-196948 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding 9606 21873209 t lperfetto "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-209702 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 RBPJ protein Q06330 UNIPROT 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-255379 RBSN protein Q9H1K0 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "Rabenosyn-5 is another FYVE-domain-containing Rab5 effector that localizes to EE" SIGNOR-260624 RBX1 protein P62877 UNIPROT CRL4(CRBN) 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 RBX1 protein P62877 UNIPROT "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR "form complex" binding 9606 17452440 t lperfetto "Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes" SIGNOR-154511 RBX1 protein P62877 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 11295495 t gcesareni "The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-106781 RBX1 protein P62877 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 14676825 t gcesareni "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-120342 RCOR1 protein Q9UKL0 UNIPROT "CoREST-HDAC complex" complex SIGNOR-C105 SIGNOR "form complex" binding 9606 BTO:0000567 11171972 t miannu "Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function." SIGNOR-222115 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 RCOR1 protein Q9UKL0 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 10449787 f 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-220695 RECQL4 protein O94761 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 9606 27287744 f "RECQL4 is important for genome stability and DNA damage repair." SIGNOR-258951 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 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 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 regorafenib chemical CHEBI:68647 ChEBI DDR2 protein Q16832 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-259208 regorafenib chemical CHEBI:68647 ChEBI EPHA2 protein P29317 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-259210 regorafenib chemical CHEBI:68647 ChEBI FGFR1 protein P11362 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-259177 regorafenib chemical CHEBI:68647 ChEBI FGFR2 protein P21802 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-259178 regorafenib chemical CHEBI:68647 ChEBI FLT1 protein P17948 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-259205 regorafenib chemical CHEBI:68647 ChEBI FLT3 protein P36888 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-259214 regorafenib chemical CHEBI:68647 ChEBI FLT4 protein P35916 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-259206 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 regorafenib chemical CHEBI:68647 ChEBI NTRK1 protein P04629 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-259212 regorafenib chemical CHEBI:68647 ChEBI PDGFRA protein P16234 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-259179 regorafenib chemical CHEBI:68647 ChEBI PDGFRB protein P09619 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-259180 regorafenib chemical CHEBI:68647 ChEBI RET protein P07949 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-259181 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR "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-259453 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR "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-259452 regorafenib chemical CHEBI:68647 ChEBI TAP1 protein Q03518 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 ABCG3" SIGNOR-259204 regorafenib chemical CHEBI:68647 ChEBI TEK protein Q02763 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-259213 RELA protein Q04206 UNIPROT B2M protein P61769 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12480693 f miannu "The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m." SIGNOR-254657 RELA protein Q04206 UNIPROT BCL2A1 protein Q16548 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 10049356 f gcesareni "Here we show thata1,abcl-2homolog up-regulated in primary lymphocytes by different mitogens, represents a novel class of rel/nf-kb-regulated prosurvival genes." SIGNOR-65020 RELA protein Q04206 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates binding 9606 10207072 t lperfetto "Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo." SIGNOR-217655 RELA protein Q04206 UNIPROT CD80 protein P33681 UNIPROT "up-regulates quantity by expression" "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-253935 RELA protein Q04206 UNIPROT CITED1 protein Q99966 UNIPROT up-regulates binding 9606 SIGNOR-C13 9660950 t gcesareni "The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276." SIGNOR-59054 RELA protein Q04206 UNIPROT COMT protein P21964 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000100 19291302 f "Regulation of expression" miannu "TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression." SIGNOR-251964 RELA protein Q04206 UNIPROT IEX-1L protein O75353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9703517 f gcesareni "Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here." SIGNOR-59542 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 RELA protein Q04206 UNIPROT IL1B protein P01584 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20975042 t svumbaca "In addition, we show that the transcription of IL1B depends on a positively acting p65/c-Rel/ikbb complex" SIGNOR-256237 RELA protein Q04206 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 27337441 t lperfetto "Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation" SIGNOR-251737 RELA protein Q04206 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 SIGNOR-C13 18174238 t gcesareni "Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment" SIGNOR-160330 RELA protein Q04206 UNIPROT MET protein P08581 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0002895 19530226 t gcesareni "Together, these results indicate that the Met gene is a direct target of NFkappaB and that Met participates in NFkappaB-mediated cell survival." SIGNOR-241929 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 RELA protein Q04206 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-253651 RELA protein Q04206 UNIPROT PCK2 protein Q16822 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000759 20137375 f miannu "NF-kappaB p65 was shown to inhibit transcription of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme in gluconeogenesis in the liver" SIGNOR-255072 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 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 RELA protein Q04206 UNIPROT SP1 protein P08047 UNIPROT up-regulates binding 9606 SIGNOR-C13 10671503 t gcesareni "Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1." SIGNOR-75004 RELA protein Q04206 UNIPROT TRAF1 protein Q13077 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f gcesareni "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2." SIGNOR-59957 RELA protein Q04206 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f lperfetto "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59960 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 REL protein Q04864 UNIPROT CSRP1 protein P21291 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14522018 f "We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter" SIGNOR-254063 REL protein Q04864 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-46945 REN protein P00797 UNIPROT AGT protein P01019 UNIPROT "up-regulates activity" cleavage 9606 16816138 t "Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I" SIGNOR-252297 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 REN protein P00797 UNIPROT ATP6AP2 protein O75787 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000142;BTO:0000671;BTO:0001260 12045255 t gcesareni "We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2" SIGNOR-88416 reserpine chemical CHEBI:28487 ChEBI SLC18A2 protein Q05940 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000318 8643547 t miannu "Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2." SIGNOR-258490 resiquimod chemical CHEBI:36706 ChEBI TLR8 protein Q9NR97 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-259247 REST protein Q13127 UNIPROT BDNF protein P23560 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21832040 f miannu "HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK)." SIGNOR-255075 REST protein Q13127 UNIPROT CARTPT protein Q16568 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 18485095 f miannu "When expression of NRSF was down-regulated in HeLa cells using a RNA interfering technique, the transcriptional activity of the CART promoter or a NRSE reporter was significantly increased. Taken together, our data suggested that CART gene expression in neuroendocrine cells is strictly controlled by NRSF, via a mechanism dependent upon the CART NRSE." SIGNOR-255073 REST protein Q13127 UNIPROT PENK protein P01210 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21832040 f miannu "HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK)." SIGNOR-255074 REST protein Q13127 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR "form complex" binding 9606 20080105 t 1 miannu "Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex." SIGNOR-239217 REST protein Q13127 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 10449787 f 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-220698 resveratrol smallmolecule CHEBI:27881 ChEBI AHR protein P35869 UNIPROT "down-regulates activity" "chemical inhibition" -1 9865727 t "Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription." SIGNOR-253640 resveratrol smallmolecule CHEBI:27881 ChEBI SIRT1 protein Q96EB6 UNIPROT "up-regulates activity" binding -1 12939617 t gcesareni "We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53" SIGNOR-238786 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 RET protein P07949 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 12242309 t lperfetto "Overexpressed rai resulted in the potentiation of the ret-dependent activation of phosphatidylinositol 3-kinase (pi3k) and akt. The ret/ptc receptor tyrosine kinase that responds to glial cell-line-derived neurotrophic factor also phosphorylated akt tyrosine residue 315 promoting activation of akt" SIGNOR-244443 RET protein P07949 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR 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-166514 RET protein P07949 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates binding 9606 12087092 t amattioni "Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret." SIGNOR-90158 RET protein P07949 UNIPROT DOK4 protein Q8TEW6 UNIPROT up-regulates binding 9606 BTO:0000938 11470823 t gcesareni "We identified two new family members, dok-4 and dok-5, that can directly associate with y1062 of c-ret dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase" SIGNOR-109513 RET protein P07949 UNIPROT DOK5 protein Q9P104 UNIPROT up-regulates binding 9606 BTO:0000938 11470823 t gcesareni "Dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase" SIGNOR-109516 RET protein P07949 UNIPROT DOK6 protein Q6PKX4 UNIPROT up-regulates binding 9606 BTO:0000671 15286081 t gcesareni "These data identify dok-6 as a novel dok-4/5-related adaptor molecule that may function in vivo to transduce signals that regulate ret-mediated processes such as axonal projection." SIGNOR-127382 RET protein P07949 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 16153436 t lperfetto "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-244643 RET protein P07949 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates binding 9606 8631863 t gcesareni "Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell" SIGNOR-41765 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 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-150875 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 17548358 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-155377 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 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-28059 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 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-40493 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 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17548358 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-155381 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 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 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-40497 RET protein P07949 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Tyr187 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-140294 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 RET protein P07949 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Tyr9 ARTTSQLyDAVPIQS 10029 BTO:0000246 12738763 t lperfetto "Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1." SIGNOR-235863 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 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-173013 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 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 21454698 t gcesareni "Strikingly, when fak and ret kinases were co-incubated in the presence of atp, a marked increased in fak tyr-576/577 and tyr-925 phosphorylation was observed together with a shift in mobility of fak, indicating conversion to an activated state" SIGNOR-173021 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr1029 TPSDSLIyDDGLSEE 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-248940 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr687 AQAFPVSySSSGARR 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-248941 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 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 14711813 t lperfetto "Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesret short and middle isoforms contain 16 tyrosine residues in their intracellular domains, and ret long isoforms have two additional tyrosines in the c-terminal tail. Among these tyrosines, tyr905, tyr1015, tyr1062, and tyr1096 are thought to be phosphorylated to become binding sites for grb7/grb10, phospholipase c_, shc/snt(frs2)/enigma, and grb2, respectively." SIGNOR-121141 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 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1096 RYPNDSVyANWMLSP 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-121149 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr806 PLLLIVEyAKYGSLR 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-121153 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 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 14711813 t gcesareni "Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation" SIGNOR-121161 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 16928683 t gcesareni "Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation" SIGNOR-148992 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 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr981 DNCSEEMyRLMLQCW 9606 14711813 t lperfetto "Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesthe 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-121169 RET protein P07949 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 8183561 t gcesareni "We have shown that the sh2 domain of the adaptor protein shc coimmunoprecipitates with all the ret." SIGNOR-36902 RET/PTC2 protein Q15300 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Y705 DPGSAAPYLKTKFIC 9606 BTO:0002306 12637586 t Manara "In addition, RET/PTC-mediated cellular transformation and proliferation of transformed cells require tyrosine 705 phosphorylation of STAT3 in NIH3T3 cells. We conclude that STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes, such as cyclin D1, vascular endothelial growth factor, and intercellular adhesion molecule 1, and for cellular transformation." SIGNOR-260917 RETREG3 protein Q86VR2 UNIPROT "Neurite outgrowth" phenotype SIGNOR-PH134 SIGNOR 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-261490 RFNG protein Q9Y644 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000975 12486116 t gcesareni "We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1." SIGNOR-96561 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 RFX1 protein P22670 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-254022 RFX1 protein P22670 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253829 RFX4 protein Q33E94 UNIPROT IFT172 protein Q9UG01 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19887680 f miannu "We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4" SIGNOR-223319 RFX5 protein P48382 UNIPROT "RFX complex" complex SIGNOR-C104 SIGNOR "form complex" binding -1 10825209 t miannu "RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes" SIGNOR-221565 RFXAP protein O00287 UNIPROT "RFX complex" complex SIGNOR-C104 SIGNOR "form complex" binding -1 10825209 t miannu "RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes" SIGNOR-221568 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DMA protein P28067 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-253993 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DMB protein P28068 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-253999 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DMB protein P28068 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11889043 f "Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment." SIGNOR-254016 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DOA protein P06340 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-253994 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DOB protein P13765 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-254000 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DPA1 protein P20036 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-253995 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DPB1 protein P04440 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-253990 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DPB1 protein P04440 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11889043 f "Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment." SIGNOR-254007 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DQA1 protein P01909 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-253991 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DQA2 protein P01906 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-253996 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DQB1 protein P01920 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-253992 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 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DQB2 protein P05538 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-253997 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DRA protein P01903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11889043 f "Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment." SIGNOR-254009 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DRB1 protein P01912 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 t "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-253977 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DRB3 protein P79483 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-254001 "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 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DRB5 protein Q30154 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-254003 RGS6 protein P49758 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates binding 9606 17609107 t flangone "Numb binds to integrin-betas and localizes to clathrin-coated structures" SIGNOR-156762 RHEB protein Q15382 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT "down-regulates activity" binding -1 25660019 t Luana "Rheb GTPase directly binds and activates PERK in vitro" SIGNOR-260873 RHEB protein Q15382 UNIPROT FKBP8 protein Q14318 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 19222999 t lperfetto "Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1." SIGNOR-233568 RHEB protein Q15382 UNIPROT FKBP8 protein Q14318 UNIPROT down-regulates binding 9606 17991864 t gcesareni "Rheb interacts directly with fkbp38 and prevents its association with mtor in a guanosine 5'-triphosphate (gtp)-dependent manner." SIGNOR-159016 RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 10090 BTO:0000011 19299511 t lperfetto "These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation." SIGNOR-235355 RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 19222999 t lperfetto "Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1." SIGNOR-232208 RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15854902 t lperfetto "Rheb binds and regulates the mTOR kinase." SIGNOR-135770 RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20006481 t lperfetto "Rheb stimulates the phosphorylation of mtor and plays an essential role in regulation of s6k and 4ebp1 in response to nutrients and cellular energy status." SIGNOR-162006 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 RHOA protein P61586 UNIPROT DIAPH1 protein O60610 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-253108 RHOA protein P61586 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-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-192114 RHOA protein P61586 UNIPROT FHL2 protein Q14192 UNIPROT up-regulates relocalization 9606 BTO:0001130 11847121 t gcesareni "Here, we show that stimulation of the rho pathway induces translocation of the transcriptional lim-only coactivator fhl2 to the nucleus and subsequent activation of fhl2- and androgen receptor-dependent genes." SIGNOR-114071 RHOA protein P61586 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" binding 9606 8824197 t areggio "We found that in the human kidney epithelial cell line, 293T, Cdc42 and all Rho proteins, RhoA, RhoB, and RhoC, but not Rac or Ras can induce activation of JNK." SIGNOR-258974 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 RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT "up-regulates activity" binding 9606 25010901 t gcesareni "Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase" SIGNOR-196740 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 RHOH protein Q15669 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 17028588 t irozzo "These findings suggest that RhoH is a critical regulator of thymocyte development and TCR signaling by mediating recruitment and activation of Zap70." SIGNOR-259084 RHO protein P08100 UNIPROT GNAT1 protein P11488 UNIPROT "up-regulates activity" binding 9606 8673138 t "We report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade." SIGNOR-260007 RHOQ protein P17081 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates binding 9606 12687004 t gcesareni "Here we show that tc10 interacts with one of the components of the exocyst complex, exo70." SIGNOR-100486 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 ribavirin chemical CHEBI:63580 ChEBI IMPDH2 protein P12268 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000736 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 "Ribonucleotide reductase" complex SIGNOR-C233 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 14583450 f miannu "Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2." SIGNOR-259365 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 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 Riluzole chemical CHEBI:8863 ChEBI KCNN1 protein Q92952 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-258021 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 Riluzole chemical CHEBI:8863 ChEBI 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-258019 Riluzole chemical CHEBI:8863 ChEBI KCNN4 protein O15554 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-258022 Riluzole chemical CHEBI:8863 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-258053 RIN1 protein Q13671 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 11784866 t gcesareni "We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1." SIGNOR-113967 RIN1 protein Q13671 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 11784866 t gcesareni "We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1." SIGNOR-113970 RING1 protein Q06587 UNIPROT FHL1 protein Q13642 UNIPROT up-regulates binding 9606 14999091 t gcesareni "The polycombprotein ring1 interacts with the lim domains of kyot2 in yeast and mammalian cells. The interaction between kyot2 and ring1 was detected both in vitro and in vivo" SIGNOR-123150 RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" binding 9606 BTO:0000007;BTO:0000459 12887920 t amattioni "Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex" SIGNOR-104255 RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" binding 9606 BTO:0002025 21525013 t amattioni "Degradation of ciaps triggers the release of receptor interacting protein kinase (ripk1) from tnf receptor i (tnfr1) to form a caspase-8 activating complex" SIGNOR-173432 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 RIPK1 protein Q13546 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "up-regulates activity" phosphorylation Ser728 PSPARSSsYSEANEP 9913 BTO:0003247 17389591 t "We further show that RIP1 (the Ser/Thr protein kinase receptor-interacting protein) associates with the GAP domain of AIP1 and mediates TNF-induced AIP1 phosphorylation at Ser-604 and JNK/p38 activation as demonstrated by both overexpression and small interfering RNA knockdown of RIP1 in EC." SIGNOR-259976 RIPK1 protein Q13546 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 18545270 t lperfetto "The death domain of the rip1 kinase binds to death receptors such as fas that is required for caspase 8 activation and apoptosis" SIGNOR-177949 RIPK1 protein Q13546 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C14 16603398 t lperfetto "Interestingly, polyubiquitinated rip1 recruits ikk through the binding between the polyubiquitin chains and nemo, a regulatory subunit of the ikk complex. Mutations of nemo that disrupt its polyubiquitin binding also abolish ikk activation." SIGNOR-145858 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 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT "up-regulates activity" phosphorylation Ser970 HSQCLNSsPLSHHSQ 9606 BTO:0000661 11369754 t lperfetto "These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994." SIGNOR-108257 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 BTO:0000661 11369754 t gcesareni "These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994." SIGNOR-108260 RIPK1 protein Q13546 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 21133840 t "simone vumbaca" "RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex" SIGNOR-256022 RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15327770 t lperfetto "TNF_ induced the polyubiquitination of RIP and the association of polyubiquitinated RIP with TAB2." SIGNOR-128406 RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT "up-regulates activity" binding 9606 BTO:0000007;BTO:0000661 16603398 t lperfetto "Taken together, these results indicate that polyubiquitination of RIP1 mediates the independent re- cruitment of TAB2 and NEMO, which in turn recruits TAK1 and IKK, respectively, to TNF-R1." SIGNOR-145861 RIPK1 protein Q13546 UNIPROT TAB3 protein Q8N5C8 UNIPROT "up-regulates activity" binding 9606 19927120 t lperfetto "Tab2 and tab3 activate the jun n-terminal kinase and nuclear factor-kappab pathways through the specific recognition of lys 63-linked polyubiquitin chains by its npl4 zinc-finger (nzf) domain." SIGNOR-161787 RIPK1 protein Q13546 UNIPROT TNFRSF10A protein O00220 UNIPROT up-regulates 9606 18545270 f gcesareni "The death domain of the rip1 kinase binds to death receptors such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1,trailr1." SIGNOR-177952 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 RIPK2 protein O43353 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" ubiquitination 9606 SIGNOR-C14 16493424 f miannu "In the case of NOD2, activation of RICK leads to K63 (Lys63)-linked polyubiquitylation of IKKgamma, the scaffold of the inhibitor of NF-kappaB (IkappaB)-kinase complex (the IKK complex), which also consists of IKKalpha and IKKbeta. This is followed by the phosphorylation of IKKbeta, as well as the phosphorylation of IkappaB and the release of nuclear factor-kappaB (NF-kappaB) for translocation to the nucleus. So, in activating the IKK complex, RICK either activates an E3 ubiquitin ligase that promotes K63-linked polyubiquitylation or inhibits an enzyme (such as cylindromatosis protein, CYLD) that de-ubiquitylates proteins that are modified with K63-linked polyubiquitin, so RICK does not require its own kinase activity for this function." SIGNOR-252413 RIPK2 protein O43353 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates activity" phosphorylation Ser176 KWRMMSLsQSRSSKS 9606 BTO:0000801 16824733 t amattioni "In summary, our results indicate that s176 is a regulatory autophosphorylation site for rip2 and that s176 phosphorylation can be used to monitor the activation state of rip2." SIGNOR-229701 RIPK3 protein Q9Y572 UNIPROT GLUD1 protein P00367 UNIPROT up-regulates binding 9606 19632174 t gcesareni "Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro." SIGNOR-187314 RIPK3 protein Q9Y572 UNIPROT PYGL protein P06737 UNIPROT up-regulates binding 9606 19632174 t gcesareni "Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro." SIGNOR-186939 RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 9606 23661684 f lperfetto SIGNOR-255323 risperidone chemical CHEBI:8871 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-258530 risperidone chemical CHEBI:8871 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-258840 risperidone chemical CHEBI:8871 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000601 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-258525 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 risperidone chemical CHEBI:8871 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-258527 risperidone chemical CHEBI:8871 ChEBI HTR1E protein P28566 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-258528 RIT1 protein Q92963 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 23791108 t "It is possible that RIT1 interacts with RAF1 and that gain-of-function mutations in RIT1 and RAF1 exert similar effects in heart development." SIGNOR-251650 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 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 ritanserin chemical CHEBI:64195 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-258691 ritonavir chemical CHEBI:45409 ChEBI CYP3A4 protein P08684 UNIPROT "down-regulates activity" "chemical inhibition" -1 18285471 t Luana "Ritonavir is the most potent and efficacious inhibitor of cytochrome P4503A (CYP3A" SIGNOR-257769 ritonavir chemical CHEBI:45409 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-258154 rituximab antibody DB00073 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0001546 20350663 t miannu "Rituximab is a class I chimeric anti-CD20 antibody that has shown efficacy in chronic lymphocytic leukemia (CLL), both as a single agent and in combination with traditional chemotherapies." SIGNOR-259902 rizatriptan chemical CHEBI:48273 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-258342 RLF protein Q13129 UNIPROT RIN1 protein Q13671 UNIPROT "up-regulates activity" binding 9606 10545207 t miannu "Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors." SIGNOR-220920 RLF protein Q13129 UNIPROT RIT1 protein Q92963 UNIPROT "up-regulates activity" binding 9606 10545207 t miannu "Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors." SIGNOR-220799 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 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 "RNA helicases p68/p72" complex SIGNOR-C34 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17011493 t miannu "We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod." SIGNOR-149967 RND1 protein Q92730 UNIPROT MAPK8 protein P45983 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-152811 RNF111 protein Q6ZNA4 UNIPROT AP2M1 protein Q96CW1 UNIPROT up-regulates ubiquitination 9606 20965945 t gcesareni "Arkadia ubiquitylated the _?2 Subunit at lys130. In addition, arkadia interacted with the ap2 complex, and modified endocytosis of epidermal growth factor receptor (egfr) induced by egf. Arkadia thus appears to regulate egf signalling by modulating endocytosis of egfr through interaction with ap2 complex." SIGNOR-168931 RNF111 protein Q6ZNA4 UNIPROT SKI protein P12755 UNIPROT down-regulates ubiquitination 9606 BTO:0000150;BTO:0000551 18451154 t gcesareni "On tgf-beta treatment, the e3 ubiquitin ligase arkadia mediates degradation of ski in a smad-dependent manner" SIGNOR-178598 RNF111 protein Q6ZNA4 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t lperfetto "Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling." SIGNOR-235394 RNF111 protein Q6ZNA4 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t lperfetto "Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling." SIGNOR-236873 RNF111 protein Q6ZNA4 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t lperfetto "Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling." SIGNOR-235388 RNF111 protein Q6ZNA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t gcesareni "Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling." SIGNOR-236876 RNF111 protein Q6ZNA4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates binding 9606 14657019 t gcesareni "Arkadia physically interacts with inhibitory smad, smad7, and induces its poly-ubiquitination and degradation." SIGNOR-119663 RNF111 protein Q6ZNA4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates ubiquitination 9606 14657019 t gcesareni "Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia" SIGNOR-119666 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 RNF146 protein Q9NTX7 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 21799911 t "By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins." SIGNOR-259996 RNF146 protein Q9NTX7 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 21799911 t "By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins." SIGNOR-259997 RNF146 protein Q9NTX7 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates quantity" ubiquitination 9606 BTO:0000007 21799911 t "By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins." SIGNOR-259998 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 RNF146 protein Q9NTX7 UNIPROT TNKS2 protein Q9H2K2 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-260005 RNF146 protein Q9NTX7 UNIPROT TNKS protein O95271 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-260004 RNF180 protein Q86T96 UNIPROT ZIC2 protein O95409 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10116 18363970 t miannu "Rinescan directly interact with Zic2. the ubiquitination of endogenous Zic2 was enhanced by Myc-Rines in rat neural stem cellline MNS70 cells. Rines-induced degradation of Zic2" SIGNOR-226303 RNF2 protein Q99496 UNIPROT "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR "form complex" binding 10090 25533466 t miannu "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-255277 RNF34 protein Q969K3 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "down-regulates quantity by destabilization" ubiquitination 26971449 t lperfetto "We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system." SIGNOR-253393 RNF4 protein P78317 UNIPROT NFYA protein P23511 UNIPROT "up-regulates activity" binding 9606 15496512 t miannu "Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter." SIGNOR-252229 RNF4 protein P78317 UNIPROT NFYB protein P25208 UNIPROT "up-regulates activity" binding 9606 15496512 t miannu "Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter." SIGNOR-252230 RNF4 protein P78317 UNIPROT NFYC protein Q13952 UNIPROT "up-regulates activity" binding 9606 15496512 t miannu "Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter." SIGNOR-252231 RNF8 protein O76064 UNIPROT RAD18 protein Q9NS91 UNIPROT up-regulates binding 9606 19396164 t gcesareni "Rnf8 depletion also significantly reduced the accumulation of rad18 to chromatin fraction after ir" SIGNOR-185593 RNF8 protein O76064 UNIPROT UBE2N protein P61088 UNIPROT up-regulates binding 9606 18678647 t gcesareni "The rnf8 ring domain signals ubc13 to sites of damage, which is sufficient for dna damage signal transduction." SIGNOR-179823 (R)-noradrenaline smallmolecule CHEBI:18357 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-258456 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1A protein P35348 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-257450 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1B protein P35368 UNIPROT "up-regulates activity" "chemical activation" -1 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-258442 (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 (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 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1D protein P25100 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-257452 (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 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2B protein P18089 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-258898 (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 (R)-noradrenaline smallmolecule CHEBI:18357 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-258899 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2C protein P18825 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-257455 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 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto "Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities" SIGNOR-137639 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 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 BTO:0000782 15326477 t lperfetto "P38sapk2 phosphorylates cyclin d3 at thr-283 and targets it for proteasomal degradation" SIGNOR-128402 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser323 QRLFRSPsMPCSVIR 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-124843 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 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 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDO/JLP/P38 complex SIGNOR-C22 SIGNOR "form complex" 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-150285 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr480 TKEDGHRtSTSAVPN 9606 BTO:0000671 10209029 t lperfetto "Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480" SIGNOR-66996 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser391 RSSMNNGsPTALSGS 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-249309 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser402 LSGSKTNsPKNSVHK 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-249304 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser413 SVHKLDVsRSPPLMV 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-249306 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser415 HKLDVSRsPPLMVKK 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-249307 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser437 SGIVTNGsFSSSNAE 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-249305 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 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 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Thr452 GLEKTQTtPNGSLQA 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-249310 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Thr575 SNSCRSStTTCPEQD 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-249299 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Thr577 SCRSSTTtCPEQDFF 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-249301 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates phosphorylation 9606 16862148 t acerquone "Rock phosphorylates filgap, and this phosphorylation stimulates its racgap activity and is a requirement for filgap-mediated bleb formation" SIGNOR-148262 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates phosphorylation Ser1150 LERGRKVsIVSKPVL 9606 BTO:0000887;BTO:0001260 19103606 t gcesareni "Rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser(1150) and attenuated p190a rhogap activity in cos7 cells." SIGNOR-182849 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 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 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Thr17 RVSSYRRtFGGAPGF -1 12686604 t lperfetto "The sites phosphorylated by Aurora-B; Thr-7/Ser-13/Ser-38 of GFAP, and Thr-16 of desmin are common with those related to Rho-associated kinase (Rho-kinase), which has been reported to phosphorylate GFAP and desmin at cleavage furrow during cytokinesis. Rho-kinase was found to phosphorylate desmin at Thr-16, Thr-75, and Thr-76" SIGNOR-100177 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr17 RVSSYRRtFGGAPGF 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-249032 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr76 LRASRLGtTRTPSSY 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-249031 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 ROCK1 protein Q13464 UNIPROT DPYSL2 protein Q16555 UNIPROT unknown phosphorylation Thr555 DNIPRRTtQRIVAPP 9534 BTO:0000298 10818093 t lperfetto "We produced an antibody that specifically recognizes CRMP-2 phosphorylated at Thr-555. Using this antibody, we found that Rho-kinase phosphorylated CRMP-2 downstream of Rho in COS7 cells. " SIGNOR-249042 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 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 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-160544 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1137 RSRGNRKsLRRTLKS 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-160548 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 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser13 ITSAARRsYVSSGEM -1 12686604 t lperfetto "We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro." SIGNOR-100181 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Thr7 tSAARRSY -1 12686604 t lperfetto "We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro." SIGNOR-100192 ROCK1 protein Q13464 UNIPROT KCNK3 protein O14649 UNIPROT down-regulates phosphorylation Ser393 GLMKRRSsV 9606 BTO:0000887 21838752 t lperfetto "Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway." SIGNOR-176029 ROCK1 protein Q13464 UNIPROT LIMK1 protein P53667 UNIPROT "up-regulates activity" phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 10652353 t lperfetto "Rho-associated kinase rock activates lim-kinase 1 by phosphorylation at threonine 508 within the activation loop." SIGNOR-74569 ROCK1 protein Q13464 UNIPROT LIMK2 protein P53671 UNIPROT "up-regulates activity" phosphorylation Thr526 NGKSYDEtVDIFSFG 9534 BTO:0000298 11018042 t lperfetto "Specific Activation of LIM kinase 2 via Phosphorylation of Threonine 505 by ROCK, a Rho-dependent Protein Kinase" SIGNOR-249053 ROCK1 protein Q13464 UNIPROT LIMK2 protein P53671 UNIPROT up-regulates phosphorylation Thr505 NDRKKRYtVVGNPYW 9606 11018042 t lperfetto "Specific activation of lim kinase 2 via phosphorylation of threonine 505 by rock, a rho-dependent protein kinase" SIGNOR-82755 ROCK1 protein Q13464 UNIPROT LPP protein Q93052 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 22886954 f miannu "Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression" SIGNOR-198118 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 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser364 TRLDRTGsSPTQGIV 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-134584 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 ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 15068801 t gcesareni "Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter." SIGNOR-123717 ROCK1 protein Q13464 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 11283607 f "Cleaved by CASP3" amattioni "Activation of rock i by caspase-3 seems to be responsible for bleb formation in apoptotic cells." SIGNOR-106549 ROCK1 protein Q13464 UNIPROT MPRIP protein Q6WCQ1 UNIPROT down-regulates phosphorylation 9606 17761936 t gcesareni "Enhanced rho kinase activity induces endothelial barrier dysfunction by a contractile mechanism via inactivation of myosin phosphatase (mp).." SIGNOR-157593 ROCK1 protein Q13464 UNIPROT MSN protein P26038 UNIPROT "up-regulates activity" phosphorylation Thr558 LGRDKYKtLRQIRQG 9534 BTO:0000298 9856983 t lperfetto "Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho, phosphorylates moesin at Thr558 in vitro. Here, using a site- and phosphorylation state-specific antibody, we found that the expression of dominant active RhoA in COS7 cells induced moesin phosphorylation and the formation of microvilli-like structures at apical membranes where the Thr558-phosphorylated moesin accumulated, whereas the expression of dominant negative Rho-kinase inhibited both of these processes." SIGNOR-249014 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 12185584 t lperfetto "Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies." SIGNOR-91542 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12185584 t gcesareni "Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies." SIGNOR-91546 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Ser19 S-->T -1 21457715 t Giulio "Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation." SIGNOR-260307 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 ROCK1 protein Q13464 UNIPROT PPP1R12A protein O14974 UNIPROT "down-regulates activity" phosphorylation Thr853 PREKRRStGVSFWTQ 10090 BTO:0005065 10601309 t lperfetto "Phosphorylation by Rho-kinase inhibited MP activity and this reflected a decrease in V(max). Activity of MP with different substrates also was inhibited by phosphorylation. Two major sites of phosphorylation on MYPT1 were Thr(695) and Thr(850)." SIGNOR-249034 ROCK1 protein Q13464 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr696 ARQSRRStQGVTLTD 9606 BTO:0000887;BTO:0001260 8662509 t "Rho-associated kinase (Rho-kinase) is activated by GTP-RhoA" gcesareni "Rho-associated kinase (rho-kinase) phosphorylated mbs and consequently inactivated myosin phosphatase. Rho appears to inhibit myosin phosphatase through the action of rho-kinase." SIGNOR-42354 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Ser229 VKIYSSNsGPTRRED 9606 BTO:0000672 15793569 t llicata "In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues." SIGNOR-134851 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Thr232 YSSNSGPtRREDKFM 9606 BTO:0000672 15793569 t llicata "In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues." SIGNOR-134855 ROCK1 protein Q13464 UNIPROT RDX protein P35241 UNIPROT unknown phosphorylation Thr573 RQIRQGNtKQRIDEF -1 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." SIGNOR-248995 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 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 ROCK1 protein Q13464 UNIPROT Satellite_cells_self-renewal phenotype SIGNOR-PH100 SIGNOR up-regulates "transcriptional regulation" BTO:0001103 23290138 f apalma "FN in the satellite cell niche is required for the maintenance of the overall satellite cell pool during muscle regeneration. Moreover, FN is necessary to potentiate Wnt7a signaling through the Fzd7/Scd4 receptor complex, which controls the regulation of satellite stem cell numbers" SIGNOR-255850 ROCK1 protein Q13464 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser181 YQPRRRKsVKNGQAE 9606 20039424 t lperfetto "Rho kinase-dependent activation of sox9 in chondrocytes. In vitro, rock directly phosphorylated sox9 at ser(181), and the overexpression of rock or the activation of the rhoa pathway in sw1353 chondrosarcoma cells increased sox9(ser181) phosphorylation" SIGNOR-162643 ROCK1 protein Q13464 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser72 SSAVRLRsSVPGVRL 9534 BTO:0000298 9565595 t lperfetto "We found that vimentin, the most widely expressed intermediate filament protein, served as an excellent substrate for Rho-associated kinase (Rho-kinase) and that vimentin phosphorylated by Rho-kinase lost its ability to form filaments in vitro. Two amino-terminal sites on vimentin, Ser38 and Ser71, were identified as the major phosphorylation sites for Rho-kinase, and Ser71 was the most favored and unique phosphorylation site for Rho-kinase in vitro. " SIGNOR-248998 ROCK2 protein O75116 UNIPROT DPYSL2 protein Q16555 UNIPROT up-regulates phosphorylation Thr555 DNIPRRTtQRIVAPP 9606 BTO:0000938 10818093 t lperfetto "Rho-kinase phosphorylated crmp-2 at thr-555 in vitro.we demonstrated that crmp-2 is phosphorylated by rho-kinase in drg neurons during lpa-induced growth cone collapse." SIGNOR-77543 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 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 ROCK2 protein O75116 UNIPROT PPP1R12A protein O14974 UNIPROT "down-regulates activity" phosphorylation Thr853 PREKRRStGVSFWTQ -1 12220642 t lperfetto "Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited." SIGNOR-249164 ROCK2 protein O75116 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Thr14 KKQFHKAtQKVSEKV 9606 16164598 t llicata "We identified the phosphorylation site of endophilin a1 at thr-14 endophilin t14d inhibited egf receptor internalization. Furthermore, phosphorylation of endophilin by rho-kinase inhibited the binding to cin85." SIGNOR-140466 romidepsin chemical CHEBI:61080 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-257996 romidepsin chemical CHEBI:61080 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-257997 romidepsin chemical CHEBI:61080 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-257993 romidepsin chemical CHEBI:61080 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-257991 romidepsin chemical CHEBI:61080 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-257989 romidepsin chemical CHEBI:61080 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-257990 romidepsin chemical CHEBI:61080 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-257992 romidepsin chemical CHEBI:61080 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-257994 romidepsin chemical CHEBI:61080 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-257995 ropinirole chemical CHEBI:8888 ChEBI DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" -1 9057850 t miannu "Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively)" SIGNOR-258600 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 ROR2 protein Q01974 UNIPROT FLNA protein P21333 UNIPROT up-regulates binding 9606 18667433 t gcesareni "Additionally, the association of ror2 with the actin-binding protein filamin a is required for wnt5a-induced jnk activation and polarized cell migration." SIGNOR-179668 ROR2 protein Q01974 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 18667433 t gcesareni "Wnt5a stimulation induces activation of the c-jun n-terminal kinase jnk at the wound edge in a ror2-dependent manner, and inhibiting jnk activity abrogates wnt5a-induced lamellipodia formation and mtoc reorientation" SIGNOR-179671 ROR2 protein Q01974 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Wnt5a induces homodimerization and activation of ror2 receptor tyrosine kinase" SIGNOR-199588 RORA protein P35398 UNIPROT CAV3 protein P56539 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 15199055 f "Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle." SIGNOR-254255 RORA protein P35398 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 15199055 f "Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle." SIGNOR-254256 RORC protein P51449 UNIPROT IL17A protein Q16552 UNIPROT up-regulates "transcriptional regulation" 9606 16990136 t mrosina "We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells" SIGNOR-255029 RORC protein P51449 UNIPROT Th17 phenotype SIGNOR-PH94 SIGNOR up-regulates 9606 16990136 t "MARCO ROSINA" "Our results demonstrate that RORgt is the transcription factor that directs the differentiation of inflammatory Th17 cells" SIGNOR-255028 rosiglitazone chemical CHEBI:50122 ChEBI PPARG protein P37231 UNIPROT "up-regulates activity" binding 9534 BTO:0004058 7768881 t "An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)" SIGNOR-251646 ROS stimulus SIGNOR-ST2 SIGNOR ARNT protein P27540 UNIPROT "up-regulates quantity by expression" 22387692 f lperfetto "Although the regulation mechanism of the ARNT expression is largely unknown, earlier studies reported that the human ARNT protein level was decreased by hydrogen peroxide or reactive oxygen species." SIGNOR-253689 ROS stimulus SIGNOR-ST2 SIGNOR ATF4 protein P18848 UNIPROT up-regulates "transcriptional regulation" 9606 19439225 f lperfetto "Oxidative and ER stress conditions induce rapid and significant activation of ATF4 downstream of eIF2alpha phosphorylation, which is responsible for Redd1 expression" SIGNOR-253729 ROS stimulus SIGNOR-ST2 SIGNOR FOXL2 protein P58012 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19010791 f miannu "Transcriptional upregulation of foxl2 during oxidative and heat stress" SIGNOR-182303 ROS stimulus SIGNOR-ST2 SIGNOR MAP3K5 protein Q99683 UNIPROT up-regulates 9606 11266364 f lperfetto "TNF- but not Fas-induced apoptosis requires ROS-dependent activation of ASK1_JNK/p38 pathways. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis." SIGNOR-226609 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 ROS stimulus SIGNOR-ST2 SIGNOR PAX2 protein Q02962 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002733 16985513 f "High glucose-induced Pax-2 gene expression is mediated, at least in part, via ROS generation and activation of the nuclear factor kappa B signaling pathway, but not via protein kinase C, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling." SIGNOR-252295 ROS stimulus SIGNOR-ST2 SIGNOR PPARGC1A protein Q9UBK2 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-253397 ROS stimulus SIGNOR-ST2 SIGNOR SNCA protein P37840 UNIPROT "up-regulates quantity" 9606 BTO:0000938 16000336 f lperfetto "The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions." SIGNOR-249699 RPA1 protein P27694 UNIPROT BRIP1 protein Q9BX63 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 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 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1616 TPQSPSYsPTSPSYS 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-248734 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 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1626 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-248736 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1644 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-248748 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1651 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-248749 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1654 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-248738 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1665 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-248750 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1672 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-248751 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1675 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-248740 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1693 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-248752 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1714 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-248753 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1717 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-248742 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1724 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-248743 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1735 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-248755 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1763 TPTSPSYsPTSPSYS 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-248756 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1766 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-248745 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1784 TPTSPNYsPTSPSYS 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-248757 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1787 SPNYSPTsPSYSPTS 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-248746 RPGRIP1L protein Q68CZ1 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates demethylation 9606 20080798 t lperfetto "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-217412 RPGRIP1L protein Q68CZ1 UNIPROT RELA protein Q04206 UNIPROT down-regulates demethylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 t miannu "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-163320 RPGRIP1 protein Q96KN7 UNIPROT RPGR protein Q92834 UNIPROT "down-regulates activity" binding 9606 20631154 t miannu "The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. As RPGRIP1 appears to link RPGR to the cilium, it is possible that RPGR's effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments." SIGNOR-253031 RPGR protein Q92834 UNIPROT RAB8A protein P61006 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 20631154 t miannu "PGR interacts with the small GTPase RAB8A, which participates in cilia biogenesis and maintenance. We show that RPGR primarily associates with the GDP-bound form of RAB8A and stimulates GDP/GTP nucleotide exchange. RPGR functions as a GEF for RAB8A and RPGR–RAB8A association may facilitate ciliary trafficking." SIGNOR-253030 RPL10 protein P27635 UNIPROT JUN protein P05412 UNIPROT down-regulates binding 9606 12138090 t miannu "The qm gene encodes a 24.5 kda ribosomal protein l10 known to be highly homologous to a jun-binding protein (jif-1), which inhibits the formation of jun-jun dimers." SIGNOR-90750 RPL10 protein P27635 UNIPROT YES1 protein P07947 UNIPROT down-regulates binding 9606 12138090 t miannu "Several c-yes kinase activity assays indicated that the qm protein reduced c-yes kinase activity by 70%" SIGNOR-90805 RPL11 protein P62913 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-205514 RPL22 protein P35268 UNIPROT RPL22L1 protein Q6P5R6 UNIPROT down-regulates 9606 23990801 f miannu "We find that rpl22 directly represses expression of rpl22l1 mrna by binding to an internal hairpin structure." SIGNOR-202600 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 RPN1 protein P04843 UNIPROT OPRM1 protein P35372 UNIPROT up-regulates binding 9606 19289571 t miannu "Ribophorin i (rpni), a component of the oligosaccharide transferase complex, could directly interact with mor. Rpni can be shown to participate in mor export by the intracellular retention of the receptor after small interfering rna knockdown of endogenous rpni." SIGNOR-184651 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 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 t lperfetto "To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells" SIGNOR-160635 RPS6KA1 protein Q15418 UNIPROT 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-172986 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 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-202113 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser295 TKRRKSMsGASPKES 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-202117 RPS6KA1 protein Q15418 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 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-202121 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 RPS6KA1 protein Q15418 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 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)" SIGNOR-169883 RPS6KA1 protein Q15418 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000938 10558990 t lperfetto "The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival." SIGNOR-72117 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 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-176883 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 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-176887 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 RPS6KA1 protein Q15418 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 11500364 t lperfetto "We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity" SIGNOR-109708 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 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 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 BTO:0002181 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 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 BTO:0002181 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 RPS6KA1 protein Q15418 UNIPROT FOS protein P01100 UNIPROT up-regulates phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni "We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling." SIGNOR-37154 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 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-119221 RPS6KA1 protein Q15418 UNIPROT 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-175687 RPS6KA1 protein Q15418 UNIPROT L1CAM protein P32004 UNIPROT "up-regulates activity" phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto "Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152." SIGNOR-248948 RPS6KA1 protein Q15418 UNIPROT METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 t gcesareni "Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro." SIGNOR-135948 RPS6KA1 protein Q15418 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 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 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-75034 RPS6KA1 protein Q15418 UNIPROT 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-174760 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 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 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 RPS6KA1 protein Q15418 UNIPROT 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-249036 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 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 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 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 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-171247 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 RPS6KA1 protein Q15418 UNIPROT 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-180462 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 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-180466 RPS6KA1 protein Q15418 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 t gcesareni "The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange." SIGNOR-69171 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 RPS6KA1 protein Q15418 UNIPROT TSC1/TSC2 complex SIGNOR-C101 SIGNOR "down-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-217900 seliciclib chemical CHEBI:45307 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206568 RPS6KA1 protein Q15418 UNIPROT 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-128634 RPS6KA1 protein Q15418 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 BTO:0000551 21423205 t lperfetto "Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin." SIGNOR-172899 RPS6KA1 protein Q15418 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 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. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity." SIGNOR-203294 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 RPS6KA1 protein Q15418 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto "We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue." SIGNOR-182497 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 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-249044 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t gcesareni "The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival." SIGNOR-184591 RPS6KA3 protein P51812 UNIPROT ATF4 protein P18848 UNIPROT up-regulates phosphorylation Ser245 TRGSPNRsLPSPGVL 9606 15109498 t lperfetto "Here, we show that rsk2 is required for osteoblast differentiation and function. We identify the transcription factor atf4 as a critical substrate of rsk2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression" SIGNOR-124436 RPS6KA3 protein P51812 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t lperfetto "The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival." SIGNOR-184595 RPS6KA3 protein P51812 UNIPROT CENPE protein Q02224 UNIPROT "up-regulates activity" 9606 BTO:0000567 20383198 f lperfetto "We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions." SIGNOR-252037 RPS6KA3 protein P51812 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 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)" SIGNOR-169887 RPS6KA3 protein P51812 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 9606 8688081 t lperfetto "MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression" SIGNOR-248951 RPS6KA3 protein P51812 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0001286 17404396 t gcesareni "Our data indicated that phosphorylation of pkr at thr(451) is mediated through erk2 and rsk2, but not through p38 kinase." SIGNOR-154183 RPS6KA3 protein P51812 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19112174 t gcesareni "S6k1 regulates estrogen receptor alpha (eralpha) by phosphorylating it on serine 167, leading to transcriptional activation of eralpha." SIGNOR-182958 RPS6KA3 protein P51812 UNIPROT GSK3A protein P49840 UNIPROT "down-regulates activity" phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000130 11583116 t lperfetto "P90-rsk and akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. These reactions were monitored with a phosphospecific antibody that only recognized the alpha- or beta-isoforms of GSK-3 when these proteins were phosphorylated on serine residues 21 and 9, respectively." SIGNOR-110827 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 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-70432 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 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-138471 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 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-119225 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 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-70436 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 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-138475 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 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-119229 RPS6KA3 protein P51812 UNIPROT HIST1H2BB protein P33778 UNIPROT up-regulates phosphorylation Ser33 DGKKRKRsRKESYSI 9606 BTO:0001253 21646345 t lperfetto "Here, we studied the histone h2b core domain and found that phosphorylation of h2b serine 32 occurs in normal cycling and mitogen-stimulated cells. Notably, this phosphorylation is elevated in skin cancer cell lines and tissues compared with normal counterparts. We identified ribosomal s6 kinase 2 (rsk2) as the kinase responsible for h2bs32 phosphorylation." SIGNOR-174026 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT "down-regulates activity" phosphorylation Ser25 KDEPQRRsARLSAKP 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-249102 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 RPS6KA3 protein P51812 UNIPROT KCNK3 protein O14649 UNIPROT up-regulates phosphorylation Ser393 GLMKRRSsV 9606 BTO:0000007 21357689 t gcesareni "The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c." SIGNOR-172470 RPS6KA3 protein P51812 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-248895 RPS6KA3 protein P51812 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT "up-regulates activity" 9606 BTO:0000567 20383198 f lperfetto "We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions." SIGNOR-252038 RPS6KA3 protein P51812 UNIPROT MAD2L1 protein Q13257 UNIPROT "up-regulates activity" 9606 BTO:0000567 20383198 f lperfetto "We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions." SIGNOR-252039 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 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 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser289 PALSRRGsLGEEGSE 10090 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-234473 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 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 t esanto "We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase." SIGNOR-133283 RPS6KA3 protein P51812 UNIPROT NR4A1 protein P22736 UNIPROT unknown phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000007 16223362 t lperfetto "In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo." SIGNOR-249295 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 2846551 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-23753 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 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 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-95483 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 12421349 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-95487 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 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-34686 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser295 FPFRNLGsPTQVISK 9606 23977114 t lperfetto "Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined" SIGNOR-202532 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser330 ASTGKSKsPCQTLGG 9606 23977114 t lperfetto "Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined" SIGNOR-202536 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 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-203302 RPS6KA3 protein P51812 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-203306 RPS6KA3 protein P51812 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto "We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue." SIGNOR-182165 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 t lperfetto "Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts" SIGNOR-249145 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 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1." SIGNOR-166661 RPS6KA4 protein O75676 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000782 17668895 t gcesareni "Msk1 and msk2 directly phosphorilate and activete transcription factors such as creb1, atf1 msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation." SIGNOR-157158 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 22187936 t gcesareni "Rsk1/2 stabilize c-fos and increases its activity." SIGNOR-191678 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni "Rsk1/2 phosphorylates the transcription factor c-fos on s362 and increases its activity." SIGNOR-37216 RPS6KA4 protein O75676 UNIPROT HIST3H3 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 BTO:0000452 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-249211 RPS6KA4 protein O75676 UNIPROT HIST3H3 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 BTO:0000452 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-249212 RPS6KA4 protein O75676 UNIPROT HMGN1 protein P05114 UNIPROT unknown phosphorylation Ser7 sSAEGAAK 10090 BTO:0000452 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 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin." SIGNOR-249216 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 RPS6KA4 protein O75676 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0001253 17429437 t gcesareni "Ser-343 and ser-196 are autophosphorylated by the c-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain." SIGNOR-154324 RPS6KA4 protein O75676 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19797274 f gcesareni "Mitogen- and stress-activated kinase 2 (msk2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, msk2 selectively suppressed the expression of a subset of p53 target genes.Msk2 can also control the the transcriptional activity of p53 in a kinase-indipendent mannermsk2 can also control the the transcriptional activity of p53 in a kinase-indipendent manner" SIGNOR-188334 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 t lperfetto "Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts" SIGNOR-249144 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD 9606 12414794 t lperfetto "We find that activation of the c-jun promoter through the atf1 site requires phosphorylation of atf1 at serine 63. atf1 can be phosphorylated by mitogen- and stress-activated protein kinase 1 (msk1), which is activated by egf and erk1/2." SIGNOR-95318 RPS6KA5 protein O75582 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000567 9687510 t lperfetto "Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb." SIGNOR-59458 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr45 PGGTLFStTPGGTRI -1 11777913 t lperfetto "Here, using mass spectrometry, we identify the serum-responsive, rapamycin-sensitive sites as Ser 65 and Thr 70. | Phosphorylation of Thr 37/Thr 46 is followed by Thr 70 phosphorylation, and Ser 65 is phosphorylated last. Finally, we show that phosphorylation of Ser 65 and Thr 70 alone is insufficient to block binding to eIF4E, indicating that a combination of phosphorylation events is necessary to dissociate 4E-BP1 from eIF4E." SIGNOR-249131 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 RPS6KA5 protein O75582 UNIPROT H2AC11 protein P0C0S8 UNIPROT down-regulates phosphorylation Ser2 sGRGKQGG 9606 15010469 t gcesareni "We found that msk1 phosphorylated histone h2a on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by msk1." SIGNOR-123383 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 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-70440 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 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-138479 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 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-119233 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 18508628 t 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-178704 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPSTGGV 9606 BTO:0000938 18508628 t 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 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 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-119237 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPATGGV 9606 BTO:0000938 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 RPS6KA5 protein O75582 UNIPROT HIST3H3 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 BTO:0000452 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-249213 RPS6KA5 protein O75582 UNIPROT HIST3H3 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 BTO:0000452 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 RPS6KA5 protein O75582 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 12628924 t lperfetto "Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276." SIGNOR-217424 RPS6KA5 protein O75582 UNIPROT NR4A1 protein P22736 UNIPROT unknown phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000007 16223362 t lperfetto "In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo." SIGNOR-249296 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 RPS6KA5 protein O75582 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 12628924 t gcesareni "Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276." SIGNOR-99210 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 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 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-131403 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser758 TSTETRSsSSESSHS 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-131407 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser212 DETERAYsFCGTIEY 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. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro." SIGNOR-131387 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser376 EKLFQGYsFVAPSIL 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. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro." SIGNOR-131391 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser381 GYSFVAPsILFKRNA 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. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro." SIGNOR-131395 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Msk (mitogen- and stress-activated kinase) 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf- b isoform p65 and stat (signal transducer and activator of transcription) 1 and 3" SIGNOR-166664 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 RPS6KA5 protein O75582 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 t "The effect has been demonstrated using P07101-3" gcesareni "Recombinant 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. studies on th from several species suggest that ser40 is the main site involved in direct activation of th" SIGNOR-95491 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 23429703 t lperfetto "Mtorc1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein s6 kinase 1 (s6k1), which directly phosphorylates s1859 on cad, the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mtorc1 thus stimulates the production of new nucleotides to accommodate an increase in rna and dna synthesis." SIGNOR-201117 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 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-176858 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 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 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-176866 RPS6KB1 protein P23443 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 11500364 t lperfetto "We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity" SIGNOR-109712 RPS6KB1 protein P23443 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-123997 RPS6KB1 protein P23443 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-34117 RPS6KB1 protein P23443 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation Ser84 LTKKRALsISPLSDA 9606 22439934 t gcesareni "In this study, we found that an activated mtor/s6k1 pathway promotes gli1 transcriptional activity and oncogenic function through s6k1-mediated gli1 phosphorylation at ser84, which releases gli1 from its endogenous inhibitor, sufu." SIGNOR-196756 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 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 "Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk." SIGNOR-186951 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 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 "Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk." SIGNOR-186955 RPS6KB1 protein P23443 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 "Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk." SIGNOR-186959 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 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser270 EFRPRSKsQSSSNCS 9606 BTO:0000975;BTO:0001760;BTO:0000142 9312143 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-51216 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser307 TRRSRTEsITATSPA 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-127908 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 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 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser639 YMPMSPKsVSAPQQI 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-127203 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 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser639 YMPMSPKsVSAPQQI 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-236599 RPS6KB1 protein P23443 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 17181399 f gcesareni "Finally, downregulation of p70 s6 kinase by sirna significantly enhanced the fgf-2-stimulated vegf release and phosphorylation of sapk/jnk." SIGNOR-149367 RPS6KB1 protein P23443 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 BTO:0000150;BTO:0000093 15905173 t lperfetto "Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain" SIGNOR-137251 RPS6KB1 protein P23443 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 BTO:0000150;BTO:0000093 15905173 t lperfetto "Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain" SIGNOR-137255 RPS6KB1 protein P23443 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 BTO:0000551 BTO:0000018 12807916 t lperfetto "We show that s6 kinase 1 (s6k1), but not akt, directly phosphorylates mtor in cell-free_ in vitro_ system and in cells." SIGNOR-102051 RPS6KB1 protein P23443 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t llicata "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, which in turn promotes the transcriptional activity of myc." SIGNOR-178590 RPS6KB1 protein P23443 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 t gcesareni "Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation." SIGNOR-150144 RPS6KB1 protein P23443 UNIPROT 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-160989 RPS6KB1 protein P23443 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 2846551 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-23757 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 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 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser385 PRRVNSAsSSNPPAE 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-128499 RPS6KB1 protein P23443 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates phosphorylation Thr1135 NRRIRTLtEPSVDFN 9606 19995915 t gcesareni "Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt" SIGNOR-161995 RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT "up-regulates activity" phosphorylation Ser235 IAKRRRLsSLRASTS 10090 15809305 t lperfetto "A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size." SIGNOR-135172 RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT "up-regulates activity" phosphorylation Ser236 AKRRRLSsLRASTSK 10090 15809305 t lperfetto "A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size." SIGNOR-135176 RPS6KB1 protein P23443 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates 10090 BTO:0002572 20670887 f lperfetto "We find that srebp1 and 2 promote proliferation downstream of mtorc1, and the activation of these transcription factors is mediated by s6k1." SIGNOR-167190 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 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-180771 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 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-180784 RPS6KB2 protein Q9UBS0 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-178594 RPS6KB2 protein Q9UBS0 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation 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-160992 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252786 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 t lperfetto "To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells" SIGNOR-252784 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252814 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 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-252793 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser295 TKRRKSMsGASPKES 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-252776 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 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-252781 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252779 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 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)" SIGNOR-252778 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000938 10558990 t lperfetto "The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival." SIGNOR-252782 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 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-252797 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 BTO:0002181 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 BTO:0002181 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-252769 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252790 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni "We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling." SIGNOR-252789 RPS6K proteinfamily SIGNOR-PF26 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto "S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity." SIGNOR-252788 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 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-252815 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 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-252808 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000938 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-252806 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR L1CAM protein P32004 UNIPROT "up-regulates activity" phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto "Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152." SIGNOR-252766 RPS6K proteinfamily SIGNOR-PF26 SIGNOR METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 t gcesareni "Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro." SIGNOR-252800 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 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 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-252791 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252794 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR NR4A3 protein Q92570 UNIPROT "down-regulates activity" phosphorylation Ser376 GRRGRLPsKPKSPLQ 9606 BTO:0000007 16223362 t lperfetto "Phosphorylation of Nur77 on Ser354 has been suggested to reduce ability of Nur77 to bind DNA; however, the kinase responsible for this phosphorylation in cells has not been clearly established. In the present study, we show that Nur77 is phosphorylated on this site by RSK (ribosomal S6 kinase)" SIGNOR-252771 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 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252813 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252812 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 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-252764 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252772 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 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-252773 RPS6K proteinfamily SIGNOR-PF26 SIGNOR SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 t gcesareni "The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange." SIGNOR-252792 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC1/TSC2 complex SIGNOR-C101 SIGNOR "down-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-256311 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 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. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity." SIGNOR-252809 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252810 RPTOR protein Q8N122 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-205627 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 RRAGA protein Q7L523 UNIPROT RAGAD complex SIGNOR-C114 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-228167 RRAGB protein Q5VZM2 UNIPROT RAGBC complex SIGNOR-C115 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-228176 RRAGB protein Q5VZM2 UNIPROT RAGBD complex SIGNOR-C116 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-228179 RRAGC protein Q9HB90 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates binding 9606 20006481 t lperfetto "Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor." SIGNOR-217547 RRAGC protein Q9HB90 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-228161 RRAGC protein Q9HB90 UNIPROT RAGBC complex SIGNOR-C115 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-228173 RRAGC protein Q9HB90 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates binding 9606 SIGNOR-C3 20006481 t gcesareni "Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor." SIGNOR-162054 RRAGD protein Q9NQL2 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates binding 9606 20006481 t lperfetto "Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor" SIGNOR-217550 RRAGD protein Q9NQL2 UNIPROT RAGAD complex SIGNOR-C114 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-228170 RRAGD protein Q9NQL2 UNIPROT RAGBD complex SIGNOR-C116 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-228182 RRAGD protein Q9NQL2 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates binding 9606 SIGNOR-C3 20006481 t gcesareni "Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor" SIGNOR-162093 RREB1 protein Q92766 UNIPROT KLK3 protein P07288 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 17550981 f "RREB-1 bound to the prostate-specific antigen (PSA) promoter as assessed by chromatin immunoprecipitation. Transient expression of RREB-1 down-regulated AR-mediated promoter activity and suppressed expression of PSA protein." SIGNOR-253661 RRM1 protein P23921 UNIPROT "Ribonucleotide reductase" complex SIGNOR-C233 SIGNOR "form complex" binding 9606 14583450 t miannu "Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2." SIGNOR-259363 RRM2B protein Q7LG56 UNIPROT RRM1 protein P23921 UNIPROT "up-regulates activity" binding 9606 BTO:0001061 14583450 t miannu "Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3." SIGNOR-259366 RRM2 protein P31350 UNIPROT "Ribonucleotide reductase" complex SIGNOR-C233 SIGNOR "form complex" binding 9606 14583450 t miannu "Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2." SIGNOR-259364 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22182578 t Luana " Salbutamol is a well-known β2 adrenoceptor (β2AR) partial agonist. | In order to gain insight, we carried out binding and functional assays for BCSDs in HEK-293T cells transfected with the human β2AR (hβ2AR). The transfected hβ2AR showed similar affinity for BCSDs and salbutamol" SIGNOR-258326 RSPO2 protein Q6UXX9 UNIPROT FZD4 protein Q9ULV1 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 22575959 f "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-260117 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 RSPO2 protein Q6UXX9 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 t "Thrombospondin domains" gcesareni "We show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling." SIGNOR-172719 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 RSPO3 protein Q9BXY4 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 t gcesareni "Here, we show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling." SIGNOR-172756 (RS)-Ppcc chemical CID:16726095 PUBCHEM SIGMAR1 protein Q99720 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0003852 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 (R)-(+)-sulpiride chemical CHEBI:64122 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-258735 RTKN protein Q9BST9 UNIPROT SEPTIN9 protein Q9UHD8 UNIPROT down-regulates 9606 16007136 f miannu "We identified rhotekin, a downstream effector for rho, as a candidate regulator organizing septin structures through filament disruption." SIGNOR-138578 RTKs proteinfamily SIGNOR-PF38 SIGNOR "A6/b4 integrin" complex SIGNOR-C174 SIGNOR "up-regulates activity" phosphorylation 9606 30889378 t miannu "The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs." SIGNOR-259032 RTKs proteinfamily SIGNOR-PF38 SIGNOR GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 17306385 t miannu "The adaptor protein Grb2 can bind with activated RTKs through an SH2 domain-phosphotyrosine interaction, while through the SH3 domain (a binding domain specific to proline-rich sequences) Grb2 interacts with the guanine nucleotide exchange factor, Sos." SIGNOR-256167 RTKs proteinfamily SIGNOR-PF38 SIGNOR ITGB4 protein P16144 UNIPROT "up-regulates activity" phosphorylation 9606 30889378 t miannu "The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs." SIGNOR-259031 RTKs proteinfamily SIGNOR-PF38 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-256166 RTKs proteinfamily SIGNOR-PF38 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" phosphorylation 9606 30889378 t miannu "The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs." SIGNOR-259030 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 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 RUNX1 protein Q01196 UNIPROT CDKN2A protein Q8N726 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 12091906 f irozzo "AML1 binds to a six base pair DNA sequence (TGT/cGGT) that is present in many hematopoietic-specific genes.The p53 promoter does not contain any perfect AML1 DNA-binding sites (TGT/cGGT), but the human p14ARF promoter contains eight such sites (Fig. 1a), as well as multiple sites that match the broader consensus sequence (PyGPy/AGGT) or that have a single change from the consensus site.AML1 regulates the p14ARF promoter through an AML1 consensus DNA-binding site." SIGNOR-255713 RUNX1 protein Q01196 UNIPROT "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "form complex" binding 9606 12495904 t irozzo "The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis" SIGNOR-255710 RUNX1 protein Q01196 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto "AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability." SIGNOR-249631 RUNX1 protein Q01196 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004850 14594802 f miannu "We find that LEF-1 and CBFalpha co-activate ELA2 expression." SIGNOR-254553 RUNX1 protein Q01196 UNIPROT ELF4/RUNX1 complex SIGNOR-C47 SIGNOR "form complex" binding 9606 BTO:0001271 10207087 t miannu "We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function" SIGNOR-66963 RUNX1 protein Q01196 UNIPROT GP1BA protein P07359 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-254195 RUNX1 protein Q01196 UNIPROT HHEX protein Q03014 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0004479 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 RUNX1 protein Q01196 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "down-regulates activity" binding 9606 22021368 t apalma "We found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-κB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-κB signaling" SIGNOR-255690 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 RUNX1 protein Q01196 UNIPROT KIT protein P10721 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0003288 30500954 f irozzo "Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug." SIGNOR-259133 RUNX1 protein Q01196 UNIPROT MECOM protein Q03112 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000565 22689058 f irozzo "Our results suggest that RUNX1 and EVI1 could be regulating each other. RUNX1 would activate EVI1 transcription, and when highly expressed, EVI1 could bind to RUNX1 at protein level, inhibiting its activity as a transcription factor, acting in a negative feedback." SIGNOR-255715 RUNX1 protein Q01196 UNIPROT miR-155 mirna MI0000681 miRBase "up-regulates quantity by expression" "transcriptional regulation" 9606 26910834 f miannu "RUNX1high was positively associated with miR-155, miR-125a, miR-99b, miR-133a, miR-130a, miR-25 and miR-92a-1. MiR-155 was previously found to function as an oncogene in CN-AML" SIGNOR-255800 RUNX1 protein Q01196 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001545 29958106 t miannu "RUNX1 represses MYC expression through direct binding at three downstream enhancer elements" SIGNOR-260093 RUNX1 protein Q01196 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0002884 23817177 f 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-255709 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 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 "BTO:0004958; BTO:0002648" 9182762 f "Giulio Giuliani" "Indeed, we identified Osf2/Cbfa1 binding sites in the promoter of four genes expressed only (the Osteocalcin genes) or highly (Œ±1(I) collagen, Bsp, and Osteopontin) in osteoblasts. Each of these elements was able to bind Osf2/Cbfa1." SIGNOR-255408 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence" SIGNOR-107160 RUNX2 protein Q13950 UNIPROT COL1A1 protein P02452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f "Osteoblast-like cell lines" lpetrilli "In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast differentiation, including alkaline phosphatase, a1 and a2 collagen, osteopontin and osteoprotegerin ligand." SIGNOR-107163 RUNX2 protein Q13950 UNIPROT COL1A2 protein P08123 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-107166 RUNX2 protein Q13950 UNIPROT COL2A1 protein P02458 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-107169 RUNX2 protein Q13950 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 20551513 t gcesareni "Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphory-lated runx2, promoting its association with the coac-tivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs." SIGNOR-166170 RUNX2 protein Q13950 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004850 14594802 f miannu "We find that LEF-1 and CBFalpha co-activate ELA2 expression." SIGNOR-254552 RUNX2 protein Q13950 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-252192 RUNX2 protein Q13950 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-255078 RUNX2 protein Q13950 UNIPROT MMP2 protein P08253 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-255082 RUNX2 protein Q13950 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 20740684 t "Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1-IC-RBP-Jk complex" gcesareni "Runx2 is an inhibitor of the notch1 signaling pathway during normal osteoblast differentiation. The n-terminal domain of runx2 was crucial to the binding and inhibition of the the n-terminus of the notch1 intracellular domain." SIGNOR-167627 RUNX2 protein Q13950 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 9182762 f gcesareni "Osf2/cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation" SIGNOR-48940 RUNX2 protein Q13950 UNIPROT RUNX2/EP300 complex SIGNOR-C211 SIGNOR "form complex" binding 10116 BTO:0002648 12697832 t "Giulio Giuliani" "More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex." SIGNOR-255419 RUNX2 protein Q13950 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944;BTO:0003166 11331591 f lperfetto "Together, these results suggest that the inhibition of cbfa1 transcription by TGF-_ requires both the presence of CBFA1 and CBFA1 binding to the cbfa1 promoter." SIGNOR-235533 RUNX2 protein Q13950 UNIPROT SNAI2 protein O43623 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-255080 RUNX2 protein Q13950 UNIPROT SNAI3 protein Q3KNW1 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-255083 RUNX2 protein Q13950 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates "transcriptional regulation" 10090 16574347 f "Giulio Giuliani" "Osx promoter activity was up-regulated by 2 fold after Runx2 over-expression in ATDC5 cells. Osx Is Phosphorylated by p38 at Ser-73 and Ser-77" SIGNOR-255410 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 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-107175 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0001616 16670084 t gcesareni "Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein." SIGNOR-245336 RUNX2 protein Q13950 UNIPROT TWIST1 protein Q15672 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-255085 RUNX3 protein Q13761 UNIPROT CAPN10 protein Q9HC96 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-255091 RUNX3 protein Q13761 UNIPROT CASP2 protein P42575 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-255094 RUNX3 protein Q13761 UNIPROT CFLAR protein O15519 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-255087 RUNX3 protein Q13761 UNIPROT CHUK protein O15111 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-255090 RUNX3 protein Q13761 UNIPROT DNASE1 protein P24855 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-255092 RUNX3 protein Q13761 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004850 14594802 f miannu "We find that LEF-1 and CBFalpha co-activate ELA2 expression." SIGNOR-254554 RUNX3 protein Q13761 UNIPROT FADD protein Q13158 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-255095 RUNX3 protein Q13761 UNIPROT HSPD1 protein P10809 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-255086 RUNX3 protein Q13761 UNIPROT IKBKB protein O14920 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-255089 RUNX3 protein Q13761 UNIPROT ING1 protein Q9UK53 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-255099 RUNX3 protein Q13761 UNIPROT ING4 protein Q9UNL4 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-255096 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 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 RUNX3 protein Q13761 UNIPROT TIAL1 protein Q01085 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-255088 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 RUNX3 protein Q13761 UNIPROT TXN2 protein Q99757 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-255093 ruxolitinib chemical CHEBI:66919 ChEBI JAK1 protein P23458 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206667 ruxolitinib chemical CHEBI:66919 ChEBI JAK3 protein P52333 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-258278 "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 "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 RWDD3 protein Q9Y3V2 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates sumoylation 9606 17956732 t lperfetto "Rsume,_a small_rwd-containing protein, enhances sumo conjugation and stabilizes hif-1alpha during hypoxia" SIGNOR-158590 RXRA protein P19793 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000166 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-254582 RXRA protein P19793 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 12771132 t gcesareni "Rxr agonists still inactivated endogenous beta-catenin via rxr alpha." SIGNOR-101293 RXRA protein P19793 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 t lperfetto "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-123091 RXRA protein P19793 UNIPROT PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR "up-regulates activity" binding 10090 BTO:0002572 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 RXRA protein P19793 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-105345 RXRA protein P19793 UNIPROT PPARD protein Q03181 UNIPROT up-regulates binding 9606 11237216 t lperfetto "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-105442 RXRA protein P19793 UNIPROT PPARG protein P37231 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-105445 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 RXRA protein P19793 UNIPROT RARB protein P10826 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-16668 RXRA protein P19793 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-16671 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 RXRA protein P19793 UNIPROT THRB protein P10828 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-81449 RXRB protein P28702 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates binding 9606 BTO:0000938 9636132 t lperfetto "The recent discovery that the nuclear transcription factor, nurr1, in heterodimeric tandem with rxr, is unequivocally necessary for the expression of dopaminergic neurons" SIGNOR-58309 RXRB protein P28702 UNIPROT NRIP1 protein P48552 UNIPROT up-regulates binding 9606 12403842 t gcesareni "Receptor interacting protein 140 (rip140) is a coregulator for a large number of transcription factors. Rip140 interacts with retinoic acid receptor (rar) and retinoid x receptor (rxr) with or without ligands" SIGNOR-95160 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 RXRB protein P28702 UNIPROT PPARD protein Q03181 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-105451 RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10882139 t lperfetto "The nuclear receptor ppargamma/rxralpha heterodimer regulates glucose and lipid homeostasis" SIGNOR-78907 RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 t lperfetto "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-105454 RXRB protein P28702 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-16674 RXRB protein P28702 UNIPROT RARB protein P10826 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-16677 RXRB protein P28702 UNIPROT RARB protein P10826 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-16680 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 RXRB protein P28702 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-81452 RXRB protein P28702 UNIPROT THRB protein P10828 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-81455 RXR proteinfamily SIGNOR-PF44 SIGNOR PPARG protein P37231 UNIPROT "up-regulates activity" binding 9606 11237216 t miannu "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-259057 RXR proteinfamily SIGNOR-PF44 SIGNOR RAR proteinfamily SIGNOR-PF45 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-256199 RYBP protein Q8N488 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8943360 t gcesareni "We identified a novel protein, aap1 (abl-associated protein 1), that associates with these c-abl domains and fails to bind to the sh3 domain in the activated oncoprotein bcrabl. we conclude that aap1 inhibits c-abl tyrosine kinase activity" SIGNOR-45325 RYK protein P34925 UNIPROT DVL1 protein O14640 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-129568 RYK protein P34925 UNIPROT DVL2 protein O14641 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-129571 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 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 S1PR1 protein P21453 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates 9606 9488656 f gcesareni "Edg-1 is known to activate the mitogen-activated protein (map) kinase known as extracellular signal-regulated kinase 2 (erk-2) through pertussis toxin (ptx)sensitive giprotein" SIGNOR-54770 S1PR1 protein P21453 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-256713 S1PR1 protein P21453 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-256992 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 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 S1PR2 protein O95136 UNIPROT GNA12 protein Q03113 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-198556 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 S1PR2 protein O95136 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-198559 S1PR2 protein O95136 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-257289 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 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 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-70664 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 S1PR2 protein O95136 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-257215 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 S1PR2 protein O95136 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-257123 S1PR3 protein Q99500 UNIPROT GNA13 protein Q14344 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-70710 S1PR3 protein Q99500 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-257437 S1PR3 protein Q99500 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-257062 S1PR3 protein Q99500 UNIPROT GNAI1 protein P63096 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-70713 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 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 S1PR3 protein Q99500 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-257263 S1PR3 protein Q99500 UNIPROT GNAS protein Q5JWF2 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-256790 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 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 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 S1RA chemical CID:44247568 PUBCHEM SIGMAR1 protein Q99720 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000195 22784008 t "Simone Vumbaca" "The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862) emerged as the most interesting candidate. Compound 28 is a highly selective σ1R antagonist and has successfully completed phase I safety and pharmacokinetic evaluation in humans." SIGNOR-261122 S3I-201 chemical CHEBI:91224 ChEBI STAT3 protein P40763 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194847 (~{s})-(4-Fluoranyl-2-Propyl-Phenyl)-(1~{h}-Imidazol-2-Yl)methanol chemical CID:126961334 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-261118 SAAL1 protein Q96ER3 UNIPROT CDK6 protein Q00534 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 30513680 f Giorgia "This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1/SAAL1 siRNA at the post-transcriptional level. The CDK6, expression of which is up-regulated by the SPACIA1/SAAL1 expression, might be a critical factor in the exacerbation of CIA." SIGNOR-260386 sabcomeline chemical CHEBI:134846 ChEBI CHRM1 protein P11229 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000142 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 sabcomeline chemical CHEBI:134846 ChEBI CHRM2 protein P08172 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000142 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 sabcomeline chemical CHEBI:134846 ChEBI CHRM4 protein P08173 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000142 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 (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 (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 (S)-adrenaline smallmolecule CHEBI:40751 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-258452 SALL4 protein Q9UJQ4 UNIPROT ABCA3 protein Q99758 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21526180 f miannu "we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples" SIGNOR-255121 SALL4 protein Q9UJQ4 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21526180 f miannu "we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples" SIGNOR-255122 SALL4 protein Q9UJQ4 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "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-255124 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 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 SALL4 protein Q9UJQ4 UNIPROT SALL1 protein Q9NSC2 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-255127 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 "Sanglifehrin A" chemical CID:5388925 PUBCHEM IMPDH2 protein P12268 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000664 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 sapitinib chemical CHEBI:132986 ChEBI EGFR protein P00533 UNIPROT 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-163727 sapitinib chemical CHEBI:132986 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190149 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190152 sapitinib chemical CHEBI:132986 ChEBI ERBB3 protein P21860 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190155 sapitinib chemical CHEBI:132986 ChEBI SHC3 protein Q92529 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000551 20145185 t 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-163733 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 Saracatinib chemical CID:10302451 PUBCHEM SRC protein P12931 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206691 SARM1 protein Q6SZW1 UNIPROT TICAM1 protein Q8IUC6 UNIPROT down-regulates binding 10090 17667936 t gcesareni "SARM utilizes its TIR domain to negatively regulate TRIF" SIGNOR-252068 SARS1 protein P49591 UNIPROT MYC protein P01106 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 24940000 t "Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation." SIGNOR-259368 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 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 SATB1 protein Q01826 UNIPROT MYB protein P10242 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-255135 SATB1 protein Q01826 UNIPROT NUMB protein P49757 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000725 23563689 f miannu "Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc" SIGNOR-224835 SATB1 protein Q01826 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "In this study, a SATB1 eukaryotic expression plasmid was transfected into the human erythroleukemia K562 cell line and individual clones that stably over-expressed the SATB1 protein were isolated. Microarray analysis revealed that hundreds of genes were either up- or down-regulated in the SATB1 over-expressing K562 cell lines. One of these was the extra-cellular matrix glycoprotein, SPARC (human secreted protein acidic and rich in cysteine). siRNA knock-down of SATB1 also reduced SPARC expression, which was consistent with elevated SPARC levels in the SATB1 over-expressing cell line." SIGNOR-255128 SATB1 protein Q01826 UNIPROT TAF11 protein Q15544 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-255130 SATB2 protein Q9UPW6 UNIPROT TP63 protein Q9H3D4 UNIPROT "down-regulates activity" binding 9606 21965674 t miannu "SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding." SIGNOR-255149 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 SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR "up-regulates activity" binding 9606 21084559 t miannu "Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst." SIGNOR-256183 SAV1 protein Q9H4B6 UNIPROT STK3 protein Q13188 UNIPROT up-regulates binding 9606 21084559 t "Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2." gcesareni "Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst." SIGNOR-169829 SAV1 protein Q9H4B6 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 21084559 t "Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2." gcesareni "Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst." SIGNOR-169832 saxagliptin chemical CHEBI:71272 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000783 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-257813 SB-202190 chemical CHEBI:79090 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206694 SB-202190 chemical CHEBI:79090 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206697 SB-202190 chemical CHEBI:79090 ChEBI PCSK7 protein Q16549 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000876 9738669 t gcesareni "Sb202190, a selective inhibitor of p38 mitogen activated protein kinase, is a powerful regulator of lps-induced mrnas in monocytes." SIGNOR-60130 "SB 203580" chemical CHEBI:90705 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000222 15208625 t fstefani "Pharmacological blockade of p38?/? Kinases by sb203580 inhibits the myogenic program3_5 by repressing the transcription of early (myogenin;myog) and late (muscle-creatine kinase;ckm) muscle genes in myoblasts induced to differentiate" SIGNOR-126052 "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 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000567 10702313 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-75389 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000567 11606413 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-111064 "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 "SB 415286" chemical CHEBI:91107 ChEBI GSK3A protein P49840 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206751 "SB 431542" chemical CHEBI:91108 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206706 "SB 505124" chemical CHEBI:100922 ChEBI ACVR1B protein P36896 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206736 "SB 505124" chemical CHEBI:100922 ChEBI ACVR1C protein Q8NER5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206739 "SB 505124" chemical CHEBI:100922 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 14978253 t gcesareni "Sb-505124 is a selective inhibitor of transforming growth factor-beta type i receptors alk4, alk5, and alk7." SIGNOR-122910 "SB 505124" chemical CHEBI:100922 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206742 SB-705498 chemical CID:9910486 PUBCHEM TRPV1 protein Q8NER1 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206826 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 SBDS protein Q9Y3A5 UNIPROT EIF6 protein P56537 UNIPROT up-regulates 9606 BTO:0001271 21536732 f miannu "Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits" SIGNOR-173536 SCAND1 protein P57086 UNIPROT MZF1 protein P28698 UNIPROT "up-regulates activity" binding -1 10777584 t miannu "Co-immunoprecipitation and yeast two-hybrid analyses demonstrate that MZF1B and RAZ1 associate in vitro via a SCAN box-dependent mechanism. The interaction between MZF1B and RAZ1 might be necessary for mediating MZF1B function" SIGNOR-221561 SCAP protein Q12770 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 12242332 f "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. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis." SIGNOR-256210 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 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDC25A protein P30304 UNIPROT up-regulates ubiquitination 9606 15340381 t lperfetto "Scfb-trcp has recently been shown to degrade phosphorylated cdc25a in the s and g2 phases." SIGNOR-217178 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 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates ubiquitination 9606 10023660 t lperfetto "These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin." SIGNOR-217181 SCF-betaTRCP complex SIGNOR-C5 SIGNOR MYC protein P01106 UNIPROT "up-regulates quantity" ubiquitination 9606 20852628 t gcesareni "Here we show that SCF²-TrCP binds to Myc by means of a characteristic phosphodegron and ubiquitylates Myc; this results in enhanced Myc stability." SIGNOR-243542 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB1 protein P19838 UNIPROT "up-regulates activity" ubiquitination 9534 BTO:0004055 11295495 t lperfetto "The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-217190 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 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" ubiquitination 9534 BTO:0004055 11295495 t lperfetto "The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-235305 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 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23431053 t lperfetto "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-230750 "SCH 23390" chemical CHEBI:73297 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-258732 SCN10A protein Q9Y5Y9 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 BTO:0000938 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-253454 SCN10A protein Q9Y5Y9 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0000938 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-253408 SCN11A protein Q9UI33 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 BTO:0000938 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-253453 SCN11A protein Q9UI33 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0000938 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 SCN1A protein P35498 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 BTO:0000938 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 SCN1A protein P35498 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0000938 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-253402 SCN2A protein Q99250 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 BTO:0000938 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-253450 SCN2A protein Q99250 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0000938 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-253404 SCN3A protein Q9NY46 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 BTO:0000938 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 SCN4A protein P35499 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0001103 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-253405 SCN5A protein Q14524 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 BTO:0000199 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 SCN5A protein Q14524 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0000199 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 SCN8A protein Q9UQD0 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 BTO:0000938 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-253452 SCN8A protein Q9UQD0 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "up-regulates quantity" relocalization 9606 BTO:0000938 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 SCN9A protein Q15858 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-253449 SCN9A protein Q15858 UNIPROT "sodium ion" smallmolecule "CID: 923" PUBCHEM "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-253403 SDC3 protein O75056 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 10090 BTO:0002314 20696709 t gcesareni "Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size." SIGNOR-244072 SDC3 protein O75056 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates activity" binding 10090 BTO:0002314 20696709 t gcesareni "Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size." SIGNOR-254329 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 SDC4 protein P31431 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1." SIGNOR-199638 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 SDC4 protein P31431 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-255847 SDC4 protein P31431 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 9606 BTO:0002314 BTO:0001103 23290138 t apalma "Rac1 is associated with Sdc4 and is activated by FN binding […] We observed that over-expression of Fzd7, or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts" SIGNOR-255849 SDCBP protein O00560 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9534 BTO:0001444 25122212 f Luana "Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation." SIGNOR-260753 SDCBP protein O00560 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-223089 SDF2L1 protein Q9HCN8 UNIPROT LRP4 protein O75096 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24140340 t llicata "Here, we show that the chaperon Mesdc2 binds to the intracellular form of Lrp4 and promotes its glycosylation and cell-surface expression. These results suggest that Mesdc2 plays an essential role in NMJ formation by promoting Lrp4 maturation." SIGNOR-237942 SDHAF2 protein Q9NX18 UNIPROT SDHB protein P21912 UNIPROT up-regulates binding 9606 19628817 t miannu "Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity" SIGNOR-187239 SDHA protein P31040 UNIPROT SDHA/SDHB complex SIGNOR-C69 SIGNOR "form complex" binding 9606 23000077 t miannu "Complex ii (also known as succinate dehydrogenase (sdh) or succinate coenzyme q reductase (sqr)) is made up of only four subunits (sdha, sdhb, sdhc and sdhd) / sdha and sdhb constitute the catalytic core of the complex that on its own can oxidize succinate (which directly binds to sdha) to fumarate in the tca cycle." SIGNOR-192079 SDHC protein Q99643 UNIPROT SDHC/SDHD complex SIGNOR-C70 SIGNOR "form complex" binding 9606 23000077 t miannu "Complex ii (also known as succinate dehydrogenase (sdh) or succinate coenzyme q reductase (sqr)) is made up of only four subunits (sdha, sdhb, sdhc and sdhd) / sdha and sdhb constitute the catalytic core of the complex that on its own can oxidize succinate (which directly binds to sdha) to fumarate in the tca cycle." SIGNOR-192085 SDHD protein O14521 UNIPROT SDHC/SDHD complex SIGNOR-C70 SIGNOR "form complex" binding 9606 23000077 t miannu "Complex ii (also known as succinate dehydrogenase (sdh) or succinate coenzyme q reductase (sqr)) is made up of only four subunits (sdha, sdhb, sdhc and sdhd) / sdha and sdhb constitute the catalytic core of the complex that on its own can oxidize succinate (which directly binds to sdha) to fumarate in the tca cycle." SIGNOR-192088 (S)-duloxetine chemical CHEBI:36795 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" -1 18387300 t Luana "Selective inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake (SNRI) has been shown to be an attractive dual pharmacology approach for the treatment of a number of diseases.1,2 For example, dual 5- HT/NA reuptake inhibitor duloxetine (1) has shown clinical efficacy in the treatment of depression, pain, and urinary incontinence." SIGNOR-257775 (S)-duloxetine chemical CHEBI:36795 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" -1 18387300 t Luana "Selective inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake (SNRI) has been shown to be an attractive dual pharmacology approach for the treatment of a number of diseases.1,2 For example, dual 5- HT/NA reuptake inhibitor duloxetine (1) has shown clinical efficacy in the treatment of depression, pain, and urinary incontinence." SIGNOR-257776 SEC13 protein P55735 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-255305 SEH1L protein Q96EE3 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-255304 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 seliciclib chemical CHEBI:45307 ChEBI CCNA2 protein P20248 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206559 seliciclib chemical CHEBI:45307 ChEBI CCNB1 protein P14635 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206562 seliciclib chemical CHEBI:45307 ChEBI CCNE1 protein P24864 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206565 seliciclib chemical CHEBI:45307 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206571 seliciclib chemical CHEBI:45307 ChEBI CDK5 protein Q00535 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206574 seliciclib chemical CHEBI:45307 ChEBI TP53 protein P04637 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206577 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 SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 t apalma "This steady-state rolling is primarily mediated by the interaction of endothelial P-selectins with their neutrophil glycoprotein counterreceptors, primarily PSGL-1." SIGNOR-255038 SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130;BTO:0000150;BTO:0000551 BTO:0000975 9129046 t gcesareni "The major ligand for p-selectin on leukocytes is p-selectin glycoprotein ligand-1 (PSGL-1)" SIGNOR-47625 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 selumetinib chemical CHEBI:90227 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190191 selumetinib chemical CHEBI:90227 ChEBI MAP2K2 protein P36507 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-258281 selumetinib chemical CHEBI:90227 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244823 SEMA3A protein Q14563 UNIPROT NRP1 protein O14786 UNIPROT down-regulates binding 9606 BTO:0000938 10196546 t gcesareni "Semaphorins a and e act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors." SIGNOR-66661 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 SEMA3C protein Q99985 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t gcesareni "Our experiments establish that small peptides containing the consensus decd sequence of sperm fertilinbeta bind specifically to an alpha6beta1 integrin receptor on the egg membrane. We conclude that fertilinbeta binds directly to the alpha6beta1 integrin on the egg surface and this partnership mediates sperm-egg fusion." SIGNOR-147564 SEMA7A protein O75326 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 10090 BTO:0000876 17377534 t lperfetto "Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin." SIGNOR-253249 SEMA7A protein O75326 UNIPROT PLXNC1 protein O60486 UNIPROT up-regulates binding 9606 BTO:0000938 10520995 t gcesareni "Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro." SIGNOR-71260 SENP1 protein Q9P0U3 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates quantity by destabilization" desumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni "Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity." SIGNOR-252736 SENP1 protein Q9P0U3 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates quantity by destabilization" desumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni "Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity." SIGNOR-252738 SENP1 protein Q9P0U3 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates desumoylation 9606 17981124 t miannu "Sumo-specific protease 1 is essential for stabilization of hif1alpha during hypoxia / our results support a model in which sumoylated hif1_ is unstable but can be stabilized when sumo is removed by senp1" SIGNOR-158891 SEPTIN12 protein Q8IYM1 UNIPROT SEPTIN6 protein Q14141 UNIPROT down-regulates binding 9606 BTO:0000567 18047794 t miannu "Sept12 interacts with sept6 and this interaction alters the filament structure of sept6 in hela cells." SIGNOR-159537 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 SEPTIN6 protein Q14141 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-148892 SEPTIN6 protein Q14141 UNIPROT SEPT6/SEPT7 complex SIGNOR-C72 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-148895 SEPTIN7 protein Q16181 UNIPROT CENPE protein Q02224 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 18460473 t lperfetto "These findings reveal a key role for the SEPT7-CENP-E interaction in the distribution of CENP-E to the kinetochore and achieving chromosome alignment. We propose that SEPT7 forms a link between kinetochore distribution of CENP-E and the mitotic spindle checkpoint." SIGNOR-252040 SEPTIN7 protein Q16181 UNIPROT SEPT6/SEPT7 complex SIGNOR-C72 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-148898 SEPTIN9 protein Q9UHD8 UNIPROT ARHGEF18 protein Q6ZSZ5 UNIPROT down-regulates binding 9606 BTO:0000567 15558029 t miannu "In transient expression analyses, sept9b inhibited sa-rhogef-dependent rho activation in cos7 and hela cells." SIGNOR-131184 Serdemetan chemical CID:11609586 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193504 "SER INCUB" stimulus SIGNOR-ST3 SIGNOR PRKAA2 protein P54646 UNIPROT down-regulates 9606 19584320 f miannu "Ampk is activated under conditions of low energy charge and typically inhibits anabolic reactions and promotes catabolism" SIGNOR-186644 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1A protein P08908 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-257516 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 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1D protein P28221 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-257518 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1F protein P30939 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-257520 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 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2B protein P41595 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-257522 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2C protein P28335 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-257523 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR4 protein Q13639 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-257524 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 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 serotonin chemical CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 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-258889 serotonin chemical CHEBI:28790 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-258846 sertindole chemical CHEBI:9122 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-258542 sertindole chemical CHEBI:9122 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-258843 sertindole chemical CHEBI:9122 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000601 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-258549 sertindole chemical CHEBI:9122 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-258545 sertindole chemical CHEBI:9122 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-258546 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 sertindole chemical CHEBI:9122 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-258548 SESN1 protein Q9Y6P5 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-253559 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 SESN3 protein P58005 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-253561 SETBP1 protein Q9Y6X0 UNIPROT HOXA10 protein P31260 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 22566606 f miannu "Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors" SIGNOR-197318 SETBP1 protein Q9Y6X0 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 22566606 f miannu "Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors" SIGNOR-197321 SETBP1 protein Q9Y6X0 UNIPROT SET protein Q01105 UNIPROT up-regulates binding 9606 BTO:0001271 22566606 t miannu "Setbp1 was shown to form a complex with set and pp2a, enhancing the stability of set and its inhibition of pp2a." SIGNOR-197324 SETD2 protein Q9BYW2 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 18158893 f gcesareni "In response to hypoxia, foxo3a transcript levels accumulate in an hif1-dependent way, resulting in enhanced foxo3a activity." SIGNOR-160201 SETD2 protein Q9BYW2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 18158893 f gcesareni "In response to hypoxia, foxo3a transcript levels accumulate in an hif1-dependent way, resulting in enhanced foxo3a activity." SIGNOR-252986 SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR PPARG protein P37231 UNIPROT "down-regulates activity" "transcriptional regulation" 10090 21952300 f FFerrentino "The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1). 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 cells" SIGNOR-253524 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 SET protein Q01105 UNIPROT NME1 protein P15531 UNIPROT down-regulates binding 9606 12628186 t miannu "Tumor suppressor nm23-h1 is a granzyme a-activated dnase during ctl-mediated apoptosis, and the nucleosome assembly protein set is its inhibitor. / nm23-h1 binds to set and is released from inhibition by gzma cleavage of set." SIGNOR-99205 SET protein Q01105 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates binding 9606 BTO:0000142 21806989 t miannu "Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac" SIGNOR-175719 SET protein Q01105 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates binding 9606 BTO:0000142 21806989 t miannu "Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac" SIGNOR-175722 SF1 protein Q15637 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates binding 9606 9660765 t miannu "Here we report that zfm1 also interacts withews / overexpression of zfm1 in hepg2 cells represses the transactivation of reporter gene expression driven by gal4-ews-ntd fusion protein and this repression correlates with zfm1 binding to ews." SIGNOR-58928 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 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 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 SGCA protein Q16586 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-255985 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 SGCD protein Q92629 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-255988 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 SGI-1776 chemical CID:24795070 PUBCHEM PIM2 protein Q9P1W9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206862 SGI-1776 chemical CID:24795070 PUBCHEM PIM3 protein Q86V86 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206896 SGI-1776 chemical CID:24795070 PUBCHEM PIM proteinfamily SIGNOR-PF34 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-259435 SGK1 protein O00141 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t gcesareni "Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna." SIGNOR-179117 SGK1 protein O00141 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr198 PGLRRRQt 9606 18570873 t gcesareni "Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna." SIGNOR-179121 SGK1 protein O00141 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates phosphorylation Ser227 QQRRRITsVQPPTGL 9606 BTO:0001271 21147854 t lperfetto "Here, we report that the serum- and glucocorticoid-inducible protein kinase sgk1 remarkably reduced the protein stability of the active form of notch1 through fbw7activated sgk1 phosphorylated fbw7 at serine 227" SIGNOR-170404 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT "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-249133 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 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-249134 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 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-252988 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser166 EPRSRHLsVSSQNPG 9534 BTO:0001538 12392720 t miannu "It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3." SIGNOR-250004 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 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser337 DPRGRLRsADSENAL 9534 BTO:0001538 12392720 t miannu "It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3." SIGNOR-250005 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser337 DPRGRLRsADSENAL 9606 12761205 t lperfetto "Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 2" SIGNOR-101216 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT down-regulates phosphorylation Ser330 LMRSRTAsGSSVTSL 9606 20416281 t llicata "Ndrg1/cap43 is phosphorylated at serine/threonine sites in its c-terminal domain by serum- and glucocorticoid-regulated kinase 1 (sgk1). we further introduced mutations at the serine and threonine sites at 328 [t328a], 330 [s330a] and 346 [t346a], which are susceptible to phosphorylation by sgk1, and also constructed double mutants [t328a, s330a], [t328a, t346a] and [s330a, t346a]. Expression of all these mutants, with the exception of [s330a, t346a], suppressed the production of cxc chemokine to similar levels as their wild-type counterpart." SIGNOR-164898 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr356 GTRSRSHtSEGTRSR 9606 BTO:0000567 18787837 t llicata "Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1." SIGNOR-180825 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr366 GTRSRSHtSEGAHLD 9606 BTO:0000567 18787837 t llicata "Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1." SIGNOR-180829 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 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 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Thr348 GNRSRSRtLSQSSES 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-129680 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT "down-regulates activity" phosphorylation 9606 15586017 t "Regulation of localization" miannu "The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane." SIGNOR-251949 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 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT up-regulates phosphorylation Ser342 SSRLRSCsVTDAVAE 9606 11742982 t lperfetto "Here we show by expression studies in xenopus laevis oocytes that the aldosterone-induced sgk1 kinase interacts with the ubiquitin protein ligase nedd4-2 in a py motif-dependent manner and phosphorylates nedd4-2 on ser444 and, to a lesser extent, ser338. Such phosphorylation reduces the interaction between nedd4-2 and enac, leading to elevated enac cell surface expression." SIGNOR-113052 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser203 DLEFSSGsPGKETNE 9606 23650397 t gcesareni "SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|SGK1 mediates CORT effects on GR phosphorylation. After 12 h, CORT (100 ¬µM) increases GR phosphorylation at S203 (n = 6; A), S211 (n = 6; B), and S226 (n = 6; C)." SIGNOR-251669 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser211 PGKETNEsPWRSDLL 9606 23650397 t gcesareni "SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|SGK1 mediates CORT effects on GR phosphorylation. After 12 h, CORT (100 ¬µM) increases GR phosphorylation at S203 (n = 6; A), S211 (n = 6; B), and S226 (n = 6; C)." SIGNOR-251670 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser226 IDENCLLsPLAGEDD 9606 23650397 t gcesareni "SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|SGK1 mediates CORT effects on GR phosphorylation. After 12 h, CORT (100 ¬µM) increases GR phosphorylation at S203 (n = 6; A), S211 (n = 6; B), and S226 (n = 6; C)." SIGNOR-251671 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 SGK2 protein Q9HBY8 UNIPROT FOXO3 protein O43524 UNIPROT "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-249130 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 SGK2 protein Q9HBY8 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 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-252991 SGK3 protein Q96BR1 UNIPROT FLII protein Q13045 UNIPROT up-regulates phosphorylation Thr818 LHRPRHAtVSRSLEG 9606 19293151 t lperfetto "Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator." SIGNOR-184692 SGK3 protein Q96BR1 UNIPROT FOXO3 protein O43524 UNIPROT "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-249135 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 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 16543730 t lperfetto "Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3." SIGNOR-249167 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 SGX-523 chemical CHEBI:90624 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206905 SH2B1 protein Q9NRF2 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 27154742 t lperfetto "The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex" SIGNOR-253078 SH2B2 protein O14492 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 10029 BTO:0000977 10854852 t lperfetto "APS-mediated recruitment of c-Cbl to the insulin receptor led to rapid ubiquitination of the insulin receptor beta-subunit in CHO. T-APS but not in parental CHO.T cells. These results suggest that the function of APS is to facilitate coupling of the insulin receptor to c-Cbl in order to catalyse the ubiquitination of the receptor and initiation of internalisation or degradation." SIGNOR-78337 SH2B2 protein O14492 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000975 11498022 t gcesareni "Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor. The aps adapter protein couples theinsulinreceptor to the phosphorylation of c-cbl and facilitates ligand-stimulated ubiquitination of theinsulinreceptor." SIGNOR-109691 SH2B2 protein O14492 UNIPROT INSR protein P06213 UNIPROT down-regulates binding 9606 BTO:0000975 11498022 t lperfetto "APS couples c-Cbl to the insulin receptor, resulting in ubiquitination of the insulin receptor." SIGNOR-109694 SH2B3 protein Q9UQQ2 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22101255 f miannu "Our results indicated that lnk/sh2b3 constrains expression of bcl-xl and participates in the regulation of hsc homeostasis by maintaining proper responses against various proapoptotic stimuli." SIGNOR-177485 SH2B3 protein Q9UQQ2 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" binding 10090 BTO:0002882 18618018 t miannu "we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions." SIGNOR-260075 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 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 SH3GLB1 protein Q9Y371 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates 9606 BTO:0000567 16227588 f gcesareni "Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change." SIGNOR-141163 SH3GLB1 protein Q9Y371 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 BTO:0000567 16227588 t gcesareni "Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change." SIGNOR-141166 1038915-60-4 chemical CID:24958200 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194402 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 SH3GLB1 protein Q9Y371 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 11894095 t gcesareni "Cbl rapidly recruits cin85 (cbl-interacting protein of 85k;ref. 6) and endophilins (regulatory components of clathrin-coated vesicles) to form a complex with activated egf receptors, thus controlling receptor internalization." SIGNOR-115826 SH3KBP1 protein Q96B97 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 24167568 t gcesareni "The cin85 sh3 domains interact with c-cbl, an e3 ubiquitin ligase, via an unconventional pxxxpr ligand sequence, with the highest affinity displayed by the sh3-b domain. Interaction with cin85 recruits c-cbl to the amap1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix." SIGNOR-203139 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni "Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks." SIGNOR-97006 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K12 protein Q12852 UNIPROT up-regulates binding 9606 BTO:0000938 11416147 t gcesareni "One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks" SIGNOR-108577 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K12 protein Q12852 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni "One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks" SIGNOR-97060 SH3RF1 protein Q7Z6J0 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 16571722 t gcesareni "We find that posh and jips directly associate with one another to form a multiprotein complex, pjac (posh-jip apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for jnk activation and cell death in response to apoptotic stimuli." SIGNOR-145393 SH3RF1 protein Q7Z6J0 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 9482736 t gcesareni "Posh interacts with the gtp form of rac but not the gdp form" SIGNOR-55811 SHC1 protein P29353 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 10090 BTO:0000944 17673906 f 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-242628 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 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 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 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t lperfetto "The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival" SIGNOR-236236 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 SHC1 protein P29353 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t gcesareni "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-66949 SHC1 protein P29353 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" 10090 BTO:0000944 17673906 f 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-242622 SHC1 protein P29353 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" 10090 BTO:0000944 17673906 f 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-242625 SHC1 protein P29353 UNIPROT SOS1 protein Q07889 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-236363 SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16729043 t gcesareni "In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation." SIGNOR-146897 SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16829981 t gcesareni "In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation." SIGNOR-147865 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 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 15618519 t gcesareni "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-132672 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 17419683 t gcesareni "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-154285 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 BTO:0001253 9811851 t gcesareni "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-61549 SHH protein Q15465 UNIPROT GLI2 protein P10070 UNIPROT "up-regulates activity" 9606 BTO:0001593 16880529 f lperfetto "Finally, Sonic hedgehog (Shh) stimulates BMP-2 promoter activity and osteoblast differentiation, and the effects of Shh are mediated by Gli2." SIGNOR-148349 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 SHH protein Q15465 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0002314 18662193 f gcesareni "In addition, 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-179632 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT "down-regulates activity" binding 9606 14556242 t lperfetto "In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other." SIGNOR-118615 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT "down-regulates activity" binding 9606 15618519 t lperfetto "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. .Ptch Exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-132675 SHH protein Q15465 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-61552 SHH protein Q15465 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-217776 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 SHOC2 protein Q9UQ13 UNIPROT PPP1CA protein P62136 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16630891 t "Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site" SIGNOR-251647 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 SHPRH protein Q149N8 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination 9606 19706603 t gcesareni "We provide evidence that similar to rad5, shprh physically interacts with the human rad6rad18 and mms2ubc13 protein complexes, and importantly, we show that it exhibits an ubiquitin ligase activity and mediates mms2ubc13-dependent polyubiquitylation of pcna. Thus, shprh is a functional homolog of rad5." SIGNOR-187757 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 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 SIAH1 protein Q8IUQ4 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR 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-254330 SIAH2 protein O43255 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" SIGNOR-149893 SIK1 protein P57059 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-249168 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates activity" phosphorylation Ser70 RSSHYGGsLPNVNQI 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-249169 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 BTO:0000007;BTO:0000567 16817901 t miannu "These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities." SIGNOR-147707 SIK1 protein P57059 UNIPROT CRTC3 protein Q6UUV7 UNIPROT down-regulates phosphorylation Ser162 SALNRTNsDSALHTS 9606 BTO:0000007;BTO:0000567 16817901 t miannu "These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities." SIGNOR-147703 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 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 20708153 t lperfetto "Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation" SIGNOR-167488 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT unknown phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 20708153 t lperfetto "Remarkably, lc-ms confirmed that the predominant serine phosphorylation site of the recombinant carboxy-terminal domain of c-nap1 is s2392 at the predicted consensus phosphorylation sequence and to a lesser extent s2394." SIGNOR-167492 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 16308421 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-142218 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 20577053 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-166372 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser794 QHLRLSTsSGRLLYA 9606 12624099 t lperfetto "Sik2 could phosphorylate ser(794) of human irs-1" SIGNOR-99059 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT up-regulates 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 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 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 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates activity" phosphorylation Ser70 RSSHYGGsLPNVNQI 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-249171 SIL1 protein Q9H173 UNIPROT HSPA5 protein P11021 UNIPROT "up-regulates activity" binding 9534 BTO:0001538 12356756 t Simone "BAP, a Mammalian BiP-associated Protein, Is a Nucleotide Exchange Factor That Regulates the ATPase Activity of BiP. In addition,BAP was associated with BiP in mammalian cells and inter-acted with BiP functionallyin vitro. BAP stimulated the ATPase activity of BiP when added alone or together with the ER DnaJ protein, ERdj4, by promoting the release of ADP from BiP. Together, these data demonstrate that BAP serves as a nucleotide exchange factor for BiP and provide insights into the mechanisms that control protein folding in the mammalian ER." SIGNOR-261045 sildenafil chemical CHEBI:9139 ChEBI PDE5A protein O76074 UNIPROT "down-regulates activity" "chemical inhibition" -1 10385692 t Luana "Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds." SIGNOR-258343 silodosin chemical CHEBI:135929 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-258450 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 SIM1 protein P81133 UNIPROT ARNT protein P27540 UNIPROT "down-regulates activity" binding -1 SIGNOR-C125 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-240756 SIM1 protein P81133 UNIPROT ARNT protein P27540 UNIPROT "up-regulates activity" binding -1 9020169 t 2 miannu "We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer." SIGNOR-240759 SIM2 protein Q14190 UNIPROT ARNT protein P27540 UNIPROT "up-regulates activity" binding -1 9020169 t 2 miannu "We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer." SIGNOR-240808 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 SIN3A protein Q96ST3 UNIPROT KLK3 protein P07288 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16254079 t "Chromatin immunoprecipitation (ChIP) and DNA affinity precipitation analysis demonstrated that Ebp1 and Sin3A associate at the PSA and E2F1 promoters. Functionally, Sin3A enhanced the ability of Ebp1 to repress transcription of androgen receptor (AR) and E2F1 regulated genes." SIGNOR-253663 SIN3A protein Q96ST3 UNIPROT TERT protein O14746 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004117 18505829 f miannu "we investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression." SIGNOR-226363 Sincalide smallmolecule CID:9833444 PUBCHEM CCKAR protein P32238 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-257466 Sincalide smallmolecule CID:9833444 PUBCHEM CCKBR protein P32239 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-257467 sirolimus chemical CHEBI:9168 ChEBI AKT1 protein P31749 UNIPROT up-regulates 9606 16452206 f gcesareni "We now show that mtor inhibition induces insulin receptor substrate-1 expression and abrogates feedback the pathway, resulting in akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, rad001." SIGNOR-252643 sirolimus chemical CHEBI:9168 ChEBI CD40 protein P25942 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002042 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-255474 sirolimus chemical CHEBI:9168 ChEBI CD86 protein P42081 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002042 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-255479 sirolimus chemical CHEBI:9168 ChEBI LILRB1 protein Q8NHL6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002042 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-255476 sirolimus chemical CHEBI:9168 ChEBI LILRB2 protein Q8N423 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002042 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 sirolimus chemical CHEBI:9168 ChEBI LILRB4 protein Q8NHJ6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002042 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-255478 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 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 17350953 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-153608 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 21757781 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 ta rget 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-174886 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000938 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 SIRT1 protein Q96EB6 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 20713551 f miannu "Overexpression of SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1. Protein expression of MDR1 and gene transcriptional activity were also up-regulated by SIRT1 overexpression." SIGNOR-255139 SIRT1 protein Q96EB6 UNIPROT ACAN protein P16112 UNIPROT "up-regulates quantity by expression" "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-255142 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 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 SIRT1 protein Q96EB6 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "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-252456 SIRT1 protein Q96EB6 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-217884 SIRT1 protein Q96EB6 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-217878 SIRT1 protein Q96EB6 UNIPROT CLOCK/ARNTL complex SIGNOR-C195 SIGNOR "down-regulates activity" binding 19299583 t 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-253722 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 SIRT1 protein Q96EB6 UNIPROT EP300 protein Q09472 UNIPROT down-regulates deacetylation Lys1020 EERSTELkTEIKEEE 9606 BTO:0000150 19047049 t gcesareni "Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024" SIGNOR-182507 SIRT1 protein Q96EB6 UNIPROT EP300 protein Q09472 UNIPROT down-regulates deacetylation Lys1024 TELKTEIkEEEDQPS 9606 BTO:0000150 19047049 t gcesareni "Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024" SIGNOR-182511 SIRT1 protein Q96EB6 UNIPROT FOXL2 protein P58012 UNIPROT down-regulates deacetylation 9606 19010791 t miannu "We find that foxl2 activity is repressed by the sirt1 deacetylase." SIGNOR-182306 SIRT1 protein Q96EB6 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates quantity by destabilization" deacetylation 10090 BTO:0001103 24003218 t lperfetto "SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3" SIGNOR-217975 SIRT1 protein Q96EB6 UNIPROT FOXO1 protein Q12778 UNIPROT "up-regulates activity" deacetylation 9606 BTO:0001103 22395773 t lperfetto "SIRT1 controls the acetylation of FOXO transcription factors, which are important regulators of lipid and glucose metabolism as well as stress response. On the other hand, SIRT1 can also stimulate the gluconeogenic transcriptional program by deacetylating and activating FOXO1." SIGNOR-253509 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" deacetylation 10090 BTO:0001103 24003218 f lperfetto "SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3" SIGNOR-217972 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" deacetylation 9606 BTO:0000007 14976264 t lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-122408 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" deacetylation 9606 BTO:0000007 14976264 t lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-122405 SIRT1 protein Q96EB6 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates deacetylation 9606 15126506 t gcesareni "Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes." SIGNOR-124714 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 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 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" binding 10090 BTO:0001103 24003218 t lperfetto "SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3" SIGNOR-252996 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" deacetylation 9606 BTO:0000007 14976264 t lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-252994 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates deacetylation 9606 15126506 t gcesareni "Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes." SIGNOR-252993 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 SIRT1 protein Q96EB6 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" 10090 BTO:0000165 12887892 t gcesareni "Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation" SIGNOR-241963 SIRT1 protein Q96EB6 UNIPROT NCOR1 protein O75376 UNIPROT up-regulates 9606 22395773 t FFerrentino "In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription." SIGNOR-253505 SIRT1 protein Q96EB6 UNIPROT NCOR2 protein Q9Y618 UNIPROT up-regulates 9606 22395773 t FFerrentino "In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription." SIGNOR-253506 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 SIRT1 protein Q96EB6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates deacetylation 9606 22223095 t gcesareni "The acetylation marks on notch1-icd are removed by the deacetylase sirt1, suggesting that both deacetylation of notch1-icd and of histones inhibit notch signaling." SIGNOR-195333 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 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" deacetylation 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-209962 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys64 RAGCCLGkAVRGAKG 9606 BTO:0000671 17098745 t gcesareni "Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells." SIGNOR-150595 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys70 GKAVRGAkGHHHPHP 9606 BTO:0000671 17098745 t gcesareni "Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells." SIGNOR-150599 SIRT1 protein Q96EB6 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20089851 f Regulation miannu "SIRT1 deacetylates and activates the FOXOs under oxidative stress, thereby inducing Mn-SOD expression" SIGNOR-251763 SIRT1 protein Q96EB6 UNIPROT TP53 protein P04637 UNIPROT down-regulates deacetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0000150 19047049 t gcesareni "Sirt1 has been shown to regulate cell fate in part by deacetylating the p53 protein at lysine 382 and inhibiting p53-mediated transcriptional activation and apoptosis." SIGNOR-182515 SIRT1 protein Q96EB6 UNIPROT XBP1 protein P17861-2 UNIPROT "down-regulates activity" deacetylation 9606 BTO:0000007 20955178 t miannu "P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR." SIGNOR-260430 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT "up-regulates activity" deacetylation Lys63;lys67;K215 "TGGMANVkAAPKIID;ANVKAAPkIIDTGGG; QENREKMkQKKFDKK" 9606 BTO:0002806 30327428 t "SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR" SIGNOR-258986 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 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 SIRT2 protein Q8IXJ6 UNIPROT MYCN protein P04198 UNIPROT "up-regulates quantity by stabilization" 9606 23175188 f miannu "Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation." SIGNOR-255147 SIRT2 protein Q8IXJ6 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" 9606 23175188 f miannu "Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation." SIGNOR-255148 SIRT2 protein Q8IXJ6 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates deacetylation 9606 BTO:0000887;BTO:0001103 12887892 t gcesareni "Sir2-mediated deacetylation of myod can be expected to inhibit its transcriptional capabilities." SIGNOR-104251 SIRT2 protein Q8IXJ6 UNIPROT NEDD4 protein P46934 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23175188 f miannu "SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16." SIGNOR-255144 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 SIRT5 protein Q9NXA8 UNIPROT ACOX1 protein Q15067 UNIPROT "down-regulates activity" "catalytic activity" 9606 BTO:0000007 29491006 t Monia "SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation." SIGNOR-261210 SIRT6 protein Q8N6T7 UNIPROT TNF protein P01375 UNIPROT up-regulates deacetylation Lys19 LAEEALPkKTGGPQG 9606 23552949 t gcesareni "Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine" SIGNOR-201658 SIRT6 protein Q8N6T7 UNIPROT TNF protein P01375 UNIPROT up-regulates deacetylation Lys20 AEEALPKkTGGPQGS 9606 23552949 t gcesareni "Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine" SIGNOR-201662 SIRT7 protein Q9NRC8 UNIPROT SAR1A protein Q9NR31 UNIPROT "up-regulates activity" deacetylation 9606 BTO:0002181 28790157 t SARA "SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding" SIGNOR-260978 SIRT7 protein Q9NRC8 UNIPROT TP53 protein P04637 UNIPROT down-regulates deacetylation 9606 18239138 t gcesareni "We found that sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo." SIGNOR-160539 sitaxentan chemical CHEBI:135736 ChEBI EDNRA protein P25101 UNIPROT "down-regulates activity" "chemical inhibition" -1 9171878 t miannu "Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist.The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a Ki of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.686 nM and a pA2 of 8.0." SIGNOR-258610 SIX4 protein Q9UIU6 UNIPROT UBA52 protein P62987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 9826681 f gcesareni "We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4." SIGNOR-62178 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 12419246 t lperfetto "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7" SIGNOR-217703 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 22298955 t lperfetto "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7" SIGNOR-217709 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 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 SKIL protein P12757 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-236099 SKIL protein P12757 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 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-253302 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 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 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-71633 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 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-236152 SKIL protein P12757 UNIPROT SMAD5 protein Q99717 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 smad8." SIGNOR-95474 SKI protein P12755 UNIPROT EP300 protein Q09472 UNIPROT down-regulates binding 9606 SIGNOR-C6 10575014 t gcesareni "Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling." SIGNOR-72664 SKI protein P12755 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 12419246 t gcesareni "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad5." SIGNOR-195630 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 10575014 t lperfetto "Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling." SIGNOR-217658 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 SKI protein P12755 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 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-253300 SKI protein P12755 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 10575014 t lperfetto "Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling." SIGNOR-232123 SKI protein P12755 UNIPROT SMAD3 protein P84022 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-236077 SKI protein P12755 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-253301 SKI protein P12755 UNIPROT SMAD4 protein Q13485 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-236074 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 SKOR1 protein P84550 UNIPROT LBX1 protein P52954 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15528197 t llicata "Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord." SIGNOR-238004 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 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 SKP2 protein Q13309 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates ubiquitination 9606 15998794 t gcesareni "Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase." SIGNOR-138490 SKP2 protein Q13309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 15998794 t gcesareni "Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3)." SIGNOR-138493 SKP2 protein Q13309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 17409098 t gcesareni "Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3)." SIGNOR-154194 SKP2 protein Q13309 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27858941 t miannu "DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1" SIGNOR-254775 SKP2 protein Q13309 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity" ubiquitination 9606 SIGNOR-C136 20852628 t gcesareni "The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain" SIGNOR-243548 SKP2 protein Q13309 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-243560 SKP2 protein Q13309 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 15314162 t gcesareni "We found that skp2, the f-box component of scfskp2, physically interacted with smad4 at the physiological levels. Several cancer-derived unstable mutants exhibited significantly increased binding to skp2, which led to their increased ubiquitination and accelerated proteolysis. These results suggest an important role for the scfskp2 complex in switching cancer mutants of smad4 to undergo polyubiquitination-dependent degradation." SIGNOR-127964 SL-327 chemical CHEBI:92211 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-104930 SL-327 chemical CHEBI:92211 ChEBI MAP2K5 protein Q13163 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-104933 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 SL-327 chemical CHEBI:92211 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 BTO:0000938 BTO:0000142 11160424 t lperfetto "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity" SIGNOR-244955 SLA2 protein Q9H6Q3 UNIPROT FLT3 protein P36888 UNIPROT "down-regulates activity" binding 10090 BTO:0000740 27458164 t miannu "We screened a panel of SH2 domain-containing proteins and identified SLAP2 as a potent interacting partner of FLT3. We demonstrated that interaction occurs when FLT3 is activated, and also, an intact SH2 domain of SLAP2 is required for binding. Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5." SIGNOR-256155 SLC11A1 protein P49279 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 BTO:0000801 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 SLC16A3 protein O15427 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 f lperfetto "Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival." SIGNOR-256581 SLC16A4 protein O15374 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 f lperfetto "Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival." SIGNOR-242519 SLC30A9 protein Q6PML9 UNIPROT NUMB protein P49757 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 11782429 t lperfetto "Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation." SIGNOR-113704 SLC34A2 protein O95436 UNIPROT EGF protein P01133 UNIPROT down-regulates 9606 BTO:0000195 BTO:0000763 11171583 f miannu "In vivo and in vitro studies showed that egf treatment decreased intestinal napi-iib mrna abundance by _50%, suggesting possible transcriptional regulation." SIGNOR-105161 SLC38A9 protein Q8NBW4 UNIPROT L-leucine chemical CHEBI:15603 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000007 29053970 t "SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins" SIGNOR-255313 SLC38A9 protein Q8NBW4 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 BTO:0000007 29053970 f "Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters." SIGNOR-255311 SLC44A2 protein Q8IWA5 UNIPROT choline smallmolecule CHEBI:15354 ChEBI "up-regulates activity" relocalization 9606 BTO:0003065 21367571 f lperfetto "Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it" SIGNOR-260409 SLC44A2 protein Q8IWA5 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 BTO:0000007 12761501 f Giorgia "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways" SIGNOR-260390 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 SLIT1 protein O75093 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 t gcesareni "Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis." SIGNOR-68327 SLIT1 protein O75093 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding 9606 16226035 t gcesareni "Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit." SIGNOR-141111 SLIT2 protein O94813 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 t gcesareni "Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis." SIGNOR-68428 SLIT2 protein O94813 UNIPROT ROBO4 protein Q8WZ75 UNIPROT up-regulates binding 9606 BTO:0000938 12941633 t gcesareni "We show that robo4 binds slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known robo receptors in the nervous system." SIGNOR-86380 SLK protein Q9H2G2 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates phosphorylation 9606 BTO:0000671 16316999 t gcesareni "Induction of apoptosis by the ste20-like kinase slk, a germinal center kinase that activates apoptosis signal-regulating kinase and p38" SIGNOR-142665 SLRP proteinfamily SIGNOR-PF31 SIGNOR ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 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 SLX4 protein Q8IY92 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR up-regulates binding 9606 24726326 t lperfetto "Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair." SIGNOR-217652 A-966492 chemical CID:16666333 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-203622 SLX4 protein Q8IY92 UNIPROT ERCC4 protein Q92889 UNIPROT up-regulates binding 9606 SIGNOR-C50 24726326 t miannu "Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair." SIGNOR-204890 SMAD1/4 complex SIGNOR-C85 SIGNOR BMP4 protein P12644 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 19896409 f lperfetto "BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others." SIGNOR-248842 SMAD1/4 complex SIGNOR-C85 SIGNOR BMP7 protein P18075 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 19896409 f lperfetto "BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others." SIGNOR-248843 SMAD1/4 complex SIGNOR-C85 SIGNOR CEBPB protein P17676 UNIPROT "up-regulates activity" binding 9606 18854943 t 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-253552 SMAD1/4 complex SIGNOR-C85 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-255789 SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD1/5/8/SMAD4 complex SIGNOR-C215 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-255838 SMAD1/5/8/SMAD4 complex SIGNOR-C215 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-255837 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 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 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 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 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates "transcriptional regulation" 9606 27563484 f ggiuliani "Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression." SIGNOR-255836 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 SMAD1 protein Q15797 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 BTO:0000007 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 SMAD1 protein Q15797 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004058 12589053 f lperfetto "Overexpression of smad6, a natural antagonist for smad1, blocked ppargamma expression and adipocytic differentiation induced by bmp2" SIGNOR-236227 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 SMAD1 protein Q15797 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "form complex" binding 9606 8893010 t ggiuliani "Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta." SIGNOR-255774 SMAD1 protein Q15797 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "form complex" binding 9606 9436979 t lperfetto "Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription." SIGNOR-103615 SMAD1 protein Q15797 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C85 21454478 t lperfetto "Upon ligand binding, the specific heteromeric transmembrane serine/threonine kinase receptor complexes undergo phosphorylation/activation and subsequently phosphorylate the two ser residues in the c-terminal sxs motif of specific r-smads, smad1/5/8 for bmp pathway and smad2/3 for tgf-_/activin signaling. The activated r-smads then associate with co-smad, smad4. The heteromeric complexes translocate into the nucleus, where they bind to dna directly or indirectly to regulate the transcription of specific genes." SIGNOR-172990 SMAD1 protein Q15797 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C85 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(co-Smad; Smad4 in mammals) and shuttle into the nucleus." SIGNOR-168734 SMAD2 protein Q15796 UNIPROT CREB1 protein P16220 UNIPROT up-regulates binding 9606 SIGNOR-C8 9689110 t gcesareni "We demonstrate that human smad2 and smad4, two essential smad proteins involved in mediating tgf-beta transcriptional responses in endothelial and other cell types, can functionally interact with the transcriptional coactivator creb binding protein (cbp). This interaction is specific in that it requires ligand (tgf-beta) activation and is mediated by the transcriptional activation domains of the smad proteins." SIGNOR-59462 SMAD2 protein Q15796 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-78988 SMAD2 protein Q15796 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 10090 BTO:0000165 BTO:0001760 SIGNOR-C8 11160896 t lperfetto "Our studies indicate that smad2 and 4 (smad2/4) complexes cooperate with mef2 regulatory proteins in a gal4-based one-hybrid reporter gene assay." SIGNOR-235846 SMAD2 protein Q15796 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" binding 9606 9670020 t lperfetto "Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4" SIGNOR-232149 SMAD2 protein Q15796 UNIPROT SMAD2/SMURF2 complex SIGNOR-C11 SIGNOR "form complex" binding 9606 11389444 t gcesareni "We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases." SIGNOR-108487 SMAD2 protein Q15796 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "up-regulates activity" binding 9606 11389444 t lperfetto "We show that in the presence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases.Thus, stimulation by TGF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation." SIGNOR-108490 SMAD2/SMAD4 complex SIGNOR-C8 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-256180 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000552 11013220 f irozzo "Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β." SIGNOR-256287 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 f "The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines" SIGNOR-253588 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 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-249550 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000552 11689553 f irozzo "To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity." SIGNOR-256291 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 19279133 t flangone "Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs." SIGNOR-242049 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002861 18682241 t flangone "We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity." SIGNOR-242044 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 BTO:0000552 11013220 t irozzo "TGF-β induces the formation and nuclear translocation of a trimeric Smad complex, which in this case is likely to consist of one monomer each of Smad2, Smad3 and Smad4. Smad2 and Smad4 associate directly with Sp1 and co-activate the transcriptional activity of Sp1." SIGNOR-256288 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR IL17A protein Q16552 UNIPROT up-regulates "transcriptional regulation" 9606 26194464 t "MARCO ROSINA" "Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes." SIGNOR-255027 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR RORC protein P51449 UNIPROT up-regulates 9606 26194464 t "MARCO ROSINA" "Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes." SIGNOR-255026 SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR STAT3 protein P40763 UNIPROT down-regulates 9606 26194464 t mrosina "In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation" SIGNOR-255036 SMAD3 protein P84022 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 "BTO:0000972; BTO:0003477" 16766264 f irozzo "This protection is conferred by Smad3’s ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter." SIGNOR-256294 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 SMAD3 protein P84022 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 23032366 f lperfetto "PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A." SIGNOR-245441 SMAD3 protein P84022 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates activity" binding 10090 12524424 t gcesareni "Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters" SIGNOR-241924 SMAD3 protein P84022 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates activity" binding 10090 12524424 t gcesareni "Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters" SIGNOR-250567 SMAD3 protein P84022 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu "Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis." SIGNOR-260432 SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 15367216 t "The TCR, IL-2R, and TbetaR must all be stimulated to induce Foxp3 + Tregs. Failure to engage any one of these receptors prevents the generation of Foxp3 + Tregs" SIGNOR-254363 SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 19701891 t "TGF-beta1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-beta1-induced-Treg generation from Smad3(-/-) mice is markedly reduced and abolished by inactivating Smad2" SIGNOR-254362 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 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11689553 t lperfetto "Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter." SIGNOR-251494 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 14993291 f gcesareni "Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes" SIGNOR-123087 SMAD3 protein P84022 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" binding 10090 BTO:0000165 11711431 t azuccotti "We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors." SIGNOR-252071 SMAD3 protein P84022 UNIPROT NKX2-1 protein P43699 UNIPROT "down-regulates activity" binding 9606 BTO:0004299 18003659 t 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. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function." SIGNOR-254169 SMAD3 protein P84022 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 14638857 t gcesareni "Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd" SIGNOR-119374 SMAD3 protein P84022 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 14638857 t gcesareni "Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd" SIGNOR-254325 SMAD3 protein P84022 UNIPROT PAX6 protein P26367 UNIPROT "down-regulates activity" binding 9606 BTO:0001874 17251190 t Regulation miannu "The paired domain of Pax6 interacts with the MH1 domain of Smad3. Smad3 prevents Pax6 paired domain from binding DNA" SIGNOR-251875 SMAD3 protein P84022 UNIPROT PAX8 protein Q06710 UNIPROT "down-regulates activity" binding 9606 14623893 t miannu "DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3." SIGNOR-251992 SMAD3 protein P84022 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 11331591 t lperfetto "Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence." SIGNOR-235902 SMAD3 protein P84022 UNIPROT SMAD3/JUN complex SIGNOR-C86 SIGNOR "form complex" binding 9606 9732876 t gcesareni "These results show a ligand-dependent association of smad3 with c-jun" SIGNOR-59873 SMAD3 protein P84022 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR "form complex" binding 9606 26194464 t mrosina "In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation" SIGNOR-255034 SMAD3 protein P84022 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 9670020 t lperfetto "Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4" SIGNOR-217227 SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "form complex" binding 9606 9843571 t lperfetto "TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus." SIGNOR-229557 SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT "up-regulates activity" binding 9606 9843571 t gcesareni "TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus." SIGNOR-235168 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR BCL2L11 protein O43521 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000972 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000552 11013220 f irozzo "Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β." SIGNOR-256286 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPA protein P49715 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-250571 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPB protein P17676 UNIPROT "down-regulates activity" "transcriptional regulation" 9606 17139329 t fferrentino "Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter" SIGNOR-253538 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPD protein P49716 UNIPROT down-regulates binding 9606 12524424 t fspada "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-97120 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 t miannu "Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes" SIGNOR-260441 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 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" binding 9606 9732876 t lperfetto "Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos" SIGNOR-229545 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR LEF1 protein Q9UJU2 UNIPROT up-regulates "transcriptional regulation" 9606 10890911 f lperfetto "Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity" SIGNOR-217169 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 f "The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines" SIGNOR-253587 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000552 11689553 f irozzo "To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity." SIGNOR-256290 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT "down-regulates activity" "transcriptional regulation" 9606 12244043 f 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-254987 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 19279133 t flangone "Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs." SIGNOR-242055 cabozantinib chemical CHEBI:72317 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207845 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR SERPINE1 protein P05121 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9606191 f lperfetto "Here we report the identification of smad3/smad4 binding sequences, termed caga boxes, within the promoter of the human pai-1 gene." SIGNOR-57776 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 12244043 f azuccotti "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-254989 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 SMAD4 protein Q13485 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11689553 t lperfetto "Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter." SIGNOR-251493 SMAD4 protein Q13485 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "form complex" binding 9606 9436979 t lperfetto "Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription." SIGNOR-103618 SMAD4 protein Q13485 UNIPROT SMAD1/5/8/SMAD4 complex SIGNOR-C215 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-255832 SMAD4 protein Q13485 UNIPROT SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR "form complex" binding 9606 9436979 t lperfetto "Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription." SIGNOR-255833 SMAD4 protein Q13485 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "form complex" binding 9606 9843571 t lperfetto "TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus." SIGNOR-229560 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 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 SMAD4 protein Q13485 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 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-255269 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 SMAD5 protein Q99717 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-168737 SMAD5 protein Q99717 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-255266 SMAD5 protein Q99717 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR "form complex" binding 9606 "BTO:0000165;BTO:0002974; BTO:0002809" 9442019 t ggiuliani "These data suggest that activation of Smad5 and subsequent Smad5-DPC4 complex formation are key steps in the BMP signaling pathway, which mediates BMP-2-induced osteoblastic differentiation of the C2C12 mesenchymal cells." SIGNOR-255775 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 SMAD5/SMAD4 complex SIGNOR-C205 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-255783 SMAD6 protein O43541 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates 10090 BTO:0000165 10564272 f gcesareni "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-236861 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 SMAD6 protein O43541 UNIPROT MAP3K7 protein O43318 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11737269 t lperfetto "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-235571 SMAD6 protein O43541 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" binding 9606 22298955 t "Create a non-functional complex with smad4 and competes with R-smad." lperfetto "On the other hand, Smad6 competes with R-Smad and forms a non-functional complex with Smad4, which will inhibit BMP signaling in bone formation. Smad6 is involved in a negative feedback loop regulating BMP signaling and is required to limit BMP signaling during endochondral bone formation." SIGNOR-195648 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 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 SMAD7 protein O15105 UNIPROT ACVRL1 protein P37023 UNIPROT down-regulates 9606 BTO:0000975 12023024 f gcesareni "Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs." SIGNOR-87673 SMAD7 protein O15105 UNIPROT BMPR1B protein O00238 UNIPROT down-regulates 10090 BTO:0000165 10564272 f gcesareni "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-236864 SMAD7 protein O15105 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0001130 15684397 f gcesareni "In the current study, our data indicate that both smad7 and p38 map kinase positively contributed to the accumulation of -catenin" SIGNOR-133447 SMAD7 protein O15105 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 9606 30017632 f miannu "Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis." SIGNOR-260433 SMAD7 protein O15105 UNIPROT MAP3K1 protein Q13233 UNIPROT down-regulates 9606 10085121 f lperfetto "Overexpression of smad7 can inhibit the mekk-1-mediated stimulation of smad2 transcriptional activity" SIGNOR-65572 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 SMAD7 protein O15105 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates binding 9606 14718519 t lpetrilli "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 t?RI." SIGNOR-121280 SMAD7 protein O15105 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates 9606 17438144 f gcesareni "Smad7 repressed smad3/4-, smad2/4-, and smad1/4-enhanced reporter gene expression." SIGNOR-154390 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3." SIGNOR-64085 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates quantity" "transcriptional repression" 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 SMAD7 protein O15105 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-199970 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT "up-regulates activity" relocalization 9606 19352540 t lperfetto "Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway." SIGNOR-185131 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 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "up-regulates activity" relocalization 9606 11163210 t lperfetto "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-104996 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "up-regulates activity" relocalization 9606 19352540 t lperfetto "Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway." SIGNOR-168450 SMAD7 protein O15105 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-112645 SMAD7 protein O15105 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates binding 9606 BTO:0001253 17384642 t lperfetto "The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling" SIGNOR-153917 SMAD7 protein O15105 UNIPROT TAB3 protein Q8N5C8 UNIPROT up-regulates binding 9606 BTO:0001253 17384642 t gcesareni "The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling." SIGNOR-153920 SMAD7 protein O15105 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-167163 Bafetinib chemical CID:24853523 PUBCHEM LYN protein P07948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190227 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 30017632 t miannu "Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. Smad7 can use both surfaces in its interaction with the ALK-2, -3, and -4 receptors, but only the basic groove is used in the interaction between Smad7 and the TGF-β type I receptor (TβRI, also known as ALK-5)." SIGNOR-260438 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "SMAD7 functions as an antagonist to TGFB by binding to the TBRI and thus inhibiting activation of SMAD2 and SMAD3." SIGNOR-64088 SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates "transcriptional regulation" 9606 27563484 f ggiuliani "Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression." SIGNOR-255784 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 SMAD9 protein O15198 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR "form complex" binding 10116 9371779 t ggiuliani "As shown in Fig. 2, immunoprecipitation of Smad8 with an anti-myc antibody could bring down the Flag-tagged Smad4 only in the presence of CA-ALK-2, indicating that only activation of ALK-2 but not ALK-4 could induce the heteromerization of Smad8 with Smad4." SIGNOR-255776 SMAD9 protein O15198 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 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-255268 SMARCA2 protein P51531 UNIPROT SMARCC1 protein Q92922 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-65432 SMARCA2 protein P51531 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-65435 SMARCA4 protein P51532 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000797 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 SMARCA4 protein P51532 UNIPROT SMARCC1 protein Q92922 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-65441 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 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 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 SMARCA4 protein P51532 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates binding 9606 20418909 t miannu "Zeb1 represses e-cadherin transcription / we reported that brg1 binds to the ntr of zeb1 acting as its co-repressor in the regulation of the e-cadherin promoter." SIGNOR-165017 SMARCAD1 protein Q9H4L7 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" binding 9606 21549307 t 1 miannu "SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin" SIGNOR-239835 SMARCAD1 protein Q9H4L7 UNIPROT TRIM28 protein Q13263 UNIPROT "up-regulates activity" binding 9606 21549307 t 1 miannu "SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin" SIGNOR-239838 SMARCB1 protein Q12824 UNIPROT CCNA1 protein P78396 UNIPROT down-regulates 9606 12226744 f miannu "We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6." SIGNOR-92779 SMARCB1 protein Q12824 UNIPROT CSF1 protein P09603 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 16267391 f miannu "Ini1/hsnf5/baf47 is involved in activation of the csf1 promoter." SIGNOR-141047 SMARCB1 protein Q12824 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates 9606 12226744 f miannu "We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6." SIGNOR-92788 SMARCB1 protein Q12824 UNIPROT SMARCA2 protein P51531 UNIPROT "up-regulates activity" 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-65181 SMARCB1 protein Q12824 UNIPROT SMARCA4 protein P51532 UNIPROT "up-regulates activity" 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-65438 SMARCB1 protein Q12824 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-132930 SMARCC1 protein Q92922 UNIPROT SMARCE1 protein Q969G3 UNIPROT "up-regulates quantity by stabilization" 9606 20829358 f miannu "We show that the mechanism of baf155-mediated stabilization of baf57 involves blocking its ubiquitination by preventing interaction with trip12, an e3 ubiquitin ligase." SIGNOR-167869 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 SMARCC2 protein Q8TAQ2 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-132936 SMARCD1 protein Q96GM5 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-132939 SMARCD3 protein Q6STE5 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding -1 22068056 t lperfetto "We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes." SIGNOR-238289 SMARCD3 protein Q6STE5 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f lperfetto "We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indire" SIGNOR-136945 SMARCE1 protein Q969G3 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-132942 SMC3 protein Q9UQE7 UNIPROT MXD1 protein Q05195 UNIPROT "down-regulates activity" binding 9534 BTO:0000318 9528857 t 2 miannu "We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions." SIGNOR-241278 SMC3 protein Q9UQE7 UNIPROT MXD3 protein Q9BW11 UNIPROT "down-regulates activity" binding 9534 BTO:0000318 9528857 t 2 miannu "We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions." SIGNOR-241281 SMC3 protein Q9UQE7 UNIPROT MXD4 protein Q14582 UNIPROT "down-regulates activity" binding 9534 BTO:0000318 9528857 t 2 miannu "We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions." SIGNOR-241284 SMC3 protein Q9UQE7 UNIPROT MXI1 protein P50539 UNIPROT "down-regulates activity" binding 9534 BTO:0000318 9528857 t 2 miannu "We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions." SIGNOR-241223 SMCR8 protein Q8TEV9 UNIPROT WIPI2 protein Q9Y4P8 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0000007 28169830 t "Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2" SIGNOR-252028 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 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Ser1089 GLSQPELsQDSYLGD 9606 23356578 t lperfetto "Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively" SIGNOR-200785 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Ser1107 SQIDVALsQDSTYQG 9606 23356578 t lperfetto "Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively" SIGNOR-200789 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Thr28 AELLGADtQGSEFEF 9606 23356578 t lperfetto "Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively" SIGNOR-200793 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 "SMN complex" complex SIGNOR-C158 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 BTO:0000567 9323129 f lperfetto "These findings suggest a role for SMN and SIP1 in spliceosomal snRNP biogenesis and function and provide a likely molecular mechanism for the cause of SMA" SIGNOR-253123 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 SMOC1 protein Q9H4F8 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-260400 SMOC1 protein Q9H4F8 UNIPROT COL1A1 protein P02452 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-260402 SMOC1 protein Q9H4F8 UNIPROT COL1A2 protein P08123 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-260404 SMOC1 protein Q9H4F8 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 SMOC1 protein Q9H4F8 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 SMO protein Q99835 UNIPROT ARRB1 protein P49407 UNIPROT up-regulates binding 9606 15618519 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-132678 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 SMO protein Q99835 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates binding 9606 15618519 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-132759 SMO protein Q99835 UNIPROT ARRB2 protein P32121 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-199153 SMO protein Q99835 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 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." SIGNOR-148484 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 SMO protein Q99835 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 9606 23074268 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-199156 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 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 SMO protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 16885213 t lperfetto "Using this assay we determined that mouse Smo couples to all members of the Gi family but does not couple to those of other G protein families." SIGNOR-148490 SMO protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT "up-regulates activity" binding 9606 23074268 t lperfetto "it was proposed that Smo might signal through activation of Gi proteins to reduce PKA activity." SIGNOR-199162 SMO protein Q99835 UNIPROT GNAI3 protein P08754 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-148493 SMO protein Q99835 UNIPROT GNAI3 protein P08754 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-199165 SMO protein Q99835 UNIPROT GNAT1 protein P11488 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-148496 SMO protein Q99835 UNIPROT GNAT1 protein P11488 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-199168 SMO protein Q99835 UNIPROT GNAT2 protein P19087 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-148534 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 SMO protein Q99835 UNIPROT GNB1 protein P62873 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-148537 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 SMO protein Q99835 UNIPROT GNB2 protein P62879 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-148589 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 SMO protein Q99835 UNIPROT GNB3 protein P16520 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 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-148592 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 SMO protein Q99835 UNIPROT GNB3 protein P16520 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 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-199180 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 SMO protein Q99835 UNIPROT GNG2 protein P59768 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-148595 SMO protein Q99835 UNIPROT GNG2 protein P59768 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-199183 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 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 SMO protein Q99835 UNIPROT GNGT1 protein P63211 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-148601 SMO protein Q99835 UNIPROT GPR161 protein Q8N6U8 UNIPROT "down-regulates activity" relocalization 10090 BTO:0000944 23332756 f "Constitutive Gpr161 activity increases cAMP levels, which is reduced upon knockdown of Gαs, suggesting it to be a Gαs-coupled receptor." SIGNOR-259937 SMO protein Q99835 UNIPROT KIF7 protein Q2M1P5 UNIPROT "up-regulates activity" relocalization 10090 19666503 t lperfetto "Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins." SIGNOR-209605 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 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 SMO protein Q99835 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates binding 9606 BTO:0000785 23074268 t gcesareni "This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1" SIGNOR-199192 SMO protein Q99835 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 20654717 t gcesareni "This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1" SIGNOR-167070 SMO protein Q99835 UNIPROT TIMP3 protein P35625 UNIPROT "up-regulates quantity" "transcriptional activation" 10090 BTO:0005300 28709001 f "We identified that ciliary Hh signaling in FAPs regulates expression of Timp3. Future experiments will determine whether Timp3 is a direct or indirect target of Hh signaling." SIGNOR-255907 SMURF1 protein Q9HCE7 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 17317136 t 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-153399 SMURF1 protein Q9HCE7 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 degradation of smads and receptors for tgf-beta and bmps." SIGNOR-195651 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 17317136 t 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-153402 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t 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-195654 SMURF1 protein Q9HCE7 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27858941 t miannu "DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1" SIGNOR-254776 SMURF1 protein Q9HCE7 UNIPROT PARD6/SMURF1 complex SIGNOR-C112 SIGNOR "form complex" binding 9606 BTO:0004183 15761148 t lperfetto "The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT." SIGNOR-227562 SMURF1 protein Q9HCE7 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates activity" ubiquitination 9606 14701828 t lperfetto "Recently we have found that smurf1 mediates the protein degradation of the osteoblast-specific transcription factor runx2/cbfa1." SIGNOR-95233 SMURF1 protein Q9HCE7 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0004325 12738770 t lperfetto "Smurf1 interacts directly with Cbfa1 and mediates Cbfa1 degradation in a ubiquitin- and proteasome-dependent manner." SIGNOR-236083 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 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 SMURF1 protein Q9HCE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t "Ubiquitin-mediated proteolysis." 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-195663 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 SMURF1 protein Q9HCE7 UNIPROT SMAD7 protein O15105 UNIPROT "down-regulates activity" ubiquitination 9606 12519765 t lperfetto "Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm" SIGNOR-97064 SMURF1 protein Q9HCE7 UNIPROT SMAD9 protein O15198 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-195669 SMURF1 protein Q9HCE7 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" ubiquitination 9606 17317136 t lperfetto "Recruitment of WW and HECT domain E3-ubiquitin ligases Smurf1 and 2 to induce type I receptor ubiquitination and subsequent receptor degradation;" SIGNOR-153414 SMURF1 protein Q9HCE7 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates activity" ubiquitination 9606 22298955 t lperfetto "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-195672 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 SMURF2 protein Q9HAU4 UNIPROT BMPR2 protein Q13873 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-193119 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 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-153417 SMURF2 protein Q9HAU4 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0000007 11016919 t lperfetto "The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway." SIGNOR-236133 SMURF2 protein Q9HAU4 UNIPROT SMAD2/SMURF2 complex SIGNOR-C11 SIGNOR "form complex" binding 9606 11389444 t gcesareni "We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases." SIGNOR-108496 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto "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-153420 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 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-193378 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 SMURF2 protein Q9HAU4 UNIPROT SMAD9 protein O15198 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-193390 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" ubiquitination 9606 11163210 t lperfetto "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-104999 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" ubiquitination 9606 17317136 t lperfetto "Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation;" SIGNOR-153423 SMURF2 protein Q9HAU4 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates activity" ubiquitination 9606 22298955 t lperfetto "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-195681 SMURF proteinfamily SIGNOR-PF29 SIGNOR SKIL protein P12757 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0002181;BTO:0005493 11389444 t lperfetto "Tgf-beta also induces the association of smurf2 with the transcriptional co-repressor snon and we show that smad2 can function to mediate this interaction. This allows smurf2 hect domain to target snon for ubiquitin-mediated degradation by the proteasome." SIGNOR-253262 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD2 protein Q15796 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0000007 11016919 t lperfetto "The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway." SIGNOR-253263 SMURF proteinfamily SIGNOR-PF29 SIGNOR 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-253259 SMURF proteinfamily SIGNOR-PF29 SIGNOR 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-253261 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD7 protein O15105 UNIPROT "down-regulates activity" ubiquitination 9606 12519765 t lperfetto "Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm" SIGNOR-253260 SMURF proteinfamily SIGNOR-PF29 SIGNOR TGFBR1 protein P36897 UNIPROT "down-regulates activity" ubiquitination 9606 17317136 t lperfetto "Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation" SIGNOR-253264 SMURF proteinfamily SIGNOR-PF29 SIGNOR TGFBR2 protein P37173 UNIPROT "down-regulates activity" ubiquitination 9606 22298955 t lperfetto "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-253265 SNAI1 protein O95863 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255156 SNAI1 protein O95863 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 19055748 f lperfetto "Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status." SIGNOR-252260 SNAI1 protein O95863 UNIPROT CLDN7 protein O95471 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 19277896 f lperfetto "We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling" SIGNOR-254104 SNAI1 protein O95863 UNIPROT CTBP1 protein Q13363 UNIPROT "up-regulates activity" 9606 BTO:0001570 19277896 f lperfetto "We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling" SIGNOR-254103 SNAI1 protein O95863 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 19055748 f lperfetto "Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status." SIGNOR-252259 SNAI1 protein O95863 UNIPROT SERPINE1 protein P05121 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-252262 SNAI1 protein O95863 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-254526 SNAI2 protein O43623 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 21044962 f miannu "knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene." SIGNOR-255176 SNAI2 protein O43623 UNIPROT CD44 protein P16070 UNIPROT "up-regulates quantity by expression" "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-255153 SNAI2 protein O43623 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255155 SNAI2 protein O43623 UNIPROT CXCL12 protein P48061 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-255169 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 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 SNAI2 protein O43623 UNIPROT HPGD protein P15428 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004078 17575121 f miannu "the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription." SIGNOR-255172 SNAI2 protein O43623 UNIPROT JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "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-255151 SNAI2 protein O43623 UNIPROT MMP9 protein P14780 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. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression." SIGNOR-255170 SNAI2 protein O43623 UNIPROT UBE2D3 protein P61077 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 21044962 f miannu "knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene." SIGNOR-255173 SNAI2 protein O43623 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-255177 SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR FN1 protein P02751 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000452;BTO:0002625 22223884 f alessandro "Taken together, our results indicate that Snail1, p65NF-κB and PARP1 interact to activate the expression of fibronectin and other ECM genes involved in cell movement. This mechanism is functional not only in epithelial cells undergoing EMT but also in fibroblasts." SIGNOR-254529 SNAPIN protein O95295 UNIPROT SNAP25 protein P60880 UNIPROT "up-regulates activity" binding 9606 BTO:0000793 18167355 t miannu "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-261171 SND1 protein Q7KZF4 UNIPROT MGLL protein Q99685 UNIPROT "down-regulates quantity by destabilization" binding 9606 26997225 t irozzo "Interaction of SND1 with MGLL resulted in ubiquitination and proteosomal degradation of MGLL. We demonstrate that interaction of SND1 with MGLL results in increased ubiquitination and subsequent proteosomal degradation of MGLL. This down-regulation of MGLL is required for SND1 to exert its pro-tumorigenic activity because forced overexpression of MGLL markedly abrogates cell proliferation." SIGNOR-259138 SND1 protein Q7KZF4 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" binding -1 12234934 t irozzo "STAT6 interacted with p100 in vitro and in vivo. Here, we show that the TAD of STAT6 is interacting with p100. p100 was found to enhance the STAT6-mediated transcription [.]." SIGNOR-259134 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 SNIP1 protein Q8TAD8 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates binding 9606 SIGNOR-C6 10887155 t gcesareni "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-78984 "SNS-314 Mesylate" chemical CID:24995523 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207099 "SNS-314 Mesylate" chemical CID:24995523 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207102 "SNS-314 Mesylate" chemical CID:24995523 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207105 SNTA1 protein Q13424 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-255991 SNTA1 protein Q13424 UNIPROT NOS1 protein P29475 UNIPROT up-regulates relocalization 9606 BTO:0001103 12456711 t gcesareni "biochemical studies showed that the N-terminal PDZ domain of nNOS binds to a similar PDZ domain of syntrophin (Fig. 1), a dystrophin-associated protein" SIGNOR-236916 SNTB1 protein Q13884 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-255992 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 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 SNTB1 protein Q13884 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates binding 10090 BTO:0002314 BTO:0001103 29681515 t apalma "Basal localization of the p38g/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through b1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38g/b1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation" SIGNOR-255901 SNTB2 protein Q13425 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-255993 SNTG2 protein Q9NY99 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-255995 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 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 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11404076 t gcesareni "We find that Notch 3 IC, like Notch 1 IC, can bind the SKIP and PCAF proteins" SIGNOR-108499 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 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-75788 SNX9 protein Q9Y5X1 UNIPROT DNM1 protein Q05193 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-133892 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 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 SNX9 protein Q9Y5X1 UNIPROT EGFR protein P00533 UNIPROT down-regulates 9606 16316319 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-142566 SOCS1 protein O15524 UNIPROT IFNG protein P01579 UNIPROT down-regulates 9606 BTO:0000801 21628332 f lperfetto "SOCS1 inhibits macrophage responses to IFN-g, and SOCS1-deficient mice develop symptoms of severe systemic autoimmune and inflammatory disease." SIGNOR-249571 SOCS1 protein O15524 UNIPROT IFNGR1 protein P15260 UNIPROT down-regulates binding 9606 18708154 t gcesareni "Suppressor of cytokine signaling (socs)-1, the key negative regulator of interferon (ifn)-gamma-dependent signaling, is induced in response to ifngamma. Socs-1 binds to and inhibits the ifngamma receptor-associated kinase janus-activated kinase (jak) 2 and inhibits its function in vitrothe binding of socs-1 to tyr441 also blocks the access of stat1 to tyr419 and that this effect may be the principal mechanism of inhibition of downstream signaling" SIGNOR-180140 SOCS1 protein O15524 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates binding 9606 BTO:0000801 12433373 t flangone "Coimmunoprecipitation analyses demonstrated association of socs-1 with irak...This Finding suggests that socs-1 might suppress myd88-dependent signal pathways at least by binding to irak" SIGNOR-95528 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 BTO:0000782 11133764 t gcesareni "Jab/socs1/ssi-1 is an il-2 induced inhibitor of il-2 signaling that functions by inhibiting jak kinase activity" SIGNOR-85352 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 t milica "Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna." SIGNOR-202042 SOCS1 protein O15524 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 14522994 t lperfetto "Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor" SIGNOR-118407 SOCS1 protein O15524 UNIPROT JAK3 protein P52333 UNIPROT "down-regulates activity" binding 9606 21508344 t lperfetto "SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR)." SIGNOR-238642 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT "down-regulates activity" binding 9606 BTO:0000887;BTO:0001103 19620279 t miannu "We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA." SIGNOR-202045 SOCS3 protein O14543 UNIPROT IRS1 protein P35568 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 23115649 t gcesareni "Irs-1 is the major signaling protein that socs3 targets to inhibit insulin signaling" SIGNOR-199361 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 SOCS3 protein O14543 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" binding 9606 24600449 t miannu "The ability of SOCS3 to simultaneously bind to JAK and to the cytokine receptor explains the specificity of the suppression. SOCS3 binds JAK and gp130 receptor simultaneously, using two opposing surfaces: while the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by the gp130 receptor, a subdomain in the SH2 domain of SOCS3 is also required for inhibition of JAK, binding in a phospho-independent manner to a non-canonical surface of JAK2 (58, 59). The KIR of SOCS3 occludes the substrate-binding groove on JAK2." SIGNOR-255329 SOCS3 protein O14543 UNIPROT JAK3 protein P52333 UNIPROT "down-regulates activity" binding 9606 21508344 t lperfetto "SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR)." SIGNOR-238645 SOCS3 protein O14543 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates 9606 16543409 f lperfetto "Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown" SIGNOR-253052 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 SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" 9606 24600449 f miannu "A main role of SOCS3 results from its binding to both the JAK kinase and the cytokine receptor, which results in the inhibition of STAT3 activation." SIGNOR-255330 SOCS6 protein O14544 UNIPROT KIT protein P10721 UNIPROT down-regulates ubiquitination 9606 21030588 t miannu "Suppressor of cytokine signaling 6 (socs6) is a member of the socs family of e3 ubiquitin ligases that can interact with c-kit and suppress c-kit-dependent pathways. / we demonstrate that socs6 has ubiquitin ligase activity toward c-kit and regulates c-kit protein turnover in cells" SIGNOR-169145 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 solifenacin chemical CHEBI:135530 ChEBI CHRM2 protein P08172 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-258311 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 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR1 protein P30872 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-257581 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 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR3 protein P32745 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-257583 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR5 protein P35346 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-257585 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000527 21679342 t gcesareni "Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date." SIGNOR-174593 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271 21041712 t gcesareni "Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date." SIGNOR-169203 sorafenib chemical CHEBI:50924 ChEBI BRAF protein P15056 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-258283 sorafenib chemical CHEBI:50924 ChEBI BRAF protein P15056 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21654832 t gcesareni "Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression." SIGNOR-174036 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 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 sorafenib chemical CHEBI:50924 ChEBI RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21654832 t gcesareni "Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression." SIGNOR-174039 "sorafenib tosylate" chemical CHEBI:50928 ChEBI BRAF protein P15056 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant)." SIGNOR-259220 "sorafenib tosylate" chemical CHEBI:50928 ChEBI FGFR1 protein P11362 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-259221 "sorafenib tosylate" chemical CHEBI:50928 ChEBI FLT1 protein P17948 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-259222 "sorafenib tosylate" chemical CHEBI:50928 ChEBI FLT3 protein P36888 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-259223 "sorafenib tosylate" chemical CHEBI:50928 ChEBI FLT4 protein P35916 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-259224 "sorafenib tosylate" chemical CHEBI:50928 ChEBI KIT protein P10721 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-259226 "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 "sorafenib tosylate" chemical CHEBI:50928 ChEBI RET protein P07949 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-259229 "sorafenib tosylate" chemical CHEBI:50928 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR "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-259454 SORBS1 protein Q9BX66 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000887 11001060 t gcesareni "Cbl is recruited to the insulin receptor by interaction with the adapter protein cap, through one of three adjacent sh3 domains in the carboxy terminus of cap" SIGNOR-82283 SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 23132018 t lperfetto "The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras." SIGNOR-39237 SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 23132018 t lperfetto "The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras." SIGNOR-59472 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-122075 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 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 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-201703 SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 21779497 t lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." SIGNOR-175259 SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000938 11560935 t lperfetto "Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras" SIGNOR-110566 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 SOS2 protein Q07890 UNIPROT KRAS protein P01116 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-175265 SOSTDC1 protein Q6X4U4 UNIPROT BMP2 protein P12643 UNIPROT "down-regulates activity" 10090 18032587 f lperfetto "SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7" SIGNOR-242746 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 SOSTDC1 protein Q6X4U4 UNIPROT BMP7 protein P18075 UNIPROT "down-regulates activity" 10090 18032587 f lperfetto "SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7" SIGNOR-242752 SOSTDC1 protein Q6X4U4 UNIPROT WNT10A protein Q9GZT5 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-242695 SOSTDC1 protein Q6X4U4 UNIPROT WNT16 protein Q9UBV4 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-242718 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 SOSTDC1 protein Q6X4U4 UNIPROT WNT2B protein Q93097 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-242701 SOSTDC1 protein Q6X4U4 UNIPROT WNT2 protein P09544 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-242724 SOSTDC1 protein Q6X4U4 UNIPROT WNT3A protein P56704 UNIPROT "down-regulates activity" 9606 BTO:0000815 21113658 f lperfetto "In this context, SOSTDC1 leads to decreased cellular proliferation and inhibition of Wnt3a- and BMP-7-induced signaling" SIGNOR-242714 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 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 SOSTDC1 protein Q6X4U4 UNIPROT WNT5A protein P41221 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-242736 SOSTDC1 protein Q6X4U4 UNIPROT WNT5B protein Q9H1J7 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-242727 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 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 SOSTDC1 protein Q6X4U4 UNIPROT WNT8A protein Q9H1J5 UNIPROT "down-regulates activity" 9606 BTO:0000815 21113658 f lperfetto "For example, SOSTDC1 decreases Wnt signaling by impeding the binding of Wnt8 to the LRP6 receptor" SIGNOR-242742 SOSTDC1 protein Q6X4U4 UNIPROT WNT9B protein O14905 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-242739 SOST protein Q9BQB4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 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-195684 SOX11 protein P35716 UNIPROT SPAST protein Q9UBP0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22574173 f miannu "we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11." SIGNOR-254886 SOX2 protein P48431 UNIPROT ABCC3 protein O15438 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-255181 SOX2 protein P48431 UNIPROT NR2E1 protein Q9Y466 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22194602 f miannu "Sox2 positively regulates tlx expression" SIGNOR-191714 SOX2 protein P48431 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 f flangone "Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes." SIGNOR-242064 SOX2 protein P48431 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-242002 SOX2 protein P48431 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-29512 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 SOX4 protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 BTO:0000038 17875931 t irozzo "We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein." SIGNOR-256138 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 SOX4 protein Q06945 UNIPROT DICER1 protein Q9UPY3 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0000848 22689055 t ".... showed that Sox4 positively regulates Dicer expression by binding to its promoter sequences and enhancing its activity. We found that knockdown of Dicer enhances the matrigel invasion of melanoma cells by at least twofold. In addition, we revealed that overexpression of exogenous Dicer reverts the enhanced melanoma cell invasion upon Sox4 knockdown" SIGNOR-258987 SOX4 protein Q06945 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001271 24183681 f apalma "Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors." SIGNOR-255676 SOX4 protein Q06945 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 24183681 f miannu "These data demonstrate an HSC cell intrinsic role for Sox4 on proliferation induced by loss of C/EBPα." SIGNOR-260133 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 SOX6 protein P35712 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003298 26893351 t "We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST" SIGNOR-255824 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 SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" binding 10090 BTO:0000011 26893351 t "SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis." SIGNOR-256073 SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0003298 26893351 t "In adipocytes, in addition to the direct regulation of PPARγ andC/EBP expression, we showed that SOX6 inhibitsWNT signaling by binding to β-catenin, potentially leading to its degradation" SIGNOR-255825 SOX6 protein P35712 UNIPROT HBG1 protein P69891 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004911 20395365 f Regulation miannu "BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors." SIGNOR-251810 SOX6 protein P35712 UNIPROT HBG2 protein P69892 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004911 20395365 f Regulation miannu "BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors." SIGNOR-251808 SOX6 protein P35712 UNIPROT MEST protein Q5EB52 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 PPARγ, C/EBPα and MEST." SIGNOR-255823 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 SOX9 protein P48436 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 20530484 f miannu "BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown." SIGNOR-255187 SOX9 protein P48436 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000849 19273910 f miannu "Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen." SIGNOR-255190 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT down-regulates "transcriptional regulation" 9606 19254573 f fspada "Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation" SIGNOR-210037 SOX9 protein P48436 UNIPROT CEBPD protein P49716 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19254573 t fspada "Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation" SIGNOR-184283 SOX9 protein P48436 UNIPROT COL11A2 protein P13942 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. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan." SIGNOR-251758 SOX9 protein P48436 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. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan." SIGNOR-251756 SOX9 protein P48436 UNIPROT COL9A2 protein Q14055 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. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan." SIGNOR-251757 SOX9 protein P48436 UNIPROT DCC protein P43146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003858 19745029 f miannu "Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2." SIGNOR-255188 SOX9 protein P48436 UNIPROT MITF protein O75030 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-255183 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 SOX9 protein P48436 UNIPROT PRAME protein P78395 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000849 19273910 f miannu "Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen." SIGNOR-255191 SP1 protein P08047 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003918 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 SP1 protein P08047 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 21854868 f miannu "Doxorubixin-evoked β-TrCP up-regulation promoted Sp1 degradation, which subsequently suppressed ADAM10 expression in MCF-7 and MCF-7/Dox cells." SIGNOR-255192 SP1 protein P08047 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19781662 f "The 5-LO promoter possesses a unique GC-rich region which contains consensus sequences for the transcription factors Sp1 and Egr-1 (GC-boxes) which are important for basal transcriptional activity" SIGNOR-254032 SP1 protein P08047 UNIPROT ATP2C1 protein P98194 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 15955096 f miannu "when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter." SIGNOR-255194 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 SP1 protein P08047 UNIPROT CD34 protein P28906 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 10989198 t lperfetto "Activation of the CD34 promoter by Sp1 requires the presence of a binding domain at -48 bp as well as the 5' untranslated region, which also binds Sp1" SIGNOR-241481 SP1 protein P08047 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000552 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 SP1 protein P08047 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-254273 SP1 protein P08047 UNIPROT DHCR24 protein Q15392 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22431021 f miannu "activation of Sp1 by oxidative stress is involved in the promotion of expression of DHCR24 by HCV." SIGNOR-255200 SP1 protein P08047 UNIPROT ENG protein P17813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002741 21146604 f miannu "In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor." SIGNOR-255201 SP1 protein P08047 UNIPROT FMR1 protein Q06787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15479157 f miannu "we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity." SIGNOR-255204 SP1 protein P08047 UNIPROT GFER protein P55789 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 18513187 f miannu "We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1." SIGNOR-254450 SP1 protein P08047 UNIPROT GGH protein Q92820 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000225 31739835 t miannu "Overexpression of Sp1 led to enhanced GGH promoter activity and GGH mRNA expression in allele-specific manners. These findings suggested that Sp1 acted as a positive regulator of human GGH transcription through the rs3758149 polymorphism in CEM/C1 cells." SIGNOR-261350 SP1 protein P08047 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-254159 SP1 protein P08047 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 9223667 t lperfetto "Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region." SIGNOR-251739 SP1 protein P08047 UNIPROT HYAL1 protein Q12794 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004796 18718911 f miannu "in cells which do not express HYAL-1, we found SP1 binding to 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-253879 SP1 protein P08047 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 SP1 protein P08047 UNIPROT IFITM5 protein A6NNB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001593 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-254218 SP1 protein P08047 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-253350 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 SP1 protein P08047 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-253903 SP1 protein P08047 UNIPROT LORICRIN protein P23490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 12200429 f miannu "Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity." SIGNOR-254538 SP1 protein P08047 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-253868 SP1 protein P08047 UNIPROT NDUFV1 protein P49821 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000931 17786189 f miannu "Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin." SIGNOR-255206 SP1 protein P08047 UNIPROT NDUFV2 protein P19404 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000931 17786189 f miannu "Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin." SIGNOR-255207 SP1 protein P08047 UNIPROT PDGFC protein Q9NRA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0001685 15247255 f "The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter" SIGNOR-254272 SP1 protein P08047 UNIPROT PON1 protein P27169 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 15380450 f miannu "These data suggest that Sp1 acts as a positive regulator of PON1 transcription, and that an interaction between Sp1 and PKC is a key mechanism for the effect of Sp1 on PON1 transcription." SIGNOR-255212 SP1 protein P08047 UNIPROT POR protein P16435 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0004428 8660656 f miannu "Regulation of the NADPH-cytochrome P-450 oxidoreductase gene is controlled by both positive and negative regulatory elements, and, of the nine Sp1 consensus sites, the two proximal sites are sufficient to support basal transcription." SIGNOR-255213 SP1 protein P08047 UNIPROT RHO protein P08100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 15781457 f miannu "Sp4 and Sp1 are activators of the rod opsin promoter" SIGNOR-225385 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 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 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 SP1 protein P08047 UNIPROT SLC2A1 protein P11166 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004058 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-241485 SP1 protein P08047 UNIPROT SLC5A8 protein Q8N695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20082847 t "Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription." SIGNOR-254059 SP1 protein P08047 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-254270 SP1 protein P08047 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8921911 f miannu "Studies using two mutant versions of this promoter, in which the Sp1 and C/EBP-related factor binding sites were deleted, respectively, revealed that Sp1 and C/EBP-related factors activate the transcription of SOD1 gene. the binding of Sp1 to the proximal upstream region of the Cu/Zn SOD might explain the expression of Cu/Zn SOD in a wide variety of cells." SIGNOR-253899 SP1 protein P08047 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR "form complex" binding 9606 19723038 t miannu "Sp1 and stat3 seem to synergistically augment renalase transcription." SIGNOR-187790 SP1 protein P08047 UNIPROT TBXA2R protein P21731 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000565 19747485 f "Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein." SIGNOR-254254 SP1 protein P08047 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944 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-β 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-β production" SIGNOR-251740 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 SP1 protein P08047 UNIPROT UGCG protein Q16739 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000738 15342415 f miannu "the results suggest that transcriptional up-regulation of GCS through DOX-induced activation of Sp1 is one potential mechanism to regulate ceramide increase and apoptosis in HL-60/ADR cells." SIGNOR-255205 SP1 protein P08047 UNIPROT UGT1A4 protein P22310 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 19546240 f miannu "our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy." SIGNOR-254076 SP2 protein Q02086 UNIPROT IRF1 protein P10914 UNIPROT "up-regulates activity" binding 9606 BTO:0000552 19482358 t miannu "Sp2 could be also able to interact with IRF-1 and this interaction is also observed on DNA indicating that by this way Sp2 is able to modulate IRF-1 transcriptional activity." SIGNOR-226478 SP3 protein Q02447 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-254813 SP3 protein Q02447 UNIPROT CYP27A1 protein Q02318 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 11867220 f miannu "Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells." SIGNOR-255197 SP3 protein Q02447 UNIPROT FMR1 protein Q06787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15479157 f miannu "we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity." SIGNOR-255203 SP3 protein Q02447 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944 9223667 t lperfetto "Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region." SIGNOR-251741 SP3 protein Q02447 UNIPROT IFITM5 protein A6NNB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001593 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 SP3 protein Q02447 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-253351 SP3 protein Q02447 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-253665 SP3 protein Q02447 UNIPROT LORICRIN protein P23490 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 12200429 f miannu "Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins." SIGNOR-254537 SP3 protein Q02447 UNIPROT MAOB protein P27338 UNIPROT "down-regulates quantity by repression" "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-253870 SP3 protein Q02447 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-251951 SP3 protein Q02447 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-255214 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 SP3 protein Q02447 UNIPROT SOX18 protein P35713 UNIPROT "down-regulates quantity by repression" "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-254820 SP4 protein Q02446 UNIPROT CRX protein O43186 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15781457 t miannu "Sp4 directly binds 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-225333 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 SP7 protein Q8TDD2 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 11792318 f "Giulio Giuliani" "Our results established that the novel transcription factor Osx is required for osteoblast differentiation and hence for bone formation." SIGNOR-255449 SPAG5 protein Q96R06 UNIPROT CENPE protein Q02224 UNIPROT "up-regulates activity" 9606 BTO:0000567 17664331 f lperfetto "Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F." SIGNOR-252041 SPAG5 protein Q96R06 UNIPROT CENPF protein P49454 UNIPROT "up-regulates activity" 9606 BTO:0000567 17664331 f lperfetto "Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F." SIGNOR-252042 SPAG9 protein O60271 UNIPROT ABL1 protein P00519 UNIPROT unknown binding 9606 BTO:0000222 SIGNOR-C21 19470755 t lperfetto "We report that abl associates with both cdo and jlp during myoblast differentiation" SIGNOR-185765 SPAG9 protein O60271 UNIPROT CDO/JLP/P38 complex SIGNOR-C22 SIGNOR "form complex" 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-150288 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 SPAG9 protein O60271 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto "Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts" SIGNOR-235545 SPAG9 protein O60271 UNIPROT MAP3K7 protein O43318 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto "Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts" SIGNOR-235548 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 SPAG9 protein O60271 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 17074887 t "Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP" lperfetto "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-149979 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 SPART protein Q8N0X7 UNIPROT WWP1 protein Q9H0M0 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-261307 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 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 SPDEF protein O95238 UNIPROT MMP9 protein P14780 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-255218 spermidine smallmolecule CHEBI:16610 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000452 BTO:0001103 14617280 f apalma "Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism" SIGNOR-255553 spermine smallmolecule CHEBI:15746 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000452 BTO:0001103 14617280 f apalma "Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism" SIGNOR-255552 "sphingosine 1-phosphate(1-)" smallmolecule CHEBI:60119 ChEBI S1PR1 protein P21453 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-257577 "sphingosine 1-phosphate(1-)" smallmolecule CHEBI:60119 ChEBI S1PR3 protein Q99500 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-257579 "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 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI LATS1 protein O95835 UNIPROT down-regulates 9606 BTO:0000007 22863277 f 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-198550 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 BTO:0000007 22863277 f 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-198553 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR1 protein P21453 UNIPROT up-regulates binding 9606 16794003 t gcesareni "The evidence suggests that s1p acting on s1p receptors coupled to gq" SIGNOR-147227 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT "up-regulates activity" binding 10116 BTO:0003574 10617617 t "We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation." SIGNOR-261141 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates binding 9606 16794003 t gcesareni "The evidence suggests that s1p acting on s1p receptors coupled to gq." SIGNOR-147230 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates binding 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 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT "up-regulates activity" binding 10116 BTO:0003574 10617617 t "We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation." SIGNOR-261142 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates binding 9606 16794003 t gcesareni "The evidence suggests that s1p acting on s1p receptors coupled to gq" SIGNOR-147233 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR4 protein O95977 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10753843 t "These results indicate that EDG-6 is a high affinity receptor for SPP, which couples to a G(i/o) protein, resulting in the activation of growth-related signaling pathways" SIGNOR-261143 SPI1 protein P17947 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-254585 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 SPI1 protein P17947 UNIPROT CD14 protein P08571 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 12393465 f apalma "In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPα-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia." SIGNOR-255696 SPI1 protein P17947 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-254286 SPI1 protein P17947 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0004730 12130514 f lperfetto "The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML." SIGNOR-249633 SPI1 protein P17947 UNIPROT FCER1A protein P12319 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000732 11971001 f "Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells" SIGNOR-254289 SPI1 protein P17947 UNIPROT FCGR1A protein P12314 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 12393465 f apalma "In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPŒ±-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia." SIGNOR-255697 SPI1 protein P17947 UNIPROT FLI1 protein Q01543 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000565 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 SPI1 protein P17947 UNIPROT GATA1 protein P15976 UNIPROT "down-regulates activity" binding 10090 BTO:0004475 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 SPI1 protein P17947 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000830 12433372 f irozzo "Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene.The above experiments suggested that PU.1 may physiologically downregulate the expression of the GATA-2 gene during the differentiation of myeloid progenitors into macrophages." SIGNOR-256069 SPI1 protein P17947 UNIPROT IRF8 protein Q02556 UNIPROT "up-regulates activity" binding 9606 BTO:0001413 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-222880 SPI1 protein P17947 UNIPROT ITGAM protein P11215 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000751 12393465 f apalma "CD11b is regulated by PU.1 and its promoter contains putative binding sites of AML1. In this case AML1-ETO interaction and down-regulation of important myeloid transcription factors like PU.1 and AML1 could explain the lower CD11b expression" SIGNOR-255661 SPI1 protein P17947 UNIPROT JUN protein P05412 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000725 17041602 f miannu "Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets." SIGNOR-256065 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 SPI1 protein P17947 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001412 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 SPI1 protein P17947 UNIPROT miR-146a mirna MI0000477 miRBase "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000725 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-256241 SPI1 protein P17947 UNIPROT miR-155 mirna MI0000681 miRBase "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000725 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 SPI1 protein P17947 UNIPROT miR-338 mirna MI0000814 miRBase "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000725 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 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 SPI1 protein P17947 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000801 16923394 f miannu "PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation" SIGNOR-256039 SPI1 protein P17947 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001412 15767686 f irozzo "These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU.1 gene expression.These data demonstrate that PU.1 protein is in a complex binding to a site within the kb −14 URE, suggesting that autoregulation through this region might be important for expression of PU.1." SIGNOR-256070 SPI1 protein P17947 UNIPROT TAL1 protein P17542 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 16298389 t irozzo "PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity" SIGNOR-256048 SPI1 protein P17947 UNIPROT TAL2 protein Q16559 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000664 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 "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 "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 spiperone chemical CHEBI:9233 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-258894 spiperone chemical CHEBI:9233 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-258859 spiperone chemical CHEBI:9233 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-258692 spironolactone chemical CHEBI:9241 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" -1 18038968 t Luana "Results of the RALES trial (Randomized Aldactone Evaluation Study) demonstrated that the published MR antagonist spironolactone, added to standard therapy, reduced mortality due to all causes by 30% as well as reduced hospitalizations and improved cardiac function in patients with severe heart failure.2" SIGNOR-257762 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 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 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 S protein P59594 UNIPROT ATF6 protein P18850 UNIPROT "down-regulates quantity" "transcriptional repression" 9606 31226023 f miannu "Activation of the ATF6 pathway by HCoV infection is less studied, and most studies have relied on indirect methods, such as luciferase reporter, due to the lack of a specific antibody. No ATF6 cleavage was detected in cells infected with SARS-CoV, and overexpression of SARSCoV S protein failed to activate ATF6 luciferase reporter." SIGNOR-260349 S protein P59594 UNIPROT CD209 protein Q9NNX6 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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 S protein P59594 UNIPROT CLEC4M protein Q9H2X3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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 S protein P59594 UNIPROT CXCL8 protein P10145 UNIPROT "up-regulates quantity" 9606 BTO:0000801 17412287 f lperfetto "The ability of S-protein to induce TNF-a" SIGNOR-260279 S protein P59594 UNIPROT DDIT3 protein P35638 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000007 16940539 f miannu "Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein." SIGNOR-260353 S protein P59594 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT "up-regulates activity" 9606 BTO:0000007 16940539 f miannu "SARS-CoV S protein specifically activated PERK but did not significantly affect IRE1/XBP1 or ATF6." SIGNOR-260439 S protein P59594 UNIPROT EIF3F protein O00303 UNIPROT "down-regulates activity" binding 9606 18231581 t lperfetto "Coronavirus spike protein inhibits host cell translation by interaction with eIF3f" SIGNOR-260255 S protein P59594 UNIPROT HSP90B1 protein P14625 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000007 16940539 f miannu "Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein." SIGNOR-260352 S protein P59594 UNIPROT HSPA5 protein P11021 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000007 16940539 f miannu "Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein." SIGNOR-260351 S protein P59594 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity" 9606 BTO:0000801 17412287 f lperfetto "The ability of S-protein to induce TNF-a" SIGNOR-260278 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 S protein P59594 UNIPROT TLR2 protein O60603 UNIPROT "up-regulates activity" binding 9606 BTO:0001025 19185596 t miannu "S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction." SIGNOR-260972 S protein P59594 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity" 9606 BTO:0000801 17412287 f lperfetto "The ability of S-protein to induce TNF-a" SIGNOR-260280 SPRY1 protein O43609 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates binding 9606 11585837 t gcesareni "Taken together, these results establish mammalian sprouty proteins as important negative regulators of growth factor signaling and suggest that sprouty proteins act downstream of the grb2.Sos Complex to selectively uncouple growth factor signals from ras activation and the map kinase pathway." SIGNOR-110948 SPRY4 protein Q9C004 UNIPROT CD82 protein P27701 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-253039 SPRY4 protein Q9C004 UNIPROT CDKN1A protein P38936 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-253041 SPRY4 protein Q9C004 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 9606 BTO:0002058 20501643 f miannu "Spry4 expression induces a reversal of the epithelial to mesenchymal transition characteristic of tumor cells. Treatment of a non-transformed lung epithelial cell line with shRNA to Spry4 led to decreased expression of epithelial markers and increased cell growth, supporting the concept of Spry4 acting as a tumor suppressor." SIGNOR-253036 SPRY4 protein Q9C004 UNIPROT MMP9 protein P14780 UNIPROT "down-regulates activity" 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-253037 SPRY4 protein Q9C004 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" binding 9606 12717443 t miannu "Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4." SIGNOR-253033 SPRY4 protein Q9C004 UNIPROT TESK1 protein Q15569 UNIPROT "down-regulates activity" binding 9606 15584898 t miannu "Spry4 negatively regulates the kinase activity of TESK1 by associating with it through the C-terminal cysteine-rich region of Spry4" SIGNOR-253032 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 SPRY4 protein Q9C004 UNIPROT TP53 protein P04637 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-253040 SPTAN1 protein Q13813 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000150;BTO:0000567 9624143 f "Cleaved by CASP3" amattioni "A-fodrin cleavage contributes to blebbing" SIGNOR-57897 SRCAP protein Q6ZRS2 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 20432434 t miannu "The SNF2-related CBP activator protein (SRCAP) serves as a coactivator for several nuclear receptors including the androgen receptor (AR). SRCAP is an ATPase that is the core subunit of a large multiprotein complex and was shown to incorporate the histone variant H2A.Z into nucleosomes. In this report, we demonstrate that SRCAP is expressed in the epithelium of normal prostate and in prostate carcinoma cells, and is associated with AR in the nucleus" SIGNOR-255221 SRCAP protein Q6ZRS2 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003160 20432434 f miannu "ShRNA mediated knockdown of SRCAP resulted in decreased H2A.Z binding at the enhancer region of the PSA promoter and decreased expression of PSA in prostate cancer cells." SIGNOR-255220 SRC proteinfamily SIGNOR-PF32 SIGNOR Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 BTO:0000830 15526160 f apalma "The SFK family of tyrosine kinases is named after its prototypic family member c-Src. SCF-induced chemotaxis of Mo7 cells was dependent on SFK activity" SIGNOR-254996 SRC proteinfamily SIGNOR-PF32 SIGNOR Degranulation phenotype SIGNOR-PH92 SIGNOR up-regulates 9606 BTO:0000830 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 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr226 KRNKPTVyGVSPNYD 9606 11847100 t lperfetto "c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function." SIGNOR-246307 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11847100 t lperfetto "c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function." SIGNOR-246311 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr451 TDPEALHyDYIDVEM 9534 BTO:0004055 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-246351 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr93 TSSLPEGyYEEAVPL 9534 BTO:0004055 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-246359 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr94 SSLPEGYyEEAVPLS 9534 BTO:0004055 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-246363 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT "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-252620 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 t lperfetto "We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation." SIGNOR-252621 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Tyr326 EVLEDNDyGRAVDWW 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-252623 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 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 t lperfetto "We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation." SIGNOR-246373 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr326 EVLEDNDyGRAVDWW 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-246377 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 SRC protein P12931 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-202796 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Tyr301 LGYRDSGyYWEVPPS 9534 BTO:0004055 9020159 t lperfetto "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. Activation of Raf-1 and A-Raf by Src requires tyrosine phosphorylation at residues 340 and 341 in Raf-1 and 301 and 302 in A-Raf." SIGNOR-236037 SRC protein P12931 UNIPROT AREG protein P15514 UNIPROT up-regulates cleavage 9606 BTO:0000586 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-236537 SRC protein P12931 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT up-regulates phosphorylation Tyr1105 RNEEENIySVPHDST 9606 9819392 t lperfetto "Phosphorylation of y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-src than by the egf receptor and was efficiently catalyzed by c-src in vitro. Mutation of y1105 from tyr to phe resulted in complete loss of p-tyr-dependent complex formation, indicating that p-y1105 was the sole p-tyr residue mediating binding to p120" SIGNOR-61670 SRC protein P12931 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Tyr156 YGPRAEEyEFLTPVE 9606 16943322 t llicata "We show here that src kinase binds and phosphorylates rhogdi both in vitro and in vivo at tyr156. analysis of rho gtpase-rhogdi complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that src-mediated phosphorylation of tyr156 causes a dramatic decrease in the ability of rhogdi to form a complex with rhoa, rac1, or cdc42." SIGNOR-149282 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr153 YGPRPEEyEFLTPVE 9606 19321744 t llicata "Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes." SIGNOR-184908 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr24 ELDSKLNyKPPPQKS 9606 19321744 t llicata "Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes." SIGNOR-184912 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 SRC protein P12931 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Tyr54 YLKERRVyVTLTCAF 9606 17456551 t lperfetto "Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors." SIGNOR-154564 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246381 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-regulates activity" phosphorylation Tyr165 PSPATDLyQVPPGPG 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" SIGNOR-246385 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-regulates activity" phosphorylation Tyr179 GGPAQDIyQVPPSAG 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" SIGNOR-246389 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-regulates activity" phosphorylation Tyr192 AGMGHDIyQVPPSMD 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" SIGNOR-246393 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-regulates activity" phosphorylation Tyr234 AQPEQDEyDIPRHLL 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" SIGNOR-246397 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-regulates activity" phosphorylation Tyr287 RDPLLEVyDVPPSVE 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" SIGNOR-246405 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246409 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-regulates activity" phosphorylation Tyr387 RPGPGTLyDVPRERV 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" SIGNOR-246413 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246417 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 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates 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 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 11604500 t lperfetto "The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding." SIGNOR-111056 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr666 GWMEDYDyVHLQGKE 9606 11604500 t lperfetto "The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding." SIGNOR-111060 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr177 GVRWAKLySLVIWGC 9606 16226010 t lperfetto "Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway." SIGNOR-141103 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr347 RKKSWEVyQGVCQKG 9606 16226010 t lperfetto "Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway." SIGNOR-141107 SRC protein P12931 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr566 RYVLDDQyVSSVGTK 9606 10688651 t lperfetto "Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk." SIGNOR-75330 SRC protein P12931 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 BTO:0001528 8629002 t "This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation." SIGNOR-251100 SRC protein P12931 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 16619028 t lperfetto "Src kinase phosphorylates caspase-8 on tyr380: a novel mechanism of apoptosis suppressionwe identified caspase-8 as a new substrate for src kinase. Phosphorylation occurs on tyr380, situated in the linker region between the large and the small subunits of human procaspase-8, and results in downregulation of caspase-8 proapoptotic function" SIGNOR-146127 SRC protein P12931 UNIPROT CAV1 protein Q03135 UNIPROT "down-regulates activity" phosphorylation Tyr14 VDSEGHLyTVPIREQ 9606 12921535 t lperfetto "Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn" SIGNOR-118007 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 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr27 SHHSGLEyADPEKFA 9606 BTO:0000017 15504032 t lperfetto "Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1." SIGNOR-129961 SRC protein P12931 UNIPROT CDC42 protein P60953 UNIPROT up-regulates phosphorylation Tyr64 DTAGQEDyDRLRPLS 9606 14506284 t gcesareni "Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation." SIGNOR-118206 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr860 DSLLVFDyEGSGSTA 9606 BTO:0000848 16371504 t lperfetto "Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated." SIGNOR-143238 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr884 SSGGEQDyDYLNDWG 9606 BTO:0000848 16371504 t lperfetto "Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated." SIGNOR-143242 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr886 GGEQDYDyLNDWGPR 9606 BTO:0000848 16371504 t lperfetto "Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated." SIGNOR-143246 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT "down-regulates activity" phosphorylation Tyr658 GEMDTTSyDVSVLNS 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-246462 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 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT up-regulates phosphorylation Tyr685 LDARPSLyAQVQKPP 9606 BTO:0000975 16909109 t llicata "In vitro src assay, the ve-cadherin cytoplasmic domain is directly phosphorylated by purified src as well as the tyrosine residue 685 (tyr)685-containing peptide finally, we found that in a vegf-induced wound-healing assay, cadherin adhesive activity was impaired by src kinase inhibitors.RPSLY(685)aqvq." SIGNOR-148818 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr74 HKPLEGKyEWQEVEK 9606 BTO:0000150 17254967 t lperfetto "Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27" SIGNOR-152831 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 BTO:0000150 17254967 t lperfetto "Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27" SIGNOR-152835 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr89 GSLPEFYyRPPRPPK 9606 BTO:0000150 17254967 t lperfetto "Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27" SIGNOR-152839 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 SRC protein P12931 UNIPROT CEACAM1 protein P13688 UNIPROT "up-regulates activity" phosphorylation Tyr520 LTATEIIySEVKKQ 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-246475 SRC protein P12931 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Tyr21 VSSDAEEyQPPIWKS 9606 17560670 t llicata "Here we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). Mutational analysis identified tyr-21 in the n-terminal regulatory region as a major phosphorylation site. these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity." SIGNOR-155713 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr442 KILEEVRyIANRFRC 9606 BTO:0000938 16251431 t lperfetto "Alpha7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinasesmutant alpha7 nachrs lacking cytoplasmic loop tyrosine residues because of alanine replacement of tyr-386 and tyr-442 were more active than wild-type receptorsexpression of active src reduced _7 nachr activity" SIGNOR-141311 SRC protein P12931 UNIPROT CLTC protein Q00610 UNIPROT up-regulates phosphorylation Tyr1477 LFITEEDyQALRTSI 9606 10089883 t gcesareni "Egf-mediated clathrin phosphorylation is followed by clathrin redistribution to the cell periphery and is the product of downstream activation of src kinase by egf receptor (egfr) signaling" SIGNOR-65714 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 BTO:0000038 11279024 t lperfetto "beta-catenin is a good substrate of pp60c- srctyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation." SIGNOR-106458 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 BTO:0000038 11279024 t lperfetto "beta-catenin is a good substrate of pp60c- src tyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654,although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation." SIGNOR-106454 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr333 NIMRTYTyEKLLWTT 9606 BTO:0000527 BTO:0000142 22056988 t lperfetto "Egfr activation induces translocation of pkm2 into the nucleus, where k433 of pkm2 binds to c-src-phosphorylated y333 of _-cateninthese findings reveal that egf induces _-catenin transactivation via a mechanism distinct from that induced by wnt/wingless and highlight the essential non-metabolic functions of pkm2 in egfr-promoted _-catenin transactivation, cell proliferation and tumorigenesis" SIGNOR-177086 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr112 PGQIVETyTEEDPEG -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-246480 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 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr257 APSRQDVyGPQPQVR -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-246488 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr280 HRFHPEPyGLEDDQR -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-246492 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr291 DDQRSMGyDDLDYGM -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-246496 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 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT "down-regulates activity" phosphorylation Tyr421 RLPSSPVyEDAASFK -1 15169891 t lperfetto "Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP." SIGNOR-246513 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 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 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr486 YPAEDSTyDEYENDL 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-98720 SRC protein P12931 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates phosphorylation Tyr361 KVMENFIyESMRYQP 9606 BTO:0000150 19556341 t amattioni "Phosphorylation of the 361-tyrosine residue is crucial in the up-regulation of aromatase activity. c-src protein directly phosphorylates aromatase on tyrosine 361." SIGNOR-186284 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 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr198 EDVEDPVyQYIVFEA 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-247076 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr220 PETEENIyQVPTSQK 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-247080 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr232 SQKKEGVyDVPKSQP 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-247084 SRC protein P12931 UNIPROT DAG1 protein Q14118 UNIPROT down-regulates phosphorylation Tyr892 PYRSPPPyVPP 9606 BTO:0000887;BTO:0001103 12795607 t lperfetto "Tyrosine 892 is now thought to be the principal site for recognition by the c-src tyrosine kinase;. We show that upon tyrosine phosphorylation, beta-dystroglycan undergoes a profound change in its sub-cellular localization (e.g., from the plasma membrane to an internal membrane compartment). One possibility is that the net negative charge at position 892 causes the redistribution of beta-dystroglycan to this intracellular vesicular location" SIGNOR-101655 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 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr736 FGMSRNLySGDYYRI 9606 16186108 t gcesareni "Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues." SIGNOR-140728 SRC protein P12931 UNIPROT DLG4 protein P78352 UNIPROT up-regulates phosphorylation Tyr523 REDSVLSyETVTQME 9606 BTO:0000938 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 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 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 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1016 DVVDADEyLIPQQGF 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-44239 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1110 GSVQNPVyHNQPLNP 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-44243 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 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000452 11983694 t lperfetto "In summary, this study describes a novel mechanism for metal-induced egfr transactivation, which is likely to be mediated by src through the phosphorylation site of tyr-845 on egfr. emanating from a variety of growth factor receptors, including egfry845 (e-e-k-e-y845-h-a-e)" SIGNOR-235921 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 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr59 SSSAASSySFSDLNS 9606 BTO:0000567 BTO:0000887 19789182 t llicata "Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf" SIGNOR-188308 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr74 TRGDADMyDLPKKED 9606 BTO:0000567 BTO:0000887 19789182 t llicata "Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf" SIGNOR-188312 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr95 KGYNDDYyEESYFTT 9606 BTO:0000567 BTO:0000887 19789182 t llicata "Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf" SIGNOR-188316 SRC protein P12931 UNIPROT ENO1 protein P06733 UNIPROT up-regulates phosphorylation Tyr44 SGASTGIyEALELRD 9606 24841372 t lperfetto "The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways" SIGNOR-205092 SRC protein P12931 UNIPROT ENO1 protein P06733 UNIPROT up-regulates phosphorylation Tyr44 SGASTGIyEALELRD 9606 BTO:0000887 7629021 t lperfetto "The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways" SIGNOR-30126 SRC protein P12931 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates quantity" phosphorylation Tyr594 TYVDPHTyEDPNQAV 9606 BTO:0000661 24457997 t gcesareni "SRC phosphorylates EPHA2 on Tyr594, thus creating a feedback loop that promotes EPHA2 destruction and thereby self-regulates its transforming potential" SIGNOR-246104 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 SRC protein P12931 UNIPROT FBXO5 protein Q9UKT4 UNIPROT up-regulates phosphorylation Tyr142 ALETSRLyEDSGYSS 9606 BTO:0001271 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 SRC protein P12931 UNIPROT FHIT protein P49789 UNIPROT "up-regulates activity" phosphorylation Tyr114 FHRNDSIyEELQKHD -1 15835917 t lperfetto "The human tumor suppressor Fhit is a homodimeric histidine triad (HIT) protein of 147 amino acids which has Ap3A hydrolase activity. We have recently discovered that Fhit is phosphorylated in vivo and is phosphorylated in vitro by Src kinaseMALDI-TOF and HPLC-ESI tandem mass spectrometry of intact Fhit and proteolytic peptides of Fhit demonstrated that Fhit is phosphorylated on Y114 on either one or both subunitsThe decreases in the values of Km and kcat for the phosphorylated forms in comparison to those of unphosphorylated Fhit favor the formation and lifetime of the Fhit_Ap3A complex, which may enhance the tumor suppressor activity of Fhit." SIGNOR-247134 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 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 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1337 QVFYNSEyGELSEPS 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-165043 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr830 PLEEQCEyLSYDASQ 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-165047 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr833 EQCEYLSyDASQWEF 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-165051 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr853 HLGRVLGyGAFGKVV 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-165055 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr259 ASVDSSLyNLPRSYS 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-236310 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr317 PPTPGNTyQIPRTFP 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-236306 RNF41 protein Q9H4P4 UNIPROT USP8 protein P40818 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0002181 23750007 t irozzo "RNF41 redistributes and ubiquitylates USP8, and reduces USP8 levels." SIGNOR-259106 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr373 ASDTDSSyCIPTAGM 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-236318 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 SRC protein P12931 UNIPROT GLRB protein P48167 UNIPROT up-regulates phosphorylation Tyr435 RDFELSNyDCYGKPI 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 t gcesareni "These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit." SIGNOR-115705 SRC protein P12931 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 t lperfetto "Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir." SIGNOR-78706 SRC protein P12931 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 t lperfetto "In our work we show that, in contrast to BCR-ABL and prolactin, NPM-ALK phosphorylates Grb2 mainly in Tyr160)Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation." SIGNOR-247138 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1105 CSEVERTyLKTKSSS -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-247163 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1267 PATGEQVyQQDWAQN -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-247167 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 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates phosphorylation Tyr1325 RLLEGNFyGSLFSVP 9606 19834457 t lperfetto "The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation sitewe also show that the tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum." SIGNOR-188531 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 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr409 TDGLGLSyLSSHIAN -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-250780 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 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr603 LKTPSAAyLWVGTGA -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-250782 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 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 SRC protein P12931 UNIPROT GTF2I protein P78347 UNIPROT "up-regulates activity" phosphorylation Tyr248 EESEDPDyYQYNIQA 9534 BTO:0004055 11934902 t lperfetto "c-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling" SIGNOR-247185 SRC protein P12931 UNIPROT HCN4 protein Q9Y3Q4 UNIPROT up-regulates phosphorylation Tyr531 RRQYQEKyKQVEQYM 9606 17977941 t fspada "These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531." SIGNOR-158707 SRC protein P12931 UNIPROT HLA-A protein P30443 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 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr23 SAALDPAyTTLEFEN 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-195883 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 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 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 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr230 QPYDPNFyDETYDYG 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-88903 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr234 PNFYDETyDYGGFTM 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-88907 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 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr380 YAGGRGSyGDLGGPI 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-88915 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr72 IKALRTDyNASVSVP 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-88919 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 SRC protein P12931 UNIPROT HSP90AB1 protein P08238 UNIPROT up-regulates phosphorylation Tyr301 DDITQEEyGEFYKSL 9606 17855507 t lperfetto "C-src directly phosphorylates hsp90 on tyrosine 300 residue and that this event is essential for vegf-stimulated enos association to hsp90 and thus no release from endothelial cells." SIGNOR-157781 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK -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-246272 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" ubiquitination 9606 11153911 t gcesareni "The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway." SIGNOR-85942 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL -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-246268 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1346 SFDERQPyAHMNGGR -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-246276 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr973 RLGNGVLyASVNPEY -1 8940173 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-247193 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr980 YASVNPEyFSAADVY -1 8940173 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-247197 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 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 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-45126 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 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 BTO:0002418 SIGNOR-C14 12707358 t lperfetto "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-100784 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 12645577 t gcesareni "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-99314 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr199 ELLEQQKyTVTVDYW 9606 SIGNOR-C14 12645577 t gcesareni "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-99318 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12645577 t lperfetto "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-217439 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12707358 t lperfetto "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-217442 SRC protein P12931 UNIPROT INPPL1 protein O15357 UNIPROT up-regulates phosphorylation Tyr986 NSFNNPAyYVLEGVP 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-92931 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 SRC protein P12931 UNIPROT ITGAL protein P20701 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000876 25624455 t miannu "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." SIGNOR-254741 SRC protein P12931 UNIPROT ITGB2 protein P05107 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000876 25624455 t miannu "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." SIGNOR-254740 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 SRC protein P12931 UNIPROT JUP protein P14923 UNIPROT "up-regulates activity" phosphorylation Tyr644 RNEGTATyAAAVLFR 9606 BTO:0003709 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 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr187 FSEEIRFyQLGEEAM 9606 BTO:0000142 11812778 t gcesareni "The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties." SIGNOR-114641 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr499 EGEEQSQyMHVGSCQ 9606 BTO:0000142 11812778 t gcesareni "The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties." SIGNOR-114645 SRC protein P12931 UNIPROT KCNB1 protein Q14721 UNIPROT up-regulates phosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000938 19622611 t flangone "In the present study we show that an n-terminal tyrosine of kv2.1 (y124), which is a known target of src kinase, is critical for the apoptotic current surge..Kv2.1-mediated k+ currents are also enhanced during non-injurious conditions through direct phosphorylation of intracellular n-terminal residue tyrosine 124 (y124) by src kinase" SIGNOR-187201 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12217858 t gcesareni "Addition of active c-src and [32p]atp to the purified romk1 protein resulted in the phosphorylation of the romk1 protein. However, c-src did not phosphorylate r1y337a in which tyrosine residue 337 was mutated to alanine. Furthermore, phosphopeptide mapping identified two phosphopeptides from the trypsin-digested romk1 protein." SIGNOR-92513 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12556363 t flangone "Inhibition of c-src with herbimycin a significantly decreased the tyrosine phosphorylation level of romk1... tyrosine dephosphorylation enhances the exocytosis of romk1" SIGNOR-97803 SRC protein P12931 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" phosphorylation Tyr900 EHAPAEMyDIMKTCW 9606 12878163 t lperfetto "C-src phosphorylates tyr900 in the second part of the kinase domain of c-kit." SIGNOR-103999 SRC protein P12931 UNIPROT KRAS protein P01116 UNIPROT up-regulates phosphorylation 9606 9096340 t gcesareni "Expression of v-src, a transforming nonreceptor tyrosine kinase, results in ras activation, and ras function in nih 3t3 cells suppresses transformation by v-src, indicating that in these cells ras-dependent signaling pathways are required for v-src to exert its biological effects." SIGNOR-47152 SRC protein P12931 UNIPROT KRT19 protein P08727 UNIPROT unknown phosphorylation Tyr391 LEGQEDHyNNLSASK 9606 21049038 t llicata "Human k19 tyrosine 391 is phosphorylated, potentially by src kinase, and is the first well-defined tyrosine phosphorylation site of any keratin protein." SIGNOR-169273 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 SRC protein P12931 UNIPROT LRP1 protein Q07954 UNIPROT "up-regulates activity" phosphorylation Tyr4507 TNFTNPVyATLYMGG 9606 BTO:0000007 12789267 t lperfetto "We recently observed that the ldl receptor-related protein 1 (lrp-1) is tyrosine phosphorylated in v-src-transformed cells.Of the four tyrosine residues present in the cytoplasmic domain of lrp-1, only tyr 63 is phosphorylated by v-src in vivo or in vitro. Using fibroblasts deficient in src, yes and fyn, we were able to show that there are multiple kinases present in the cell that can phosphorylate lrp-1. Tyrosine-phosphorylated lrp-1 associates with shc, a ptb and sh2 domain containing signaling protein that is involved in the activation of ras" SIGNOR-101535 SRC protein P12931 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Tyr4473 VEIGNPTyKMYEGGE 9606 18381291 t lperfetto "The observation that the wild type protein was phosphorylated to a higher level than the y4473f mutant again indicates that phosphorylation of the tyr4473 residue by v-src is occurring in these cellsmutation of tyr4473 to alanine, which abolishes snx17 binding, resulted in impaired receptor recycling and reduced amounts of the mature form of lrp1 on the cell surface" SIGNOR-178159 SRC protein P12931 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 f gcesareni "C-src was suggested to be involved in bmk1 activation from the experiments with herbimycin a and pp2, specific inhibitors of src family kinases." SIGNOR-113779 SRC protein P12931 UNIPROT MMP14 protein P50281 UNIPROT unknown phosphorylation Tyr573 GTPRRLLyCQRSLLD 9606 17389600 t llicata "We show that mt1-mmp is phosphorylated on the unique tyrosine residue located within this cytoplasmic sequence (tyr(573)) and that this phosphorylation requires the kinase src. accordingly, overexpression of a nonphosphorylable mt1-mmp mutant (y573f) blocked sphingosine-1-phosphate-induced migration of human umbilical vein endothelial cells and ht-1080 (human fibrosarcoma) cells and failed to stimulate migration of cells lacking the enzyme (bovine aortic endothelial cells)." SIGNOR-154006 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr241 SHQGPVIyAQLDHSG 9606 11751924 t lperfetto "Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr" SIGNOR-113406 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr263 NKSESVVyADIRKN 9606 11751924 t lperfetto "Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr" SIGNOR-113410 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 12408982 t gcesareni "Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity." SIGNOR-95242 SRC protein P12931 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates phosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 BTO:0000801 9792645 t llicata "C-src phosphorylates i?B? On tyrosine 42 the prolonged expression and activation of c-src in response to tnf (19) and, its extended connection with i?B?, Suggest this association prompts prolonged tyrosine phosphorylation and perhaps tof i?B? Compared with the short survival of the serine-phosphorylated inhibitory protein." SIGNOR-60879 SRC protein P12931 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Tyr151 IEFVNQYyGSFKEAK 9606 19875457 t llicata "We identify human inos residue tyr(1055) as a target for src-mediated phosphorylation. src kinase-mediated phosphorylation stabilizes inducible nitric-oxide synthase in normal cells and cancer cells." SIGNOR-188974 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 SRC protein P12931 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation Tyr130 VLDVLKFyDSNTVKQ 9606 12215529 t llicata "Pak2 became tyrosine phosphorylated in its n-terminal regulatory domain, where y130 was identified as the major phosphoacceptor site. Tyrosine phosphorylation-mediated superactivation of pak2 could be induced by overexpression of different src kinases or by inhibiting cellular tyrosine phosphatases with pervanadate and could be blocked by the src kinase inhibitor pp1 or by mutating the y130 residue." SIGNOR-92460 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Tyr9 ARTTSQLyDAVPIQS 9606 BTO:0000007 11481331 t lperfetto "Using site-directed mutants, we show that, although phosphorylation on tyr-373/376 is important for pdk1 activity, phosphorylation on tyr-9 has no effect on the activity of the kinase. Both of these residues can be phosphorylated by v-src tyrosine kinase in vitro, and co-expression of v-src leads to tyrosine phosphorylation and activation of pdk1." SIGNOR-109533 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 BTO:0000887;BTO:0001260 20643654 t miannu "Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376" SIGNOR-166718 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 BTO:0000887;BTO:0001260 20643654 t miannu "Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376" SIGNOR-166722 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 SRC protein P12931 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-247316 SRC protein P12931 UNIPROT PLSCR1 protein O15162 UNIPROT "up-regulates activity" phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 BTO:0000671 12871937 t lperfetto "Cell stimulation by egf results in tyr phosphorylation of plscr1, its association with both shc and egf receptors, and rapid cycling of plscr1 between plasma membrane and endosomal compartments.We Now report evidence that upon egf stimulation, plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77. The in vivo interaction between plscr1 and shc requires the src-mediated phosphorylation on tyrosines 69 and 74. Furthermore, our data suggest that deletion of plscr1 from the plasma membrane results in marked reduction in egf-initiated activation of c-src kinase.\ We propose that PLSCR1, through its interaction with Shc, promotes Src kinase activation through the EGF receptor." SIGNOR-103769 SRC protein P12931 UNIPROT PLSCR1 protein O15162 UNIPROT "up-regulates activity" phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 BTO:0000671 12871937 t lperfetto "Cell stimulation by egf results in tyr phosphorylation of plscr1, its association with both shc and egf receptors, and rapid cycling of plscr1 between plasma membrane and endosomal compartments.We Now report evidence that upon egf stimulation, plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77. The in vivo interaction between plscr1 and shc requires the src-mediated phosphorylation on tyrosines 69 and 74. Furthermore, our data suggest that deletion of plscr1 from the plasma membrane results in marked reduction in egf-initiated activation of c-src kinase." SIGNOR-103773 SRC protein P12931 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates phosphorylation Tyr307 VTRRTPDyFL 9606 BTO:0000938 23796501 t llicata "We found that ?-Syn gene overexpression in sk-n-sh cells and primary neurons led to pp2a/c phosphorylation at y307, a known target of src kinase, and consequent phosphatase inhibition." SIGNOR-202192 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr265 RVIGRGSyAKVLLVR 9606 11713277 t llicata "Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain." SIGNOR-111920 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr432 KEGWMVHyTSKDTLR 9606 BTO:0000567 12637538 t lperfetto "Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation." SIGNOR-247320 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 BTO:0000567 12637538 t lperfetto "Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation." SIGNOR-247324 SHH protein Q15465 UNIPROT SMO protein Q99835 UNIPROT "up-regulates activity" 10090 16885213 f lperfetto "Binding of Hh to Ptch relieves the repression of Smo, allowing Smo to signal." SIGNOR-148481 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr502 TTANVVYyVGENVVN 9606 BTO:0000567 12637538 t lperfetto "Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation." SIGNOR-247328 SRC protein P12931 UNIPROT PROM1 protein O43490 UNIPROT unknown phosphorylation Tyr828 RMDSEDVyDDVETIP 9606 19296573 t llicata "Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src" SIGNOR-184772 SRC protein P12931 UNIPROT PROM1 protein O43490 UNIPROT unknown phosphorylation Tyr852 GYHKDHVyGIHNPVM 9606 19296573 t llicata "Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src" SIGNOR-184776 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 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 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Tyr397 SVSETDDyAEIIDEE 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-157767 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 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-150476 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 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-150480 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 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 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-134212 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr742 HMVQTNHyQVSGYPG 9606 BTO:0000195 17289681 t "The effect has been demonstrated using P34152-3" gcesareni "We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress." SIGNOR-152967 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 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-150492 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000195 17289681 t "The effect has been demonstrated using P34152-3" gcesareni "We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress." SIGNOR-152971 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 BTO:0000007 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 SRC protein P12931 UNIPROT PTPRA protein P18433 UNIPROT "up-regulates activity" phosphorylation Tyr798 YIDAFSDyANFK 9606 BTO:0000007 7518772 t "The effect has been demonstrated using P18433-2" lperfetto "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." SIGNOR-111306 SRC protein P12931 UNIPROT RAC1 protein P63000 UNIPROT up-regulates phosphorylation 9606 17991704 t gcesareni "N attractive hypothesis consistent with our present data is that the gef responsible for rac activation in mce cells may be activated by src family kinase tyrosine phosphorylationour results present a novel mechanism by which the pi3k and src signaling cascades cooperate to activate rac and promote intestinal epithelial cell migration downstream of egfr." SIGNOR-158954 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr228 LNEGKHLyTLDGGDI 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-94796 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 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 10998357 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-82150 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 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 7692235 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-32081 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 SRC protein P12931 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 15320955 t llicata "C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases." SIGNOR-128273 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 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr168 TLMEKDSyPRFLKSP 9606 12588871 t miannu "Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. / this result suggests src phosphorylates native rgs16 at residue tyr177 in vitro." SIGNOR-98271 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 12588871 t lperfetto "Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. hosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr)." SIGNOR-98275 SRC protein P12931 UNIPROT RHOU protein Q7L0Q8 UNIPROT "down-regulates activity" phosphorylation Tyr254 SKSWWKKYCCFV 9606 BTO:0002552 20547754 t miannu "Regulation of the Rho family small GTPase Wrch-1/RhoU by C-terminal tyrosine phosphorylation requires Src. Phosphorylation at Y254 negatively regulates Wrch-1-mediated biological functions.Serum-stimulated tyrosine phosphorylation and relocalization of Wrch-1 decreases its activation of downstream effectors in a Y254-dependent manner." SIGNOR-259814 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT unknown phosphorylation Tyr488 DVYDDGKyVYVVTEL 9606 BTO:0000007 18156174 t llicata "The results showed that tyr-488 is a major site of src but mutations at tyr-529 or tyr-707 did not significantly decrease src-dependent tyrosine phosphorylation of rsk2 (fig. 4c). However, we have previously characterized the tyr-488 site that is also phosphorylated by fgfr3 (14), and substitution of tyr-488 did not affect rsk2 activation." SIGNOR-160056 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 SRC protein P12931 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Tyr45 GLEPVGHyEEVELTE 9606 16640565 t llicata "Src kinase phosphorylates s6k in the n-terminus. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vitro. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vivo." SIGNOR-146292 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 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 SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t lperfetto "Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway." SIGNOR-44866 SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t lperfetto "Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway." SIGNOR-44870 SRC protein P12931 UNIPROT SPRY2 protein O43597 UNIPROT up-regulates phosphorylation Tyr55 AIRNTNEyTEGPTVV 9606 15564375 t lperfetto "Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human sprouty 2 (hspry2) on residue y55. we show that hspry2 is a direct substrate for src family kinases, including src itself.Phosphorylation of hspry2 is required for hspry2 to inhibit activation of the extracellular signal-regulated kinase pathway." SIGNOR-131189 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" phosphorylation Tyr530 FTSTEPQyQPGENL 9606 8755732 t lperfetto "Rapid digestion of pp60c-src tyrosine kinase (src TK) in combination with electrospray ionization mass spectrometry enabled the determination of the time course for autophosphorylation of three tyrosine sites (Y338, Y419, and Y530) and a correlation with src TK activity. Here, conditions were identified which promoted essentially complete autophosphorylation of y530. Phosphorylation of y530 was directly correlated to a decrease in tyrosine kinase activity" SIGNOR-43315 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 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 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr22 GVLPSHYyESFLEKK 9606 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 Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src." SIGNOR-247333 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr322 GDGPAVDyENQDVAS 9606 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 Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src." SIGNOR-247337 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 SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 9566874 t lperfetto "Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein.We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis." SIGNOR-235445 SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 14551213 t lperfetto "In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants." SIGNOR-247341 SRC protein P12931 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 11641791 t gcesareni "Src can thus directly tyrosine-phosphorylate the activation site of stat5 (tyr 694 in stat5a), and src may contribute to epo-induced signal transduction via stat5." SIGNOR-111078 SRC protein P12931 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr679 DRPKDEVySKYYTPV 9606 12621061 t llicata "Stat5 is activated by a broad spectrum of cytokines, as well as non-receptor tyrosine kinases, such as src. these conformational differences may in part be due to differential effects of prl and src on stat5b tyrosine phosphorylation, since src induced several additional sites of tyrosine phosphorylation of stat5b at residues other than tyr-699, including tyr-724 and tyr-679." SIGNOR-99002 SRC protein P12931 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates phosphorylation Tyr284 KIFPYEEyASWKTEK 9606 19114990 t gcesareni "Tbetarii can also be phosphorylated by src, a non-rtk, on y284, which can serve as a docking site for the recruitment of grb2 and shc, thereby bridging tbetarii to mapk activation." SIGNOR-182963 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 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t gcesareni "Although sh2 domains have not been reported previously to be phosphorylated, the tensin-3 sh2 domain is a physiologic substrate for src. Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding." SIGNOR-187854 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1173 QDTSKFWyKADISRE 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata "Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate" SIGNOR-187843 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1206 SHSFRGAyGLAMKVA 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata "Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate" SIGNOR-187847 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1256 KGCSNEPyFGSLTAL 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata "Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate" SIGNOR-187851 SRC protein P12931 UNIPROT TXK protein P42681 UNIPROT "up-regulates activity" phosphorylation Tyr420 RYVLDDEyVSSFGAK 9606 BTO:0000782 11353545 t lperfetto "We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association." SIGNOR-247346 SRC protein P12931 UNIPROT UGT2B7 protein P16662 UNIPROT up-regulates phosphorylation Tyr438 RVINDPSyKENVMKL 9606 BTO:0000150 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 ERN1 protein O75460 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "down-regulates activity" phosphorylation 9606 31226023 f miannu "The kinase activity of IRE1 also activates a signaling cascade that ultimately activates c-Jun N-terminal kinase (JNK)" SIGNOR-260177 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 SRC protein P12931 UNIPROT VCL protein P18206 UNIPROT "down-regulates activity" phosphorylation Tyr100 QMLQSDPySVPARDY 9534 15229287 t lperfetto "The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail." SIGNOR-247424 SRC protein P12931 UNIPROT VCL protein P18206 UNIPROT "down-regulates activity" phosphorylation Tyr1133 WVRKTPWyQ 9534 15229287 t lperfetto "The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail." SIGNOR-247428 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT "up-regulates activity" phosphorylation Tyr256 LKAALKLyHVSDSEG 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-247433 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 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT "up-regulates activity" phosphorylation Tyr81 EQGAAAIyTTQMDDF 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-247441 SRC protein P12931 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates phosphorylation Tyr125 PIPLQETyDVCEQPP 9606 16317717 t lperfetto "The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex" SIGNOR-142724 SRD5A1 protein P18405 UNIPROT 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI "up-regulates activity" "small molecule catalysis" 9606 15861399 t miannu "Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-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 SREBF1 protein P36956 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 12923220 f 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 SREBF1 protein P36956 UNIPROT Lipogenesis phenotype SIGNOR-PH30 SIGNOR up-regulates 10090 15589694 f lperfetto "In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin induced glucose metabolism (particularly in lipogenesis)," SIGNOR-228614 SREBF1 protein P36956 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-254462 SREBF1 protein P36956 UNIPROT MTTP protein P55157 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000575 11111091 f miannu "SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100." SIGNOR-252113 SREBF1 protein P36956 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 17921436 f 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 SREBF1 protein P36956 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f 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-142297 SREBF1 protein P36956 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20577053 f 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-166381 SREBF1 protein P36956 UNIPROT PPARG protein P37231 UNIPROT "up-regulates activity" 10090 BTO:0000011 9539737 f gcesareni "Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands" SIGNOR-170607 SREBF1 protein P36956 UNIPROT SND1 protein Q7KZF4 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000599 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-259137 SREBF1 protein P36956 UNIPROT VLDL_assembly phenotype SIGNOR-PH62 SIGNOR up-regulates 9606 BTO:0000575 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 SREBF2 protein Q12772 UNIPROT ABCG5 protein Q9H222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000398 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 SREBF2 protein Q12772 UNIPROT ABCG8 protein Q9H221 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000398 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 SREBF2 protein Q12772 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 12923220 f 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-253133 SREBF2 protein Q12772 UNIPROT LDLR protein P01130 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-254453 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 SREBF2 protein Q12772 UNIPROT NPC1L1 protein Q9UHC9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "Our results showed a positive correlation between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA expression, a finding that supports the notion that these transcription factors stimulate intestinal NPC1L1 expression." SIGNOR-254452 SREBF2 protein Q12772 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-254459 SREBF2 protein Q12772 UNIPROT PON2 protein Q15165 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19497963 f miannu "UPA upregulated PON2 expression in a sterol regulatory binding protein-2 (SREBP-2)-dependent manner, since blocking SREBP-2 maturation by 4-(2-aminoethyl)-benzenesulfonyl fluoride abolished uPA-stimulation of PON2, whereas inhibition of SREBP-2 catabolism by N-acetyl-leucyl-norleucinal had an opposite effect." SIGNOR-255225 SREBF2 protein Q12772 UNIPROT SND1 protein Q7KZF4 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000599 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 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 SRF protein P11831 UNIPROT CNN1 protein P51911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni "In particular, high expression of vsmc-specific genes, such as smooth muscle -actin (sma), calponin1 (cnn), and sm22 (sm22) are associated with the contractile vsmc phenotype. Transcription of contractile genes is regulated by srf through a dna sequence motif known as the carg box (cc(a/t)6gg), which is present in the promoters of vsmc-specific genes." SIGNOR-174358 SRF protein P11831 UNIPROT IL6 protein P05231 UNIPROT up-regulates 9606 22225874 t FFerrentino "Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy." SIGNOR-255966 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 SRF protein P11831 UNIPROT PLAU protein P00749 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000161 15514113 f miannu "We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1." SIGNOR-255227 SRF protein P11831 UNIPROT PLG protein P00747 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000161 15514113 f miannu "We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1." SIGNOR-255226 SRF protein P11831 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates 9606 22225874 t FFerrentino "Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy." SIGNOR-255965 SRF protein P11831 UNIPROT SERPINE1 protein P05121 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000161 15514113 f miannu "We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1." SIGNOR-255228 SRF protein P11831 UNIPROT TAGLN protein Q01995 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni "The contractile phenotype of smooth muscle (sm) cells is controlled by serum response factor (srf), which drives the expression of sm-specific genes including sm alpha-actin, sm22, and others." SIGNOR-174393 SRGAP1 protein Q7Z6B7 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-260515 SRGAP2 protein O75044 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-260517 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 SRGAP3 protein O43295 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 12447388 t miannu "Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo." SIGNOR-95967 SRP19 protein P09132 UNIPROT SRP54 protein P61011 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-261168 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 SRP19 protein P09132 UNIPROT SRP72 protein O76094 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-261166 SRP54 protein P61011 UNIPROT SRPRA protein P08240 UNIPROT "up-regulates activity" binding -1 30649417 t miannu "The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site." SIGNOR-261163 SRP54 protein P61011 UNIPROT SRPRB protein Q9Y5M8 UNIPROT "up-regulates activity" binding -1 30649417 t miannu "The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site." SIGNOR-261165 SRP54 protein P61011 UNIPROT SRSF2 protein Q01130 UNIPROT "up-regulates activity" binding -1 8816452 t Monia "We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65)." SIGNOR-261160 SRP54 protein P61011 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR "up-regulates activity" binding -1 8816452 t Monia "We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65)." SIGNOR-261162 SRP72 protein O76094 UNIPROT SRP68 protein Q9UHB9 UNIPROT "up-regulates activity" binding -1 30649417 t miannu "Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction." SIGNOR-261164 SRPK1 protein Q96SB4 UNIPROT RBM8A protein Q9Y5S9 UNIPROT down-regulates phosphorylation Ser166 RRGGRRRsRSPDRRR 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-139551 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 SRPK2 protein P78362 UNIPROT ACIN1 protein Q9UKV3 UNIPROT up-regulates phosphorylation Ser1180 GPRSRSRsRDRRRKE 9606 BTO:0001271 18559500 t lperfetto "Here, we show that srpk2 binds and phosphorylates acinus, an sr protein essential for rna splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin a1 but not a2 up-regulation. Acinus s422d, an srpk2 phosphorylation mimetic, enhances cyclin a1 transcription, whereas acinus s422a, an unphosphorylatable mutant, blocks the stimulatory effect of srpk2" SIGNOR-179006 SRSF2 protein Q01130 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001109 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 SRSF7 protein Q16629 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates binding 9606 18364396 t miannu "9g8 and srp20 also enhance the tap rna-binding activity" SIGNOR-161338 SRT1720 chemical CID:25232708 PUBCHEM SIRT1 protein Q96EB6 UNIPROT "up-regulates activity" "chemical activation" 9606 18046409 t Selleck gcesareni "Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol." SIGNOR-207114 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 SS18 protein Q15532 UNIPROT SS18/MLLT10 complex SIGNOR-C75 SIGNOR "form complex" binding 9606 BTO:0001271 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-108927 (S,S)-asenapine chemical CHEBI:71257 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-258566 (S,S)-asenapine chemical CHEBI:71257 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-258848 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000601 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-258570 (S,S)-asenapine chemical CHEBI:71257 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-258567 (S)-selisistat chemical CHEBI:90371 ChEBI SIRT1 protein Q96EB6 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191511 SSH1 protein Q8WYL5 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-248762 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT "up-regulates activity" dephosphorylation Ser2 sFRKVVRQ 9606 17350576 t "Coronin 1B inhibits filament nucleation by Arp2/3 complex and this inhibition is attenuated by phosphorylation of Coronin 1B at Serine 2, a site targeted by SSH1L. Coronin 1B also directs SSH1L to lamellipodia where SSH1L likely regulates Cofilin activity via dephosphorylation" SIGNOR-248763 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates dephosphorylation Ser2 sFRKVVRQ 9606 17350576 t gcesareni "Coronin 1b inhibits filament nucleation by arp2/3 complex and this inhibition is attenuated by phosphorylation of coronin 1b at serine 2, a site targeted by ssh1l." SIGNOR-153604 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 SSH3 protein Q8TE77 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-248759 SST protein P61278 UNIPROT SSTR4 protein P31391 UNIPROT up-regulates binding 9606 10433861 t gcesareni "The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity." SIGNOR-82496 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 SSTR1 protein P30872 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-256679 SSTR1 protein P30872 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-256822 SSTR2 protein P30874 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-256684 SSTR2 protein P30874 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-256827 SSTR3 protein P32745 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-256677 SSTR3 protein P32745 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-256820 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 SSTR4 protein P31391 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-256680 SSTR4 protein P31391 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-256823 SSTR5 protein P35346 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-256690 SSTR5 protein P35346 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-256833 SSTR5 protein P35346 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-256969 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 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1623 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-248816 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1626 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-248805 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1644 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-248817 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 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 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1654 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-248807 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1665 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-248819 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1668 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-248808 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1672 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-248820 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1675 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-248809 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 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 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1724 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-248812 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1735 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-248824 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1738 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-248813 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1763 TPTSPSYsPTSPSYS -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-248825 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1766 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-248814 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 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1787 SPNYSPTsPSYSPTS -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-248815 (S)-(-)-sulpiride chemical CHEBI:64119 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-258734 (S)-(-)-sulpiride chemical CHEBI:64119 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-258733 STARD13 protein Q9Y3M8 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-260521 STARD8 protein Q92502 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-260520 STARD8 protein Q92502 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-260519 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 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 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001103 9551976 f "Federica Ferrentino" "A role for STAT1 in regulation of the CIITA promoter is shown by the rescue of IFN-gamma induction by expression of STAT1 in STAT1-defective U3A cells" SIGNOR-255752 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0001103 21576360 t "When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita" SIGNOR-256249 STAT1 protein P42224 UNIPROT IL12A protein P29459 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-249499 STAT1 protein P42224 UNIPROT IL12B protein P29460 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-249500 STAT1 protein P42224 UNIPROT IRF2 protein P14316 UNIPROT "up-regulates activity" binding 9606 15778351 t miannu "We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2." SIGNOR-254532 STAT1 protein P42224 UNIPROT IRF7 protein Q92985 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 16628196 f miannu "The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection." SIGNOR-255231 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 STAT1 protein P42224 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR "form complex" binding 10090 BTO:0000667 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235612 STAT1 protein P42224 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-255233 STAT1 protein P42224 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000249 17179173 f miannu "IFNgamma, through its receptor, activates STAT1, which binds with CBP/p300 coactivator, sequesters it from the cell system, and thus inhibits transcriptional induction of the MMP13 gene in chondrocytes." SIGNOR-255235 STAT1 protein P42224 UNIPROT MUC4 protein Q99102 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001861 19757157 t 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-254099 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 STAT1 protein P42224 UNIPROT NOS2 protein P35228 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-249497 STAT1 protein P42224 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 16481475 t gcesareni "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-144561 STAT1 protein P42224 UNIPROT S100A10 protein P60903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567;BTO:0002923 12645529 f miannu "IFN-gamma induced a rapid tyrosine phosphorylation and nuclear translocation of STAT1 protein, which is involved in the binding to the GAS-2 site in the p11 promoter by EMSA analysis. These data suggest that IFN-gamma-induced p11 expression is mediated through the binding of STAT1 to GAS sites in the p11 promoter." SIGNOR-255237 STAT1 protein P42224 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR "form complex" binding 10090 BTO:0000667 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235661 STAT1 protein P42224 UNIPROT TAP1 protein Q03518 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15778351 f miannu "We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested." SIGNOR-254531 STAT1 protein P42224 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 f "T-bet is a transcription factor detected in Th1, but not in Th0 or Th2 cells. Its expression is up-regulated by IFN-gamma, through a STAT-1-dependent mechanism" SIGNOR-254293 STAT1 protein P42224 UNIPROT TLR3 protein O15455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 16628196 f miannu "The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection." SIGNOR-255230 STAT2 protein P52630 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-240603 STAT2 protein P52630 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 17923090 t lperfetto "We then examined STAT2 acetylation within the b-barrel DBD. A direct interaction between the STAT2-DBD (315485) and STAT1 was detected (Figure 6E) (Li et al., 1997)." SIGNOR-217957 STAT3 protein P40763 UNIPROT BIRC5 protein O15392 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001033 26512963 f miannu "DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells." SIGNOR-254762 STAT3 protein P40763 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25787076 f miannu "We determined that Stat3 activation increases caspase-3 expression in C2C12 cells." SIGNOR-255335 STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 18177723 f "andrea cerquone perpetuini" "We identified cyclin D1 as a STAT3 target gene product downregulated in satellite cells from IL-6-deficient muscle in vitro and in vivo." SIGNOR-255411 STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16510571 f lperfetto "Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene." SIGNOR-253049 STAT3 protein P40763 UNIPROT CD274 protein Q9NZQ7 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001911;BTO:0003238 27141364 t irozzo "STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia.The protein-DNA binding assay revealed that pSTAT3 was bound to the PD-L1 promoter region in H23 cells transfected with EML4-ALK." SIGNOR-259188 STAT3 protein P40763 UNIPROT CD46 protein P15529 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17699108 f miannu "The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays." SIGNOR-255238 STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24011072 f miannu "To assess whether Stat3 affects C/EBPŒ¥ expression, we co-transfected C2C12 myoblasts with a plasmid expressing a C/EBPŒ¥promoter-driven luciferase plus a lentivirus expressing the constitutively active Stat3C-GFP. Overexpression of Stat3C increased C/EBPŒ¥promoter activity compared to that in lentivirus expressing GFP control" SIGNOR-255333 STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25787076 f miannu "P-Stat3 stimulates C/EBPδ expression and activity, which increases myostatin and MAFbx/Atrogin-1 and MuRF-1. Both pathways result in protein losses in muscle." SIGNOR-255334 ADIPOQ protein Q15848 UNIPROT ADIPOR1 protein Q96A54 UNIPROT up-regulates binding 9606 BTO:0000142 16622416 t milica "Two adiponectin receptors, adipor1 and adipor2, have recently been identified." SIGNOR-146170 STAT3 protein P40763 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 10090 11426647 f "Constitutive activation of Stat3 signaling is accompanied by upregulation of cyclin D1, c-Myc, and Bcl-x, changes consistent with subversion of normal cellular growth and survival control mechanisms." SIGNOR-252090 STAT3 protein P40763 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22669242 f miannu "Thus we infected C2C12 myofibers with a recombinant adenovirus expressing a mutant, constitutively activated STAT3 (cSTAT3) known to possess increased DNA binding/transcriptional activity. Consistent with wasting, atrogin-1 expression was also markedly increased (Fig. 3A). Thus STAT3 activation is by itself sufficient to induce muscle fiber wasting in cell culture." SIGNOR-255331 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 f "Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA)" SIGNOR-254364 STAT3 protein P40763 UNIPROT HAMP protein P81172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001950 18671304 f miannu "HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter." SIGNOR-255239 STAT3 protein P40763 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-255240 STAT3 protein P40763 UNIPROT HSPA1B protein P0DMV9 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-255241 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates "transcriptional regulation" 9606 28713870 f svumbaca "These data argue that, in TH2 cells, STAT3 is required for T cell IL-10 production, which in turn reinforces its own expression" SIGNOR-256234 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 22378047 f "IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype" SIGNOR-254515 STAT3 protein P40763 UNIPROT 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. our findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB." SIGNOR-254795 STAT3 protein P40763 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR "form complex" binding 10090 BTO:0000667 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235658 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 STAT3 protein P40763 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 10347215 f lperfetto "The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages." SIGNOR-249547 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 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 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 18177723 f miannu "Altogether, these data demonstrate that IL-6 loss results in deficient STAT3 signaling in activated satellite cells, leading to their reduced proliferation and myogenic progression, and highlight the major role played by the IL-6/STAT3 axis in controlling these processes during compensatory hypertrophy." SIGNOR-255632 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto "STAT3 signaling controls satellite cell expansion and skeletal muscle repair" SIGNOR-245048 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003298 BTO:0001103 30029643 f "In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway." SIGNOR-256256 STAT3 protein P40763 UNIPROT RORC protein P51449 UNIPROT up-regulates 9606 18454151 f "The inflammatory cytokines IL-6, IL-21 and IL-23 share signaling pathways by activating both STAT1 and STAT3, while IL-1beta is thought to activate the kinases IRAK1 and IRAK2 through recruitment of the adaptor MyD88. Thus, STAT3 is likely to be a common denominator in the induction of RORgammaT and IL-17 expression" SIGNOR-254303 STAT3 protein P40763 UNIPROT SALL4 protein Q9UJQ4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000815 19151334 f miannu "We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4 expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4." SIGNOR-255244 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002553 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 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 STAT3 protein P40763 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR "form complex" binding 10090 BTO:0000667 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235664 STAT3 protein P40763 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 22378047 f "IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype" SIGNOR-254517 STAT3 protein P40763 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0003266 12545153 t luana "Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells. " SIGNOR-259456 STAT4 protein Q14765 UNIPROT LAMTOR5 protein O43504 UNIPROT "up-regulates activity" binding 9606 BTO:0000150 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 STAT4 protein Q14765 UNIPROT PRF1 protein P14222 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000914 12372421 f miannu "IL-12-induced expression of the perforin gene in NK cells is directly regulated by STAT4, which binds, most likely as a homo-tetramer, to the tandem STAT-binding sequences in the perforin gene promoter." SIGNOR-255245 STAT4 protein Q14765 UNIPROT S100A4 protein P26447 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 22740693 f 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." SIGNOR-255246 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 STAT5A protein P42229 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001096 14530308 f apalma "Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells" SIGNOR-256583 STAT5A protein P42229 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0001096 14530308 f apalma "Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells" SIGNOR-256663 STAT5A protein P42229 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0002405 26059451 t "… these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells" SIGNOR-255631 STAT5A protein P42229 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu "Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors." SIGNOR-256074 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 t "We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell" SIGNOR-254301 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 t "We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell" SIGNOR-254365 STAT5A protein P42229 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 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-251787 STAT5A protein P42229 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 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-251784 STAT5A protein P42229 UNIPROT IGF1 protein P05019 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 10050749 t lperfetto "Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α" SIGNOR-251743 STAT5A protein P42229 UNIPROT IRF5 protein Q13568 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 25506346 t lperfetto "The GM-CSF receptor forms a dodecamer structure and recruits JAK2, leading to the activation of STAT5, extracellular signal-regulated kinase (ERK), V-Akt murine thymoma viral oncogene homolog 1 (AKT), and the nuclear translocation of NF-kappaB and IRF5" SIGNOR-249508 STAT5A protein P42229 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 BTO:0000801 22025054 f lperfetto "The activation of receptors for both GM-CSF and IFN-g stimulates the Jak kinaseSTAT transcription factor pathway, and an ISRE in the Irf5 promoter can bind STAT1 and STAT2, which suggests a possible mechanism for IRF5 expression induced by GM-CSF and IFN-g. Consequently, high expression of IRF5 results in polarization of the macrophage phenotype toward M1." SIGNOR-249510 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 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 16146838 t 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-249621 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 16146838 t 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-249622 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 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004479 29507660 f irozzo "FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance." SIGNOR-255733 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f "Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression" SIGNOR-254302 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 f miannu "Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release." SIGNOR-256233 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu "Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors." SIGNOR-255682 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 STAT6 protein P42226 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates 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-254101 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 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 STAT6 protein P42226 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 12947222 t "GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6" SIGNOR-254299 STAT6 protein P42226 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15632317 f miannu "IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation." SIGNOR-255249 STAT6 protein P42226 UNIPROT KDM6B protein O15054 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 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 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000801 25934862 f miannu "IL-4-induced macrophage polarization involves induction of STAT6 and KLF4 that induce each other and promote M2 polarization." SIGNOR-254519 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 22378047 t lperfetto "STAT6 coordinates and synergizes with both PPAR? and KrŸppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function." SIGNOR-249568 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 STAT6 protein P42226 UNIPROT PPARA protein Q07869 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-249534 STAT6 protein P42226 UNIPROT PPARGC1A protein Q9UBK2 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-249538 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 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 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 STAT6 protein P42226 UNIPROT SOCS1 protein O15524 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 17093501 t lperfetto "We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent." SIGNOR-249570 STAT6 protein P42226 UNIPROT STAT1 protein P42224 UNIPROT "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-249552 staurosporine chemical CHEBI:15738 ChEBI PRKCH protein P24723 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-258286 STC2/HMOX1 complex SIGNOR-C244 SIGNOR heme smallmolecule CHEBI:30413 ChEBI "down-regulates quantity by destabilization" BTO:0000298 22503972 t lperfetto "Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme." SIGNOR-260405 STC2 protein O76061 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 10090 BTO:0000298 29207625 f lperfetto "STC2 activates STAT3 signaling pathway in the hypothalamus and GT1-7 cells" SIGNOR-260406 STC2 protein O76061 UNIPROT STC2/HMOX1 complex SIGNOR-C244 SIGNOR "form complex" binding BTO:0000298 22503972 t Giorgia "Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme." SIGNOR-260387 STIL protein Q15468 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates binding 9606 BTO:0001271 16024801 t miannu "Cell cycle-dependent phosphorylation of sil is required for its interaction with pin1, a regulator of mitosis. Point mutation of the seven (s/t)p sites between amino acids 567 and 760 reduces mitotic phosphorylation of sil, pin1 binding, and spindle checkpoint duration." SIGNOR-138677 STING1 protein Q86WV6 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-260153 STIP1 protein P31948 UNIPROT HSP90AA1 protein P07900 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 27353360 t miannu "Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine." SIGNOR-261411 STIP1 protein P31948 UNIPROT HSP90AB1 protein P08238 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 27353360 t miannu "Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle4. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine." SIGNOR-261412 STK10 protein O94804 UNIPROT MSN protein P26038 UNIPROT down-regulates phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0000661 19255442 t llicata "Evidence in jurkat cells that lok phosphorylates erm and that erm phosphorylation impedes migration." SIGNOR-184433 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "up-regulates activity" phosphorylation -1 14976552 t lperfetto "We 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)." SIGNOR-242602 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation -1 14614828 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-217469 STK11 protein Q15831 UNIPROT BRSK1 protein Q8TDC3 UNIPROT up-regulates phosphorylation Thr189 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-122413 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 STK11 protein Q15831 UNIPROT MARK1 protein Q9P0L2 UNIPROT up-regulates phosphorylation Thr215 TVGNKLDtFCGSPPY 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-122545 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation Thr208 TFGNKLDtFCGSPPY 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-122628 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT "up-regulates activity" phosphorylation Ser215 KLDTFCGsPPYAAPE 9606 BTO:0000568 12879020 t lperfetto "Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211." SIGNOR-104059 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT "up-regulates activity" phosphorylation Thr211 TVGGKLDtFCGSPPY 9606 BTO:0000568 12879020 t lperfetto "Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211." SIGNOR-104063 STK11 protein Q15831 UNIPROT MARK4 protein Q96L34 UNIPROT up-regulates phosphorylation Thr214 TLGSKLDtFCGSPPY 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-122682 STK11 protein Q15831 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr167 NKDYHLQtCCGSLAY 9606 16216881 t fstefani "Site-directed mutagenesis indicated that thr167 and ser171, located between the dfg and ape motifs in the activation loop or t-loop, need to be autophosphorylated for melk to be active as a protein kinase (fig. 5). These sites are conserved in all other ampk-related protein kinases (fig. 4a), and the site corresponding to thr167 has been shown to be phosphorylated by protein kinase lkb1 (5)." SIGNOR-141038 STK11 protein Q15831 UNIPROT NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Thr211 QKDKFLQtFCGSPLY 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-122686 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 STK11 protein Q15831 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates phosphorylation Thr109 QWARLLQtSNITKSE 9606 20400510 t esanto "Lkb1 suppresses p21-activated kinase-1 (pak1) by phosphorylation of thr109 in the p21-binding domain." SIGNOR-164814 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14614828 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-119179 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser380 EPDHYRYsDTTDSDP 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-161118 STK11 protein Q15831 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-161122 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr383 HYRYSDTtDSDPENE 9606 18321849 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-161126 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Ser385 RYSDTTDsDPENEPF 9606 BTO:0001938 15987703 t lperfetto "We provide evidence suggesting that LKB1 phosphorylates PTEN at residue S385 in combination either with S380, T382 or T383" SIGNOR-247446 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT up-regulates phosphorylation Thr182 KSGEPLStWCGSPPY 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-122784 STK11 protein Q15831 UNIPROT SIK2 protein Q9H0K1 UNIPROT up-regulates phosphorylation Thr175 KSGELLAtWCGSPPY 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-122788 STK11 protein Q15831 UNIPROT SIK3 protein Q9Y2K2 UNIPROT up-regulates phosphorylation Thr163 TPGQLLKtWCGSPPY 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-122835 STK11 protein Q15831 UNIPROT SNRK protein Q9NRH2 UNIPROT "up-regulates activity" phosphorylation Thr173 QPGKKLTtSCGSLAY 9606 BTO:0000567 15733851 t lperfetto "we identify the sucrose non-fermenting protein (SNF1)-related kinase (SNRK), a largely unstudied AMPK subfamily member, as a novel substrate for LKB1. We demonstrate that LKB1 activates SNRK by phosphorylating the T-loop residue (Thr173)," SIGNOR-247493 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 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT "up-regulates activity" phosphorylation Thr185 KPGNLLLtTGGTLKI 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-101840 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT "up-regulates activity" phosphorylation Thr336 KDRWRSMtVVPYLED 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-101844 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT "up-regulates activity" phosphorylation Thr363 IEDDIIYtQDFTVPG 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-101848 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 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-150830 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 STK16 protein O75716 UNIPROT DRG1 protein Q9Y295 UNIPROT unknown phosphorylation T100 VAAYEFTTLTTVPGVI -1 18184589 t Manara "It is therefore likely that MPSK1 regulates DRG1 function by either phosphorylation or through competition with other DRG1 binding partners." SIGNOR-260806 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation S1967 DWAAQRCTISYRA -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-260804 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation T185 HVEGSRQALTLQD -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 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Y198 DWAAQRCTISYRA -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-260805 STK17A protein Q9UEE5 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000776 17339337 t gcesareni "Genetic and biochemical studies have shown that ser20 phosphorylation in the transactivation domain of p53 mediates p300-catalyzed dna-dependent p53 acetylation and b-cell tumor suppression. a cell-free ser20 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 ser20 kinases." SIGNOR-153532 STK24 protein Q9Y6E0 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-260265 STK24 protein Q9Y6E0 UNIPROT STK24 protein Q9Y6E0 UNIPROT up-regulates phosphorylation Thr190 DTQIKRNtFVGTPFW 9606 BTO:0000671 17046825 t gcesareni "Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (mst3) involves paxillin and protein-tyrosine phosphatase-pest." SIGNOR-150131 STK24 protein Q9Y6E0 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Thr442 DWVFLNYtYKRFEGL 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-142510 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 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Ser39 ELERVNLsAAQTLRA 9606 19370760 t llicata "Stk25 phosphorylates ccm3 at serine 39 and threonine 43" SIGNOR-185388 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Thr43 VNLSAAQtLRAAFIK 9606 19370760 t llicata "Stk25 phosphorylates ccm3 at serine 39 and threonine 43" SIGNOR-185392 STK26 protein Q9P289 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. Mst4 phosphorylates the regulatory t567 residue of ezrin." SIGNOR-185563 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 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 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 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-96683 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 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates activity" phosphorylation S109 KSHSRQASTDAGTAG 9606 BTO:0000038 25601544 t Luana "We performed mass spectrometry to determine additional sites on YAP1 targeted by NDR, identifying three additional serines, namely S61, S109, and S164, to also be phosphorylated by NDR in vitro " SIGNOR-259856 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates activity" phosphorylation S127 PQHVRAHSSPASLQL 9606 BTO:0000038 25601544 t Luana "We show that mammalian NDR1/2 kinases phosphorylate YAP1 on S127 and thereby negatively regulate YAP1 activity in tissue-cultured cells." SIGNOR-259855 STK39 protein Q9UEW8 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 14563843 t gcesareni "Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress," SIGNOR-118848 STK39 protein Q9UEW8 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 BTO:0000142 10980603 t gcesareni "Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress," SIGNOR-81541 STK3 protein Q13188 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto "Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3" SIGNOR-181056 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 t "Two of these, S909 and T1079, were required for Lats1 activation." milica "Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1." SIGNOR-133544 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 BTO:0000007 15688006 t "Two of these, S909 and T1079, were required for Lats1 activation." milica "Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1." SIGNOR-132927 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 21808241 t gcesareni "Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2." SIGNOR-175797 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica "MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation" SIGNOR-201274 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 21808241 t gcesareni "Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2." SIGNOR-175801 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 23431053 t milica "MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation" SIGNOR-201278 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 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-175805 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 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-201282 STK3 protein Q13188 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-201286 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 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 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-201290 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 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 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-201294 STK3 protein Q13188 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser438 EKNYQLKsRQILGMR 9606 21076410 t lperfetto "Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins" SIGNOR-169539 STK3 protein Q13188 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates phosphorylation -1 BTO:0000007 16930133 t milica "In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav" SIGNOR-230716 STK3 protein Q13188 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Thr180 DTMAKRNtVIGTPFW 9606 BTO:0000150 20231902 t gcesareni "Consistent with previous studies, sts alone induces mst2 cleavage and autophosphorylation of thr180, an indicator of mst2 activation, as well as apoptosis." SIGNOR-164310 STK4 protein Q13043 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto "Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3" SIGNOR-181060 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 STK4 protein Q13043 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 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. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1." SIGNOR-178186 STK4 protein Q13043 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 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. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1." SIGNOR-191847 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 18394876 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-178190 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 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 STK4 protein Q13043 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 18394876 t gcesareni "The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1" SIGNOR-178193 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation 9606 18394876 t gcesareni "The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1" SIGNOR-253002 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 18394876 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-253001 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 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. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1." SIGNOR-252999 STK4 protein Q13043 UNIPROT HIST1H2BB protein P33778 UNIPROT up-regulates 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 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 t milica "We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity." SIGNOR-133551 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 BTO:0000007 15688006 t milica "We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity." SIGNOR-133555 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 21808241 t gcesareni "Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2." SIGNOR-175821 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica "MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation" SIGNOR-201298 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 21808241 t gcesareni "Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2." SIGNOR-175825 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 23431053 t milica "MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation" SIGNOR-201302 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 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-175829 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 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-201306 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 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 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 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 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-201314 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 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-175841 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 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-201318 STK4 protein Q13043 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates -1 16930133 t lperfetto "In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav" SIGNOR-217833 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Thr183 DTMAKRNtVIGTPFW 9534 BTO:0004055 12223493 t lperfetto "Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity." SIGNOR-247577 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Thr187 KRNTVIGtPFWMAPE 9534 BTO:0004055 12223493 t lperfetto "Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity." SIGNOR-247581 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr129 ITEIADLtQKIFDLR 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182049 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182053 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr31 SNYRAYAtEPHAKKK 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182057 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr51 SRKLQLKtLLLQIAK 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182061 STMN1 protein P16949 UNIPROT TTL protein Q8NG68 UNIPROT down-regulates binding 9606 23624152 t miannu "Stathmin depresses ttl tubulin tyrosination activityin vitro." SIGNOR-193465 STOML2 protein Q9UJZ1 UNIPROT ATP smallmolecule CHEBI:15422 ChEBI "up-regulates quantity" 9606 BTO:0000782 20359165 f Giorgia "In addition, mitochondrial and whole-cell ATP levels in resting SLP-2hi T cells were significantly higher than those in SLP-2lo T cells (P < 0.05) (Fig. 7d). Such an increase in ATP levels in SLP-2hi T cells correlated with increased resistance to depletion of mitochondrial ATP with oligomycin" SIGNOR-260384 STOML2 protein Q9UJZ1 UNIPROT CD3E protein P07766 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 18641330 t Giorgia "We observed that SLP-2 steadily associated with the CD3-epsilon chain of the TCR complex under resting conditions and during the 60 min of stimulation|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-260375 STOML2 protein Q9UJZ1 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 18641330 f 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-260376 STOML2 protein Q9UJZ1 UNIPROT MFN2 protein O95140 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000782 20359165 f Giorgia "Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion." SIGNOR-260380 STOML2 protein Q9UJZ1 UNIPROT NDUFV1 protein P49821 UNIPROT "up-regulates activity" 9606 BTO:0000782 20359165 f Giorgia "We found that SLP-2hi cells had significantly higher activities of NADH dehydrogenase and succinate dehydrogenase (P < 0.05), complexes I and II of the electron transport chain." SIGNOR-260382 STOML2 protein Q9UJZ1 UNIPROT OPA1 protein O60313 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000782 20359165 f Giorgia "Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion." SIGNOR-260381 STOML2 protein Q9UJZ1 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 18641330 f 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 STOML2 protein Q9UJZ1 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000782 21746876 f Giorgia "We performed real-time RT-PCR to measure the levels of PGC-1alpha mRNA and found that these were increased in SLP-2hi cells (Fig. 3h), supporting the idea that upregulation of SLP-2 expression is associated with an increase in the expression of mitochondrially targeted genes." SIGNOR-260379 STOML2 protein Q9UJZ1 UNIPROT SDHD protein O14521 UNIPROT "up-regulates activity" 9606 BTO:0000782 20359165 f Giorgia "We found that SLP-2hi cells had significantly higher activities of NADH dehydrogenase and succinate dehydrogenase (P < 0.05), complexes I and II of the electron transport chain." SIGNOR-260383 STOML2 protein Q9UJZ1 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 18641330 f 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-260377 STOM protein P27105 UNIPROT SLC2A1 protein P11166 UNIPROT "down-regulates activity" binding 9606 10562431 t Giulio "Similar to the results obtained in the RBC, Glut1 and stomatin immunoprecipitated with each other in lysates of Clone 9 cells. The above results suggest that stomatin is closely associated with Glut1 in the plasma membrane and that overexpression of stomatin results in a depression in the basal rate of glucose transport." SIGNOR-261278 streptozocin chemical CHEBI:9288 ChEBI SLC2A2 protein P11168 UNIPROT "down-regulates quantity" "chemical inhibition" 10090 BTO:0000783 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 Stress_granules phenotype SIGNOR-PH124 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-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-260866 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 21454478 t gcesareni "In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner" SIGNOR-172993 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner" SIGNOR-195687 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 21454478 t gcesareni "In addition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r/co-smad complex and further promoting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner" SIGNOR-172996 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activi-ties of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manne" SIGNOR-195690 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 STX16 protein O14662 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-253079 STYX protein Q8WUJ0 UNIPROT FBXW7 protein Q969H0 UNIPROT "down-regulates activity" binding 9606 28007894 t "STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti-correlated in breast cancer patients," SIGNOR-251663 SUB1 protein P53999 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 20080105 t 1 miannu "We have found that PC4 directly interacts with the REST–CoREST complex. we found that there was a substantial reduction of REST–CoREST complex on the SCN2 promoter upon PC4 silencing in 293T cells." SIGNOR-239325 "Substance P" smallmolecule CHEBI:80308 ChEBI TACR1 protein P25103 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-257586 sufentanil chemical CHEBI:9316 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 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 SUFU protein Q9UMX1 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" binding 15367681 t lperfetto "Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1" SIGNOR-249591 SUFU protein Q9UMX1 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates activity" relocalization 10090 16316410 t lperfetto "We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms" SIGNOR-129065 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates activity" relocalization 10090 10433919 t lperfetto "Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling" SIGNOR-129068 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 SUFU protein Q9UMX1 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t miannu "Hsu(fu) associated with itself / homo- or heterodimers of hsu(fu) might function to bring together other effector proteins" SIGNOR-72311 sulindac chemical CHEBI:9352 ChEBI RXRA protein P19793 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001109 20541701 t Luana "NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling" SIGNOR-257847 sulpiride chemical CHEBI:32168 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" -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. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I)." SIGNOR-258431 sulpiride chemical CHEBI:32168 ChEBI DRD3 protein P35462 UNIPROT "down-regulates activity" "chemical inhibition" -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. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I)." SIGNOR-258430 "Sumanirole maleate" chemical CID:9818478 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-207594 sumatriptan chemical CHEBI:10650 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-258340 SUN2 protein Q9UH99 UNIPROT RAB5A protein P20339 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10818110 t Sara "Rab5ip represents a novel rab5 interacting protein that may function on endocytic vesicles as a receptor for rab5-GDP and participate in the activation of rab5" SIGNOR-261309 sunitinib chemical CHEBI:38940 ChEBI CSF1R protein P07333 UNIPROT "down-regulates activity" "chemical inhibition" 9606 17367763 t miannu "Sunitinib (SU-11248, Sutent) inhibits at least eight receptor protein-tyrosine kinases including vascular endothelial growth factor receptors 1-3 (VEGFR1-VEGFR3), platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta), stem cell factor receptor (Kit), Flt-3, and colony-stimulating factor-1 receptor (CSF-1R)." SIGNOR-259319 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 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-172908 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 21993628 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-176748 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 sunitinib chemical CHEBI:38940 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-258290 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0004479 20570526 t Luana "Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors]," SIGNOR-257849 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 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-172911 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 21993628 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-176751 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 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-163941 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0004479 20570526 t Luana "Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors]," SIGNOR-257848 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 21993628 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-176754 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 sunitinib chemical CHEBI:38940 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-258292 sunitinib chemical CHEBI:38940 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-258291 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 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 sunitinib chemical CHEBI:38940 ChEBI PDGFRA protein P16234 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-163953 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 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 21993628 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-176766 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 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-163956 suprofen chemical CHEBI:9362 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-257809 suprofen chemical CHEBI:9362 ChEBI PTGS2 protein P35354 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-257808 "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 "Survival Factors" stimulus SIGNOR-ST8 SIGNOR GRB2 protein P62993 UNIPROT "up-regulates activity" 19282669 f lperfetto "Activation of receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) by growth factors or mitogens leads to the recruitment of an adaptor protein Grb2 (growth factor receptor bound protein) and the guanine nucleotide exchange factor (SOS). The SOS activates Ras to recruit and activate Raf at the plasma membrane by phosphorylation at multiple sites. MEK1/2 is which then phosphorylated at two serine residues that subsequently phosphorylates ERK1/2 on both threonine and tyrosine. Activated ERK1/2 phosphorylates RSK and both RSK and ERK translocate to the nucleus where they activates multiple transcription factors ultimately resulting in effector protein synthesis and causing changes in cell proliferation and survival. ERK phosphorylation of MEK and possibly Raf can inactivate the pathway at those steps creating a negative feedback loop." SIGNOR-250559 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 SUV39H1 protein O43463 UNIPROT MYOG protein P15173 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-249601 SUZ12/EZH2 complex SIGNOR-C77 SIGNOR SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR "form complex" binding 10090 BTO:0000165;BTO:0002314 20887952 t lperfetto "TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter." SIGNOR-235577 SUZ12/EZH2 complex SIGNOR-C77 SIGNOR YY1 protein P25490 UNIPROT "up-regulates activity" binding 10090 BTO:0000165;BTO:0002314 20887952 t lperfetto "TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter." SIGNOR-235574 SUZ12 protein Q15022 UNIPROT PRC2 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-241900 SUZ12 protein Q15022 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 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-254150 SUZ12 protein Q15022 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 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-146764 SUZ12 protein Q15022 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 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-254155 (S)-verapamil chemical CHEBI:77736 ChEBI ABCC1 protein P33527 UNIPROT "up-regulates activity" "chemical activation" 10036 BTO:0000120 17646169 t Federica "(S)-Verapamil acts as a “killer” by activation of MRP1-mediated GSH efflux, leading to the death of potentially resistant tumor cells." SIGNOR-261081 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 12138206 f irozzo "INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex [.]. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G(0)-G(1) arrest. These results together indicate that cyclin D1 is a direct target for repression by INI1/hSNF5." SIGNOR-256293 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-256299 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0002586 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 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 10090 BTO:0001957 16452181 f irozzo "C-myc is a direct target of SWI/SNF complex–dependent promoter repression. These results indicate that repression of c-myc is indeed dependent on the activity of SWI/SNF–related complexes and specifically on complexes that contain ARID1A." SIGNOR-256292 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR "form complex" binding 9606 BTO:0001103 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-151703 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "Myog/SWI/SNF complex" complex SIGNOR-C94 SIGNOR "form complex" binding 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-151706 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002586 12226744 f irozzo "The hSNF5/INI1 gene encodes a member of the SWI/SNF chromatin remodelling complexes.Here, we show that the ectopic expression of wild-type hSNF5/INI1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into S phase of MRT cells." SIGNOR-256298 "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 SYDE2 protein Q5VT97 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-260522 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr178 LLEDEADyVVPVEDN 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-96040 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 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr84 EHSDSEMyVMPAEEN 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-96048 SYK protein P43405 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr281 LEETNNDyETADGGY -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 pointFyn 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-247590 SYK protein P43405 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 pointFyn 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-246551 SYK protein P43405 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates phosphorylation Tyr397 EDEPEGDyEEVLEPE 9606 BTO:0000776 9104825 t llicata "Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis." SIGNOR-47342 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 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 SYK protein P43405 UNIPROT IL15RA protein Q13261 UNIPROT "up-regulates activity" phosphorylation Tyr227 AVSLLACyLKSRQTP 9606 BTO:0001154 11714793 t lperfetto "Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells" SIGNOR-246556 SYK protein P43405 UNIPROT LCK protein P06239 UNIPROT "down-regulates activity" phosphorylation Tyr192 NLDNGGFyISPRITF 9606 BTO:0000782 8798764 t lperfetto "Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling" SIGNOR-246562 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 SYK protein P43405 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Tyr18 MEDHAGTyGLGDRKD 9606 BTO:0000938 18070606 t lperfetto "We established that tyrosine 18 was the primary residue in tau phosphorylated by sykphosphorylation of tau by syk could be involved in neurite outgrowth." SIGNOR-159648 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0000776 8657103 t lperfetto "Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771." SIGNOR-246572 SYK protein P43405 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates activity" phosphorylation Tyr658 SDFEGFSyVNPQFVH 9606 BTO:0000830 12881490 t lperfetto "We present evidence that Tyr-662 and Tyr-658 of PKCbetaI and PKCalpha, respectively, are phosphorylated by Syk in the membrane compartment of FcepsilonRI-stimulated mast cells. These phosphorylations require prior PKC autophosphorylation of the adjacent serine residues (Ser-661 and Ser-657, respectively) and generate a binding site for the SH2 domain of the adaptor protein Grb-2." SIGNOR-246581 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 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT "up-regulates activity" phosphorylation Tyr448 GDDSDEDyEKVPLPN 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-246596 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 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-59635 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 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 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-59643 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr21 ENLEQEEyEDPDIPE -1 10942405 t "The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton" SIGNOR-251411 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr8 MEELQDDyEDMMEEN -1 10942405 t "The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton" SIGNOR-251413 SMAD6 protein O43541 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 11737269 t lperfetto "Smad6 interacts with tak1 and tab1, and smad7 with tab1" SIGNOR-112636 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr21 ENLEQEEyEDPDIPE 9606 10942405 t llicata "Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites." SIGNOR-80788 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr8 MEELQDDyEDMMEEN 9606 10942405 t llicata "Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites." SIGNOR-80792 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr125 VDPDNEAyEMPSEEG 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-113061 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 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr136 SEEGYQDyEPEA 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-113069 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 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 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 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 SYK protein P43405 UNIPROT TUBA4A protein P68366 UNIPROT "up-regulates activity" phosphorylation Tyr432 MAALEKDyEEVGIDS 9606 BTO:0000776 9490415 t lperfetto "Syk, Activated by Cross-linking the B-cell Antigen Receptor, Localizes to the Cytosol Where It Interacts with and Phosphorylates alpha-Tubulin on Tyrosine" SIGNOR-246626 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 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 TAB1 protein Q15750 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates 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-205437 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 17299140 t lperfetto "The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells." SIGNOR-153031 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 8638164 t lperfetto "The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells." SIGNOR-41941 TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" binding 10116 BTO:0003324 16407200 t lperfetto "In contrast to MKK3-induced p38 kinase downstream effects, TAB-1-induced p38 kinase activation does not induce expression of pro-inflammatory genes, cardiac marker gene expression, or changes in cellular morphology. Rather, TAB-1 binds to p38 and prevents p38 nuclear localization." SIGNOR-143576 TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" binding 9606 11847341 t lperfetto "Here, we report an unexpected activation mechanism for p38alpha MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38alpha with TAB1 [transforming growth factor-beta-activated protein kinase 1 (TAK1)-binding protein 1] leading to autophosphorylation and activation of p38alpha." SIGNOR-114843 SMAD7 protein O15105 UNIPROT STRAP protein Q9Y3F4 UNIPROT up-regulates binding 9606 10757800 t gcesareni "Strap recruits smad7 to the activated type i receptor and forms a complex" SIGNOR-76771 TAB1 protein Q15750 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 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-205440 TAB1 protein Q15750 UNIPROT ROR2 protein Q01974 UNIPROT down-regulates phosphorylation 9606 18762249 t gcesareni "Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain" SIGNOR-180566 TAB2 protein Q9NYJ8 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates 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-205443 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 8638164 t lperfetto "The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1." SIGNOR-105860 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 14670075 t lperfetto "Our results indicate that 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. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages" SIGNOR-120268 TAB2 protein Q9NYJ8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 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-205446 TAB3 protein Q8N5C8 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates 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-205449 TAB3 protein Q8N5C8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 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 tacedinaline chemical CHEBI:90195 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-258008 tacedinaline chemical CHEBI:90195 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-258007 TACR1 protein P25103 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-257423 TACR1 protein P25103 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-257048 TACR1 protein P25103 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-257161 TACR1 protein P25103 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-256919 TACR1 protein P25103 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-257249 TACR1 protein P25103 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-257374 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 TACR2 protein P21452 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-257131 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 TACR2 protein P21452 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-256879 TACR2 protein P21452 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-257015 TACR3 protein P29371 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-257389 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 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 TACR3 protein P29371 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-257066 TACR3 protein P29371 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-257179 TACR3 protein P29371 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-256937 TACR3 protein P29371 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-257267 TACR3 protein P29371 UNIPROT GNAS protein Q5JWF2 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-256794 "tacrolimus (anhydrous)" chemical CHEBI:61049 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-127242 "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 tadalafil chemical CHEBI:71940 ChEBI PDE11A protein Q9HCR9 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000815 21189023 t Luana "All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11" SIGNOR-257888 tadalafil chemical CHEBI:71940 ChEBI PDE5A protein O76074 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000815 21189023 t Luana "All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11" SIGNOR-257887 TAF12 protein Q16514 UNIPROT ATF7 protein P17544 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 15735663 t miannu "We show that overexpression of hsTAF12 potentiates ATF7-induced transcriptional activation through direct interaction with ATF7, suggesting that TAF12 is a functional partner of ATF7." SIGNOR-225249 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser280 VDGTGDTsSEEDEDE 9606 11278496 t lperfetto "TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels" SIGNOR-246630 TAF1 protein P21675 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 15053879 t llicata "Phosphorylation on thr-55 by taf1 mediates degradation of p53" SIGNOR-123651 TAF3 protein Q5VWG9 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-181611 TAF3/TRF3 complex SIGNOR-C23 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 10090 BTO:0000165 17704303 f llicata "Here we report that differentiation of myoblast to myotubes involves the disruption of the canonical holo-TFIID and replacement by a novel TRF3/TAF3 (TBP-related factor 3/TATA-binding protein-associated factor 3) complex." SIGNOR-237621 TAF4 protein O00268 UNIPROT ATF7 protein P17544 UNIPROT "down-regulates activity" binding 9534 BTO:0004055 15735663 t miannu "These results not only demonstrate an interaction between ATF7 and TAF4 but also indicate, as in the case of TAF12 (see Figure 3e), that no additional cellular component is required for this binding. They also suggest that TAF4 may interfere with the formation of ATF7–TAF12 subcomplexes, thereby inhibiting ATF7-induced transactivation." SIGNOR-225300 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 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 TAK-960 chemical CID:53357478 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207200 TAL1 protein P17542 UNIPROT ANGPT2 protein O15123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000574 22792348 f miannu "Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation." SIGNOR-198279 TAL1 protein P17542 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-253924 TAL1 protein P17542 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR "up-regulates activity" 10090 BTO:0004911 23319051 f "Analysis of SclΔ40/Δ40 embryonic stem (ES) cells revealed impaired erythroid differentiation, which was accompanied by a failure to upregulate Scl when erythropoiesis was initiated." SIGNOR-259971 TAL1 protein P17542 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 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-259970 TAL1 protein P17542 UNIPROT FUBP1 protein Q96AE4 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000664 30653565 t irozzo "TAL1 directly activates the FUBP1 promoter, leading to increased FUBP1 expression during erythroid differentiation." SIGNOR-259131 TAL1 protein P17542 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C" SIGNOR-254209 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 tamoxifen chemical CHEBI:41774 ChEBI ESR1 protein P03372 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20512796 t miannu "Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth." SIGNOR-258587 tamoxifen chemical CHEBI:41774 ChEBI ESR2 protein Q92731 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20512796 t miannu "Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth." SIGNOR-258588 tamoxifen chemical CHEBI:41774 ChEBI GPER1 protein Q99527 UNIPROT up-regulates binding 9606 BTO:0000150 15539556 t gcesareni "The finding that the antiestrogens tamoxifen and ici 182,780, and an environmental estrogen, ortho,para-dichlorodiphenyldichloroethylene (o,p'-dde), have high binding affinities to the receptor and mimic the actions of e2 has important implications for both the development and treatment of estrogen-dependent breast cancer." SIGNOR-130395 "tamoxifen citrate" chemical CHEBI:9397 ChEBI ESR1 protein P03372 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000150 20512796 t miannu "Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth." SIGNOR-259301 tamsulosin chemical CHEBI:9398 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-258470 tamsulosin chemical CHEBI:9398 ChEBI ADRA1D protein P25100 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-258471 "Tandospirone citrate" chemical CHEBI:32182 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-258861 tandutinib chemical CHEBI:90237 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-258296 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 tandutinib chemical CHEBI:90237 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207212 tandutinib chemical CHEBI:90237 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-258298 tandutinib chemical CHEBI:90237 ChEBI PDGFRB protein P09619 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-258299 TAOK1 protein Q7L7X3 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 9786855 t lperfetto "The activation of and binding to MEK3 by TAO1 implicates TAO1 in the regulation of the p38-containing stress-responsive MAP kinase pathway" SIGNOR-60818 TAOK1 protein Q7L7X3 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "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-201321 TAOK1 protein Q7L7X3 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "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-201324 TAOK2 protein Q9UL54 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000007 12665513 t lperfetto "Transfection studies demonstrated that TAO2 stimulates phosphorylation of the TCF Elk1 on the major activating site, Ser383, and that TAO2 stimulates transactivation of Elk1 and the related TCF, Sap1." SIGNOR-246638 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" binding -1 10497253 t lperfetto "Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7." SIGNOR-70947 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 11279118 t lperfetto "Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells" SIGNOR-106462 TAOK2 protein Q9UL54 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" binding 9606 BTO:0001130 10660600 t lperfetto "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-74864 TAOK2 protein Q9UL54 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "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-201327 TAOK2 protein Q9UL54 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2" SIGNOR-201330 TAOK3 protein Q9H2K8 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2" SIGNOR-201333 TAOK3 protein Q9H2K8 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "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-192762 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT "up-regulates activity" phosphorylation Thr181 PANSFVGtPYWMAPE 9534 BTO:0004055 10559204 t lperfetto "These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK." SIGNOR-246298 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT "up-regulates activity" phosphorylation Tyr183 NSFVGTPyWMAPEVI 9534 BTO:0004055 10559204 t lperfetto "These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK." SIGNOR-246302 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR "up-regulates activity" phosphorylation 9606 23431053 t miannu "The thousand-and-one (TAO) amino acids kinase or TAOK1 – 3 has been shown to directly phosphorylate and activate Hpo or MST1/2." SIGNOR-256182 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 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK4 protein Q13043 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-230710 TARBP2 protein Q15633 UNIPROT DICER1 protein Q9UPY3 UNIPROT up-regulates binding 9606 16142218 t miannu "Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si? Or mi?RISCs In mammalian cells, but it may also facilitate the cleavage of pre?miRNAs By dicer." SIGNOR-140226 TARBP2 protein Q15633 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR "form complex" binding 9606 16142218 t lperfetto "Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer." SIGNOR-140229 taurine smallmolecule CHEBI:15891 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-258579 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 tazarotene chemical CHEBI:32184 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-258028 tazarotene chemical CHEBI:32184 ChEBI RARG protein P13631 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-258029 TBC1D4 protein O60343 UNIPROT SLC2A4 protein P14672 UNIPROT down-regulates 9606 12637568 f gcesareni "These findings strongly indicate that insulin-stimulated phosphorylation of as160 is required for glut4 translocation and that this phosphorylation signals translocation through inactivation of the rab gap function." SIGNOR-99303 TBCA protein O75347 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR "up-regulates quantity by stabilization" binding 9606 28158450 t miannu "These intermediates interact with a series of five tubulin-specific chaperones (termed TBCA-E); these function together as a nanomachine that assembles the α/β tubulin heterodimer" SIGNOR-261169 TBK1 protein Q9UHD2 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto "Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling." SIGNOR-252608 TBK1 protein Q9UHD2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto "Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling." SIGNOR-172132 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000782 14679297 t lperfetto "We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i." SIGNOR-120355 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser385 MARVGGAsSLENTVD -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-178391 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser386 ARVGGASsLENTVDL -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-178395 TBK1 protein Q9UHD2 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-178399 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser398 VDLHISNsHPLSLTS -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-178403 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser402 ISNSHPLsLTSDQYK -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-178407 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser405 SHPLSLTsDQYKAYL -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-178411 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 TBK1 protein Q9UHD2 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser158 QRMLPSLsLTEDVKW 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-196528 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 TBK1 protein Q9UHD2 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 11815618 t lperfetto "Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha." SIGNOR-246643 TBK1 protein Q9UHD2 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-260157 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 TBK1 protein Q9UHD2 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser403 ESLSQMLsMGFSDEG 9606 BTO:0000801 22921120 t llicata "Tbk-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on ser-403, a residue essential for its role in autophagic clearance." SIGNOR-191944 TBK1 protein Q9UHD2 UNIPROT STAT6 protein P42226 UNIPROT up-regulates phosphorylation Ser407 PIQLQALsLPLVVIV 9606 22000020 t gcesareni "We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing." SIGNOR-176771 TBK1 protein Q9UHD2 UNIPROT STAT6 protein P42226 UNIPROT up-regulates phosphorylation Tyr641 MGKDGRGyVPATIKM 9606 22000020 t gcesareni "We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing." SIGNOR-176775 TBL1XR1 protein Q9BZK7 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 24243687 t miannu "We showed that tblr1 physically interacts with ar and directly occupies the androgen-response elements of the affected ar target genes in an androgen-dependent manner. / we characterized tblr1 as a coactivator of ar" SIGNOR-203235 TBL1XR1 protein Q9BZK7 UNIPROT BCL3 protein P20749 UNIPROT down-regulates ubiquitination 9606 20547759 t miannu "We also defined the e3 ligase tblr1 as a protein involved in bcl-3 degradation" SIGNOR-166111 TBL1Y protein Q9BQ87 UNIPROT CTBP1 protein Q13363 UNIPROT "down-regulates quantity by destabilization" binding 9606 18374649 t Luana "TBL1 interacts in vivo with CtBP and promote its proteasomal degradation" SIGNOR-260902 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 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 TBX1 protein O43435 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001176 20439995 f "Regulation of expression" miannu "Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene." SIGNOR-251869 TBX21 protein Q9UL17 UNIPROT GATA3 protein P23771 UNIPROT down-regulates 9606 16386358 f "Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both" SIGNOR-254295 TBX21 protein Q9UL17 UNIPROT IFNG protein P01579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 17541280 f "T-bet is crucially implicated in Th1 differentiation due to its strong promoting activity for IFN-gamma gene transcription" SIGNOR-254508 TBX21 protein Q9UL17 UNIPROT IL10 protein P22301 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000782 20154735 f azuccotti "Similarly, an increase in IL-10 expression was observed in mice deficient for the TH1 cell-specific transcription factor T-bet (also known as TBX21) that were infected with M.tuberculosis, suggesting that T-bet might have a role in the negative regulation of IL-10 expression by TH1 cells" SIGNOR-254524 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 TBX21 protein Q9UL17 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 t "In turn, T-bet is an IFN-gamma activator (Szabo et al., 2000), thus creating an indirect positive feedback. Furthermore, it has been shown that ectopic T-bet is able to induce the transcription of its own gene" SIGNOR-254294 TBX2 protein Q13207 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002267 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-249593 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 TBX3 protein O15119 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002267 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-249602 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 TBX5 protein Q99593 UNIPROT CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "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-255253 TBX5 protein Q99593 UNIPROT FGF10 protein O15520 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000562 18451335 f miannu "TBX5 is expressed, among others, in the embryonic heart and forelimbs.8 In the heart, it regulates transcription of downstream genes such as the atrial natriuretic factor (NPPA) and fibroblast growth factor 10 (FGF10) by the binding to T-box binding elements (TBEs),11 often in combination with the NKX2-5 transcription factor." SIGNOR-255383 TBX5 protein Q99593 UNIPROT MTA2 protein O94776 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-255256 TBX5 protein Q99593 UNIPROT MTSS1 protein O43312 UNIPROT "up-regulates quantity by expression" "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-255254 TBX5 protein Q99593 UNIPROT NPPA protein P01160 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000562 18451335 f miannu "TBX5 is expressed, among others, in the embryonic heart and forelimbs.8 In the heart, it regulates transcription of downstream genes such as the atrial natriuretic factor (NPPA) and fibroblast growth factor 10 (FGF10) by the binding to T-box binding elements (TBEs),11 often in combination with the NKX2-5 transcription factor." SIGNOR-255384 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 TBXA2R protein P21731 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-257139 TBXA2R protein P21731 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-257023 TBXA2R protein P21731 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-256744 TCEA1 protein P23193 UNIPROT UBR5 protein O95071 UNIPROT up-regulates binding 9606 21127351 t miannu "We show that the e3 ubiquitin ligase ubr5 associates with the cdk9 subunit of positive transcription elongation factor b to mediate its polyubiquitination in human cells. Tfiis also binds ubr5 to stimulate cdk9 polyubiquitination." SIGNOR-170258 T_cell_activation phenotype SIGNOR-PH73 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu "The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm." SIGNOR-261022 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IFNG protein P01579 UNIPROT "up-regulates quantity" 9606 BTO:0000782 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-260967 TCF12 protein Q99081 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR "form complex" binding 9606 16847330 t 2 miannu "The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation." SIGNOR-241119 TCF12 protein Q99081 UNIPROT NOTCH3 protein Q9UM47 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "Hebalt positively regulates t-cell genes, such as pt_ and notch3" SIGNOR-197517 TCF12 protein Q99081 UNIPROT PTCRA protein Q6ISU1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "Hebalt positively regulates t-cell genes, such as pt_ and notch3" SIGNOR-197520 TCF3 protein P15923 UNIPROT BBC3 protein Q96PG8 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23684607 f miannu "The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins." SIGNOR-255386 TCF3 protein P15923 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23684607 f miannu "The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins." SIGNOR-255385 TCF3 protein P15923 UNIPROT CR2 protein P20023 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11739509 f miannu "We have previously described the presence of an intronic element that is required for both cell- and stage-specific expression of CR2. In this study, we report the identification of a cell type-specific repressor element within the proximal promoter. By supershift analysis this element binds members of the basic helix-loop-helix family of proteins, in particular E2A gene products. Mutational analysis demonstrates that binding of E2A proteins is critical for functioning of this repressor. Thus, E2A activity is key not only for early B cell development, but also for controlling CR2 expression, a gene expressed only during later stages of ontogeny." SIGNOR-255387 TCF3 protein P15923 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 BTO:0000887 1649701 t "E12/E47-like proteins interact in vivo with the myogenic HLH proteins MyoD and myogenin" lperfetto "In addition we demonstrate that myod, in conjunction with e12/e47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators." SIGNOR-20540 TCF3 protein P15923 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR "form complex" binding 10090 BTO:0001103 18094043 t lperfetto "MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells." SIGNOR-241551 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 TCF4 protein P15884 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20459685 f miannu "Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling." SIGNOR-255389 TCF4 protein P15884 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20459685 f miannu "Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling." SIGNOR-255388 TCF4 protein P15884 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22777675 f miannu "we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays." SIGNOR-255390 TCF4 protein P15884 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18852287 f "Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription." SIGNOR-253324 TCF4 protein P15884 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR "form complex" binding 9606 16847330 t 2 miannu "The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation." SIGNOR-241382 TCF4 protein P15884 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22777675 f miannu "we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays." SIGNOR-255391 TCF4 protein P15884 UNIPROT SOX9 protein P48436 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15240568 f "The β-catenin–TCF4 complex activity is required for SOX9 expression." SIGNOR-253323 TCF4 protein P15884 UNIPROT SSTR2 protein P30874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001976 10207097 t Luana "Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain." SIGNOR-261618 TCF7L2 protein Q9NQB0 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR "down-regulates activity" "transcriptional regulation" 20492721 f FFerrentino "These findings suggested that miR-210 could promote adipogenesis by repressing WNT signaling through targeting Tcf7l2." SIGNOR-253519 TCL1A protein P56279 UNIPROT AKT1 protein P31749 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-81680 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 TCL1B protein O95988 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t gcesareni "In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation." SIGNOR-81713 TCL1B protein O95988 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t gcesareni "In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation." SIGNOR-81716 TCL1B protein O95988 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto "In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation." SIGNOR-244452 TCR complex SIGNOR-C153 SIGNOR 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-259935 TCR complex SIGNOR-C153 SIGNOR ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9534 1423621 f "We have recently identified a 70 kd tyrosine phosphoprotein (ZAP-70) that associates with zeta and undergoes tyrosine phosphorylation following TCR stimulation|Moreover, tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP-70 may interact to mediate TCR signal transduction." SIGNOR-252304 TDGF1 protein P13385 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-251938 TDGF1 protein P13385 UNIPROT ACVR2A protein P27037 UNIPROT down-regulates binding 9606 BTO:0000007 12682303 t acerquone "Here we show that cripto can form a complex with activin and actrii/iib cripto inhibited crosslinking of activin to alk4 and the association of alk4 with actrii/iib." SIGNOR-100052 TDGF1 protein P13385 UNIPROT MSTN protein O14793 UNIPROT down-regulates 9606 BTO:0002314 BTO:0000887;BTO:0001103 23129614 f fstefani "We provide evidence that cripto modulates myogenic cell determination and promotes proliferation by antagonizing the tgf-beta ligand myostatin." SIGNOR-192436 TDGF1 protein P13385 UNIPROT NODAL protein Q96S42 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-251937 TDGF1 protein P13385 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0002314 BTO:0000887;BTO:0001103 23129614 f miannu "Cripto, a regulator of early embryogenesis, is a novel regulator of muscle regeneration and satellite cell progression toward the myogenic lineage." SIGNOR-192439 TDGF1 protein P13385 UNIPROT TGFB1 protein P01137 UNIPROT "down-regulates activity" binding 9606 BTO:0002181;BTO:0000599 17030617 t lperfetto "ere, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-beta. Cripto bound TGF-beta and reduced the association of TGF-beta with its type I receptor, TbetaRI." SIGNOR-150006 TDRD3 protein Q9H7E2 UNIPROT SNRPN protein P63162 UNIPROT unknown binding -1 15955813 t miannu "the TDRD3 GST-Tudor protein interacted strongly with methylated SmB/B′ and SmD but not with SmE. These results suggest that the Tudor domains of SMN and SPF30 likely interact with assembled snRNPs, whereas the Tudor domain of TDRD3 might bind unassembled methylated Sm proteins." SIGNOR-253518 TEAD1 protein P28347 UNIPROT BMP4 protein P12644 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 23673366 f gcesareni "Taz induces bmp4 transcription through the tead family of transcription factors, which mediate bmp4 promoter activation through binding to tead response element 1 (tre1)." SIGNOR-202049 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 20153295 f lperfetto "We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-235849 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 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-195534 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 TEAD1 protein P28347 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 21211055 f gcesareni "Tead1 can regulate transcription of the foxo3a gene through the binding to the m-cat element, demonstrated with independent chip-pcr analysis, emsa and luciferase reporter system assay. The over-expression and inhibition analysis suggest that foxo3a was positively regulated by tead1." SIGNOR-170976 TEAD1 protein P28347 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 20153295 f lperfetto "We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-235599 TEAD1 protein P28347 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 21527258 f gcesareni "We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-173445 TEAD proteinfamily SIGNOR-PF22 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "up-regulates activity" binding 9606 23431053 t miannu "YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death" SIGNOR-230722 TEC protein P42680 UNIPROT BMX protein P51813 UNIPROT "up-regulates activity" phosphorylation Tyr216 SSTSLAQyDSNSKKI 9606 BTO:0000873 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.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk" SIGNOR-246647 TEC protein P42680 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-98094 TEC protein P42680 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 BTO:0000873 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." SIGNOR-246652 TEC protein P42680 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 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. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated" SIGNOR-98098 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 TEK protein Q02763 UNIPROT MYH1 protein P12882 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241541 TEK protein Q02763 UNIPROT MYH2 protein Q9UKX2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241538 TEK protein Q02763 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241532 TEK protein Q02763 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241535 TEK protein Q02763 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "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-252728 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr1048 GMTCAELyEKLPQGY -1 11513602 t lperfetto "Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km." SIGNOR-109786 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr1102 MLEERKTyVNTTLYE 10090 BTO:0000944 12082108 t lperfetto "Recently, insights into Tie2 activation were provided by a solution of the Tie2 crystal structure (12). This structural analysis revealed several novel features, including two potential autoinhibitory mechanismsIn the unphosphorylated state, the hydroxyl groups of two important tyrosine residues, Tyr1101 and Tyr1112 (murine residue numbers), are hydrogen-bonded to surrounding residues, which may stabilize the C tail in this inhibitory conformationDeletion of the Tie2 C Tail Enhances Autophosphorylation and Kinase Activity in VitroDeletion of the C tail dramatically enhanced Tie2 autophosphorylation, despite the removal of Tyr1112, which was previously shown to be an important autophosphorylation site" SIGNOR-246657 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr1102 MLEERKTyVNTTLYE 9606 BTO:0001176 20973951 t miannu "This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor." SIGNOR-259834 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr1108 TYVNTTLYEKFTYAG 9606 BTO:0001176 20973951 t miannu "This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor." SIGNOR-259833 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr992 LSRGQEVyVKKTMGR -1 11513602 t lperfetto "Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km." SIGNOR-109790 Telatinib chemical CID:9808844 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207221 Telatinib chemical CID:9808844 PUBCHEM KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207224 Telatinib chemical CID:9808844 PUBCHEM KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207227 Telatinib chemical CID:9808844 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207230 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 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 teniposide chemical CHEBI:75988 ChEBI TOP2A protein P11388 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-259329 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 terazosin chemical CHEBI:9445 ChEBI ADRA1A protein P35348 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001260 9379432 t miannu "Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication" SIGNOR-258671 terazosin chemical CHEBI:9445 ChEBI ADRA1B protein P35368 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001260 9379432 t miannu "Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication" SIGNOR-258669 terbutaline chemical CHEBI:9449 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-257872 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 Terfenadine chemical CHEBI:9453 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 19660947 t Luana " hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7" SIGNOR-257825 Terfenadine chemical CHEBI:9453 ChEBI KCNH2 protein Q12809 UNIPROT "down-regulates activity" "chemical inhibition" -1 19660947 t Luana " hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7" SIGNOR-257826 Terfenadine chemical CHEBI:9453 ChEBI KCNH2 protein Q12809 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9395068 t miannu "We have previously shown that terfenadine can inhibit both Kv1.5 and HERG with its effects on HERG being approximately 10‐fold more potent" SIGNOR-258673 Ternatin chemical CID:5459184 PUBCHEM EEF1A1 protein P68104 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001109 26651998 t "Simone Vumbaca" "Ternatins inhibit protein synthesis with potencies that correlate with their ability to block cell proliferation, and photo-ternatin 5 identified eEF1A as aplausible target." SIGNOR-261126 tertatolol chemical CHEBI:135244 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-258862 "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 BTO:0003238 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 "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 BRD4 protein O60885 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000176 20871596 t "Simone Vumbaca" "JQ1 displaces BRD4 from nuclear chromatin in cells" SIGNOR-261123 TERT protein O14746 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR up-regulates 11327115 f lperfetto "Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers" SIGNOR-252292 TESK1 protein Q15569 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11294912 t lperfetto "These results suggest that TESK1 functions downstream of integrins and plays a key role in integrin-mediated actin reorganization, presumably through phosphorylating and inactivating cofilin. We propose that tesk1 and lim-kinases commonly phosphorylate cofilin but are regulated in different ways and play distinct roles in actin reorganization in living cells." SIGNOR-106777 TESK1 protein Q15569 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 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-246723 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 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 TESK2 protein Q96S53 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11418599 t lperfetto "Like tesk1, tesk2 phosphorylated cofilin specifically at ser-3 and induced formation of actin stress fibers and focal adhesions." SIGNOR-108753 TESK2 protein Q96S53 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-246711 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 testolactone chemical CHEBI:9460 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.We report here that 1,4-androstadiene 3,17-dione (Ki 0.32 microM; kinact 0.91 X 10(-3)/sec) and testolactone (Ki 35 microM; kinact 0.36 X 10(-3)/sec) also cause a similar loss of aromatase activity." SIGNOR-258406 TET1 protein Q8NFU7 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-259094 TET1 protein Q8NFU7 UNIPROT PTEN protein P60484 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0003053 27121319 t irozzo "We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands" SIGNOR-259096 TET1 protein Q8NFU7 UNIPROT SLIT2 protein O94813 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 TET1 protein Q8NFU7 UNIPROT ZNF382 protein Q96SR6 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-259095 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 TET2 protein Q6N021 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo "Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation." SIGNOR-255704 TET2 protein Q6N021 UNIPROT WT1 protein P19544 UNIPROT "up-regulates activity" binding 9606 BTO:0000670;BTO:0000738 25601757 t irozzo " In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes." SIGNOR-255703 TET3 protein O43151 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-200729 tetrabenazine chemical CHEBI:9467 ChEBI SLC18A2 protein Q05940 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000318 8643547 t miannu "Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2." SIGNOR-258491 TFAP2A protein P05549 UNIPROT ADM protein P35318 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9480831 t "These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells." SIGNOR-254048 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 TFAP2A protein P05549 UNIPROT CRYAB protein P02511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21556774 t miannu "Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53" SIGNOR-253636 TFAP2A protein P05549 UNIPROT DCC protein P43146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003858 19745029 f miannu "Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2." SIGNOR-255189 TFAP2A protein P05549 UNIPROT ECM1 protein Q16610 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-255401 TFAP2A protein P05549 UNIPROT SULT1E1 protein P49888 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-255397 TFAP2B protein Q92481 UNIPROT CRYAB protein P02511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21556774 t miannu "Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53" SIGNOR-253637 TFAP2B protein Q92481 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" binding 9606 21556774 t miannu "These data suggest that AP-2Œ≤ enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2Œ≤ interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2Œ≤ up-regulates the transcription of the CRYAB gene through stabilizing p53." SIGNOR-255422 TFAP2C protein Q92754 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-255398 TFAP2C protein Q92754 UNIPROT ECM1 protein Q16610 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-255396 TFAP2C protein Q92754 UNIPROT SULT1E1 protein P49888 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-255399 TFAP4 protein Q01664 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" binding 9606 BTO:0001109 19505873 t miannu "We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads." SIGNOR-226590 TFAP4 protein Q01664 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001109 19505873 f miannu "AP-4 Mediates E-box-dependent Complex Formation for Transcriptional Repression of HDM2" SIGNOR-226596 TFAP4 protein Q01664 UNIPROT NFIA protein Q12857 UNIPROT "up-regulates activity" binding 9606 BTO:0001109 19505873 t miannu "We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads." SIGNOR-226586 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 TFAP4 protein Q01664 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 BTO:0001109 19505873 t miannu "We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads." SIGNOR-226593 TFCP2 protein Q12800 UNIPROT TF protein P02787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20796026 f miannu "Ectopic expression of CP2 led to increased transferrin expression at both the mRNA and protein levels, whereas knockdown of CP2 down-regulated transferrin mRNA and protein expression." SIGNOR-255429 TFDP1 protein Q14186 UNIPROT CCNE1 protein P24864 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-253857 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 TFDP1 protein Q14186 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-253860 TFDP1 protein Q14186 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-253862 TFDP1 protein Q14186 UNIPROT PCNA protein P12004 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-253858 TFDP1 protein Q14186 UNIPROT RRM1 protein P23921 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-253866 TFDP1 protein Q14186 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-253861 TFE3 protein P19532 UNIPROT MYH9 protein P35579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 11467950 f miannu "we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies." SIGNOR-222504 TFEC protein O14948 UNIPROT MYH9 protein P35579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 11467950 f miannu "we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies." SIGNOR-222551 TFG protein Q92734 UNIPROT SEC16A protein O15027 UNIPROT up-regulates binding 9606 21478858 t miannu "We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits." SIGNOR-173242 TFG protein Q92734 UNIPROT SEC16B protein Q96JE7 UNIPROT up-regulates binding 9606 21478858 t miannu "We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits." SIGNOR-173279 TFPI protein P10646 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni "Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi" SIGNOR-106353 TG101209 chemical CHEBI:90304 ChEBI JAK3 protein P52333 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207266 TG101209 chemical CHEBI:90304 ChEBI RET protein P07949 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207269 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 TGFA protein P01135 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" binding 9606 BTO:0000584 16585207 t "Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines" gcesareni "Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo." SIGNOR-93199 TGFB1 protein P01137 UNIPROT ACTA2 protein P62736 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000764 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-251923 TGFB1 protein P01137 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-252282 TGFB1 protein P01137 UNIPROT CDK2 protein P24941 UNIPROT down-regulates 9606 SIGNOR-C16 10611320 f gcesareni "Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2." SIGNOR-73537 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193630 TGFB1 protein P01137 UNIPROT CDK4 protein P11802 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000763 8402878 f gcesareni "Here we show that tgf beta 1 induces suppression of cdk4 synthesis in g1 in mink lung epithelial cells." SIGNOR-39045 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 TGFB1 protein P01137 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7592908 f gcesareni "The steadystate level of p15ink4b mrna was induced 30-fold upon tgf-beta treatment, implicating p15ink4b as a primary effector of the tgf-beta-mediated cell cycle arrest" SIGNOR-29582 TGFB1 protein P01137 UNIPROT COL1A2 protein P08123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8182090 f gcesareni "Tgf-beta stimulates transcription of the human alpha 2(i) collagen gene (col1a2) promoter by increasing the affinity of an sp1-containing protein complex for its cognate dna-binding site" SIGNOR-36783 TGFB1 protein P01137 UNIPROT COL4A1 protein P02462 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000764 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-251922 TGFB1 protein P01137 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "down-regulates activity" 9606 10611320 f lperfetto "Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2." SIGNOR-217502 TGFB1 protein P01137 UNIPROT ENG protein P17813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002741 21146604 f miannu "In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor." SIGNOR-255202 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 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 TGFB1 protein P01137 UNIPROT HBB protein P68871 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-251797 TGFB1 protein P01137 UNIPROT ITGA2 protein P17301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001596 1744142 f lperfetto "TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way." SIGNOR-253354 TGFB1 protein P01137 UNIPROT ITGA3 protein P26006 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001596 1744142 f lperfetto "TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way." SIGNOR-253353 TGFB1 protein P01137 UNIPROT KRT1 protein P04264 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16258965 f Regulation miannu "TGFβ1 and TGFβ2 induce loss of epithelial morphology, cytokeratin, and membrane-associated Zonula Occludens-1 and increase the smooth muscle markers calponin and caldesmon" SIGNOR-251884 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 TGFB1 protein P01137 UNIPROT LPP protein Q93052 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 22886954 f miannu "Tgf-_1-induced lpp expression dependant on rho kinase during differentiation and migration of bone marrow-derived smooth muscle progenitor cells" SIGNOR-191768 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 TGFB1 protein P01137 UNIPROT OMD protein Q99983 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16970923 f miannu "We found tgf-beta1 to down regulate osad" SIGNOR-149565 TGFB1 protein P01137 UNIPROT PAX6 protein P26367 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001874 17251190 f Regulation miannu "The effect of TGFbeta on Pax6 expression was studied in the FHL124 lens epithelial cell line and was found to cause up to a 50% reduction in Pax6 mRNA levels within 24 h. Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling." SIGNOR-251874 TGFB1 protein P01137 UNIPROT PAX8 protein Q06710 UNIPROT "down-regulates activity" binding 9606 14623893 t miannu "DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3." SIGNOR-251993 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 TGFB1 protein P01137 UNIPROT PIK3CG protein P48736 UNIPROT "up-regulates activity" 9606 19114990 f lperfetto "First, TGF-beta can rapidly activate PI3K, as indicated by the phosphorylation of its downstream effector Akt" SIGNOR-217812 TGFB1 protein P01137 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9606 19114990 t lperfetto "While association of the TGF_RI receptor with p85 requires TGF-_ stimulation." SIGNOR-217960 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 TGFB1 protein P01137 UNIPROT RNF111 protein Q6ZNA4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14657019 f lpetrilli "Expression of arkadia is down-regulated by tgf-beta." SIGNOR-119669 TGFB1 protein P01137 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001593 11331591 f lperfetto "Tgf-b caused a 50% reduction of cbfa1 mrna." SIGNOR-235998 TGFB1 protein P01137 UNIPROT SALL2 protein Q9Y467 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-255427 TGFB1 protein P01137 UNIPROT SFTPB protein P07988 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004299 18003659 f miannu "TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells." SIGNOR-254170 TGFB1 protein P01137 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" 10090 BTO:0000944 17673906 f 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-242631 TGFB1 protein P01137 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates 9606 21212736 f gcesareni "Skp2, a f-box protein that determines the substrate specificity for scf ubiquitin ligase, has recently been demonstrated to be degraded by cdh1/apc in response to tgfbeta signaling." SIGNOR-171013 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 TGFB1 protein P01137 UNIPROT SLC5A5 protein Q92911 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0003873 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 TGFB1 protein P01137 UNIPROT TAGLN protein Q01995 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000764 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 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 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 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 9606 22326956 t "giulio giuliani" "In Tgfbr2fl/fl control MEPM cells, radioactive TGF-β2 ligands (12.5 kDa) bind to TβRI (53 kDa), TβRII (70 kDa), and TβRIII (100–200 kDa, highly glycosylated molecule) and form the ligand-receptor complexes of TβRI::TGF-β2 (65.5 kDa), TβRII::TGF-β2 (82.5 kDa), and TβRIII::TGF-β2 (112.5–212.5 kDa)" SIGNOR-255960 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 9606 22326956 t lperfetto "TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family." SIGNOR-196022 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 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 26194464 t "MARCO ROSINA" "TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI)." SIGNOR-255030 TGFB1 protein P01137 UNIPROT TSHB protein P01222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14623893 t miannu "TGF-β inhibits thyroid-stimulated hormone (TSH)-induced NIS mRNA and protein levels in a dose-dependent manner. This effect takes place at the transcriptional level, as TGF-β inhibits TSH-induced transcription" SIGNOR-251991 TGFB2 protein P61812 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-252283 TGFB2 protein P61812 UNIPROT KRT1 protein P04264 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16258965 f Regulation miannu "Immunolocalization of the epithelial marker cytokeratin demonstrates decreased staining by 48 hr after the addition of TGFβ1 or TGFβ2" SIGNOR-251885 TGFB2 protein P61812 UNIPROT TGFB2 protein P61812 UNIPROT up-regulates binding 9606 16885528 t gcesareni "The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge" SIGNOR-148608 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 TGFB2 protein P61812 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 11157754 t gcesareni "We show that tbetarii-b, an alternatively spliced variant of the tgf-beta type ii receptor, is a tgf-beta2 binding receptor, which mediates signalling via the smad pathway in the absence of any tgf-beta type iii receptor" SIGNOR-104795 TGFB2 protein P61812 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 1310899 t gcesareni "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-16690 TGFB2 protein P61812 UNIPROT TGFBR3 protein Q03167 UNIPROT up-regulates binding 9606 10746731 t gcesareni "Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors." SIGNOR-76473 TGFB3 protein P10600 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-252284 TGFB3 protein P10600 UNIPROT TGFB3 protein P10600 UNIPROT up-regulates binding 9606 16885528 t gcesareni "The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge" SIGNOR-148611 TGFB3 protein P10600 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 11157754 t miannu "T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation" SIGNOR-104798 TGFBI protein Q15582 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 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-253269 TGFBI protein Q15582 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "up-regulates activity" binding 10090 BTO:0001175 10906123 t lperfetto "In addition, we demonstrated the functional receptor for betaig-h3 is alpha(3)beta(1) integrin. These results, therefore, establish the essential motifs within the 2nd and the 4th domains of betaig-h3, which interact with alpha(3)beta(1) integrin to mediate HCE cell adhesion to betaig-h3 and suggest that other proteins containing Asp-Ile in their fas-1 domains could possibly function as cell adhesion molecules." SIGNOR-253211 TGFBI protein Q15582 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 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-253267 TGFBI protein Q15582 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 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-253283 TGFBI protein Q15582 UNIPROT "a7/b1 integrin" complex SIGNOR-C126 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-253266 TGFBI protein Q15582 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 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-253270 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 TGFb proteinfamily SIGNOR-PF5 SIGNOR SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "up-regulates quantity by expression" "transcriptional activation" 9606 30017632 f miannu "Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis." SIGNOR-260428 TGFb proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 protein P37173 UNIPROT "up-regulates activity" binding 9606 22326956 t miannu "TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family." SIGNOR-256178 TGFb proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 protein P37173 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 22703233 t miannu "TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex." SIGNOR-256179 TGFBR1 protein P36897 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates phosphorylation Ser300 EMHHEALsEALPGDN 9606 BTO:0000150 20832312 t llicata "Phosphorylation of eef1a1 at ser300 by t_r-i results in inhibition of mrna translation." SIGNOR-167943 TGFBR1 protein P36897 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 26194464 f "MARCO ROSINA" "TbRI phosphorylates not only the C-termini of R-Smads but also activates various protein kinases including mitogen-activated protein kinases (MAPKs): extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK (p38), which then phosphorylate the variable linker regions of R-Smad" SIGNOR-255033 TGFBR1 protein P36897 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-252730 TGFBR1 protein P36897 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227525 TGFBR1 protein P36897 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227531 TGFBR1 protein P36897 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 9606 19726546 t lperfetto "Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity." SIGNOR-227496 TGFBR1 protein P36897 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" 9606 19726546 t lperfetto "Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity." SIGNOR-227499 TGFBR1 protein P36897 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 10090 BTO:0005065 17673906 t lperfetto "We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases." SIGNOR-227503 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 10973958 t lperfetto "The pathway restricted (r)Smads (e.g. Smad1, 2, 3, and 5) are serine/threonine kinase activated proteins that interact in an unphosphorylated state with a TGF-b superfamily receptor. Upon ligand binding they are phosphorylated by the receptor and released." SIGNOR-249549 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 t lperfetto "Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 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-236107 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 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto "A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus" SIGNOR-235385 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto "A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus" SIGNOR-235380 TGFBR1 protein P36897 UNIPROT SPTBN1 protein Q01082 UNIPROT up-regulates phosphorylation 9606 12543979 t gcesareni "This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead." SIGNOR-97626 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 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser68 FLEQPICsVQPIDLN 9606 23166821 t llicata "We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5" SIGNOR-199785 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 18922473 t gcesareni "We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors" SIGNOR-241918 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 18758450 t lperfetto "Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis." SIGNOR-236119 TGFBR1 protein P36897 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-62868 TGFBR2 protein P37173 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates phosphorylation Ser345 RGDGSGFsL 9606 BTO:0000551 23249950 t lpetrilli "Transforming growth factor ? (tgf-?) Has been shown to regulate cell plasticity through the phosphorylation of par6 on a conserved serine residue (s345) by the type ii tgf-? Receptor." SIGNOR-200193 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 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 TGFBR2 protein P37173 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-252732 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT "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-217830 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227521 TGFBR2 protein P37173 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227528 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto "Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta" SIGNOR-246728 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 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 t lperfetto "The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling." SIGNOR-32744 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 t lperfetto "The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling." SIGNOR-32748 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates activity" phosphorylation Ser416 SVDDLANsGQVGTAR 9606 9155023 t lperfetto "Tbetarii kinase is regulated intricately by autophosphorylation on at least three serine residues. Phosphorylation of ser416 inhibits receptor function." SIGNOR-48412 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates activity" phosphorylation Ser416 SVDDLANsGQVGTAR 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-246737 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Ser213 TRKLMEFsEHCAIIL 9606 BTO:0002181 9155023 t lperfetto "Here we show that TbetaRII kinase is regulated intricately by autophosphorylation on at least three serine residues. 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." SIGNOR-236087 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 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Tyr259 KGRFAEVyKAKLKQN -1 9169454 t lperfetto "Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor." SIGNOR-48859 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Tyr336 AKGNLQEyLTRHVIS -1 9169454 t lperfetto "Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor." SIGNOR-48863 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Tyr424 GQVGTARyMAPEVLE -1 9169454 t lperfetto "Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor." SIGNOR-48867 TGFBR2 protein P37173 UNIPROT VPS39 protein Q96JC1 UNIPROT "up-regulates activity" binding 9543 BTO:0001538 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-261374 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 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 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 THBS1 protein P07996 UNIPROT NGF protein P01138 UNIPROT up-regulates binding 9606 10708953 t lpetrilli "We have identified a mechanism for the activation of latent tgf-beta that involves binding of the secreted and extracellular matrix protein, thrombospondin-1 (tsp-1), to the latent precursor." SIGNOR-75624 THBS2 protein P35442 UNIPROT CD47 protein Q08722 UNIPROT up-regulates binding 9606 8550562 t gcesareni "We report here that iap is a receptor for the ts1 cbd and its vvm-containing peptides and that a function-blocking anti-iap mab inhibits the chemotactic response to ts1 and its cbd peptides in endothelial cells." SIGNOR-39749 THEM4 protein Q5T1C6 UNIPROT AKT1 protein P31749 UNIPROT down-regulates binding 9606 11598301 t gcesareni "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-111003 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 thioridazine chemical CHEBI:9566 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-258839 THPO protein P40225 UNIPROT MPL protein P40238 UNIPROT up-regulates binding 9606 11784712 t miannu "Thrombopoietin(tpo) controls the formation of megakaryocytes and platelets from hematopoietic stem cells via activation of the c-mplreceptorand multiple downstream signal transduction pathways." SIGNOR-113955 THRAP3 protein Q9Y2W1 UNIPROT SFPQ protein P23246 UNIPROT down-regulates binding 9606 20932480 t miannu "Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion." SIGNOR-168441 THRA protein P10827 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 15650024 t gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-133240 THRA protein P10827 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 15650024 t gcesareni "Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-133243 THRA protein P10827 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 15650024 t gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-133246 Thrombin smallmolecule CHEBI:9574 ChEBI F2RL2 protein O00254 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-257486 Thrombin smallmolecule CHEBI:9574 ChEBI F2RL3 protein Q96RI0 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-257487 thromboxane smallmolecule CHEBI:26995 ChEBI TBXA2R protein P21731 UNIPROT "up-regulates activity" binding 19747485 t "Thromboxane plays an essential role in hemostasis, regulating platelet aggregation and vessel tone. In humans, it signals through the TPalpha and TPbeta isoforms that are transcriptionally regulated by distinct promoters Prm1 and Prm3, respectively." SIGNOR-254264 tiagabine chemical CHEBI:9586 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-258477 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 tibolone chemical CHEBI:32223 ChEBI AR protein P10275 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 19464167 t Luana "In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1)." SIGNOR-257823 tibolone chemical CHEBI:32223 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 19464167 t Luana "In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1)." SIGNOR-257821 tibolone chemical CHEBI:32223 ChEBI PGR protein P06401 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000567 19464167 t Luana "In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1)." SIGNOR-257822 TICAM1 protein Q8IUC6 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 9606 20404851 t lperfetto "TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation." SIGNOR-216313 TICAM1 protein Q8IUC6 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 14530355 t lperfetto "Toll/il-1 receptor domain-containing adaptor inducing ifn-beta (trif) associates with tnf receptor-associated factor 6 and tank-binding kinase 1, and activates two distinct transcription factors, nf-kappa b and ifn-regulatory factor-3, in the toll-like receptor signaling" SIGNOR-118458 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 Tifluadom chemical CHEBI:9591 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-258665 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 TIMP1 protein P01033 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-252272 TIMP2 protein P16035 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-252273 TIMP3 protein P35625 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR "down-regulates activity" 10090 BTO:0005300 28709001 f "Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes" SIGNOR-255906 TIMP3 protein P35625 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-252274 TIMP3 protein P35625 UNIPROT MMP14 protein P50281 UNIPROT "down-regulates activity" binding 10090 BTO:0005300 28709001 t "FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis." SIGNOR-255908 Tiospirone chemical CID:55752 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-258863 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 9606 25948473 t lperfetto "Stimulation of Toll-like receptor (TLR) 4 leads to the activation of both MyD88-dependent and MyD88-independent pathways through the recruitment of adaptors TIRAP/MyD88 and TRIF/TRAM, respectively." SIGNOR-110215 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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 TJP1 protein Q07157 UNIPROT ARVCF protein O00192 UNIPROT "up-regulates activity" binding 9615 BTO:0000837 15456900 t "Regulation of binding" miannu "We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. E-cadherin, ZO-1, and ARVCF are recruited to sites of initial cell-cell contact. Binding of the ZO-1 PDZ domains per se does not facilitate membrane recruitment of ARVCF, indicating a requirement for the intact ZO-1 and possibly its association with membrane proteins and/or the cytoskeleton for this process." SIGNOR-252121 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 TJP2 protein Q9UDY2 UNIPROT ARVCF protein O00192 UNIPROT "down-regulates activity" relocalization 9615 BTO:0000837 15456900 t "Regulation of binding" miannu "We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. ZO-2, in contrast, relocated to the nucleus with ARVCF, and, given the interaction between the ZO-2 PDZ domains and ARVCF, raised the possibility that ZO-2 may play a role in nuclear localization of ARVCF. Such a role for ZO-2 is indeed supported by the ability of the ZO-2 PDZ domain to efficiently relocate ARVCF from the plasma membrane to the nucleus in a process that required the ability of the two proteins to interact and the presence of a functional NLS in the ZO-2 PDZ domains. Thus, ZO-2 could be involved in nuclear translocation and/or retention of ARVCF and play a role in regulating postulated functions of ARVCF in gene expression" SIGNOR-252122 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 TJP2 protein Q9UDY2 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23829894 t milica "The Crumbs complex component AMOT co-localizes with MST1_ 2, LATS1_ 2 and YAP in a complex at the tight junction to control cell growth. Zona occludens-2 (ZO-2) in the tight junction, and a-catenin, b-catenin, or PTPN14 in the adherence junction, also bind to YAP_TAZ." SIGNOR-230754 TLE1 protein Q04724 UNIPROT LEF1 protein Q9UJU2 UNIPROT "down-regulates activity" binding -1 19460168 t "Our data shows that Groucho/TLE repression requires two sites of interaction in LEF-1 and that a central, conserved amino acid sequence within the primary region (F S/T/P/xx y I/L/V) is critical." SIGNOR-260109 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 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 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 TLE4 protein Q04727 UNIPROT PAX2 protein Q02962 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 25631048 t "In cell culture, Grg4 suppresses Pax2-mediated transcriptional activation and inhibits phosphorylation of the Pax2 activation domain by WNT signaling and JNK" SIGNOR-251710 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 TLE5 protein Q08117 UNIPROT SIX3 protein O95343 UNIPROT "down-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. AES abrogates SIX3- and SIX6-induced phenotypes" SIGNOR-234586 TLE5 protein Q08117 UNIPROT SIX6 protein O95475 UNIPROT "down-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. AES abrogates SIX3- and SIX6-induced phenotypes" SIGNOR-234589 TLE5 protein Q08117 UNIPROT ZNF503 protein Q96F45 UNIPROT "down-regulates activity" binding 9543 BTO:0000298 19056829 t miannu "these results show that Grg5 can specifically interact with the C-terminus of Nolz1. these data suggest that Nolz1 functions as a repressor molecule, and that Grg5 interactions with Nolz1 serve to modulate Nolz1 repressor function. Mechanistically, Grg5 is known to modulate Grg co-repressor activity, raising the possibility that classical Grg proteins mediate Nolz1-dependent transcriptional repression. GalNolz1ΔC22 showed increased repressor activity compared with GalNolz1, consistent with the ability of Grg5 to modulate Nolz1 repressor function." SIGNOR-261192 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Thr355 EPSTVPGtPPPKKFR 9606 24376897 t "The effect has been demonstrated using Q9UKI8-2" llicata "Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue." SIGNOR-203503 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 TLK2 protein Q86UE8 UNIPROT ASF1A protein Q9Y294 UNIPROT "up-regulates quantity by stabilization" phosphorylation S192 STSENSLNVML 9606 BTO:0002181 20016786 t Manara "We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | Consistent" SIGNOR-260787 TLK2 protein Q86UE8 UNIPROT ASF1B protein Q9NVP2 UNIPROT unknown phosphorylation S198 PGCIPGLLPENSMD 9606 BTO:0002181 20016786 t Manara "We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | hASF1b stability does not appear to depend on phosphorylation by TLKs, but recently it has been shown that hASF1b transcription is controlled by the cell-cycle regulated E2F transcription factors" SIGNOR-260788 TLN1 protein Q9Y490 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 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-257616 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 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 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 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 TLN1 protein Q9Y490 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 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-257611 TLN1 protein Q9Y490 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 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-257612 TLN1 protein Q9Y490 UNIPROT "A6/b1 integrin" complex SIGNOR-C164 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-257613 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 TLN1 protein Q9Y490 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 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-257614 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 TLN1 protein Q9Y490 UNIPROT "AD/b2 integrin" complex SIGNOR-C172 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-257623 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 TLN1 protein Q9Y490 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 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-257624 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 TLN1 protein Q9Y490 UNIPROT "AM/b2 integrin" complex SIGNOR-C170 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-257620 TLN1 protein Q9Y490 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 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-257622 TLN1 protein Q9Y490 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 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-257626 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 TLN1 protein Q9Y490 UNIPROT "Av/b6 integrin" complex SIGNOR-C179 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-257632 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 TLN1 protein Q9Y490 UNIPROT "AX/b2 integrin" complex SIGNOR-C171 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-257621 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 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 TLN1 protein Q9Y490 UNIPROT ITGB2 protein P05107 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-257618 TLN1 protein Q9Y490 UNIPROT ITGB4 protein P16144 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-257627 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 TLN1 protein Q9Y490 UNIPROT ITGB6 protein P18564 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-257631 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 TLN1 protein Q9Y490 UNIPROT ITGB8 protein P26012 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-257636 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 TLR4 protein O00206 UNIPROT Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20596954 f fstefani "Regulation of toll-like receptor signaling in the innate immunity." SIGNOR-166488 TLR4 protein O00206 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" 9606 BTO:0000801 19592489 f lperfetto "The transcription factor AP-1 consists of a variety of dimers composed of members of the Jun, Fos, and ATF families of proteins. The Jun proteins can both homo- and heterodimerize with Fos members to form transcriptionally active complexes. The stimulation of macrophage TLR4 receptor rapidly activates not only the NF-kappaB pathway but also MAPK pathways, including JNK, ERK, and p38. Many of the downstream targets of MAPK pathways are transcription factors that include c-Jun." SIGNOR-249518 TLR4 protein O00206 UNIPROT MAP3K8 protein P41279 UNIPROT "up-regulates activity" 10090 BTO:0004732 16484370 f "Our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells" SIGNOR-256083 TLR4 protein O00206 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 10090 22664090 t gcesareni "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-252065 TLR4 protein O00206 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 9606 BTO:0000801 7635431 f lperfetto "The activation of NF-kB is triggered by different stimuli, eg., lipopolysaccharides (LPSs), muramyl peptides, viruses,e inflammatory cytokines tumor necrosis factor-alpha(TNF-a) and interleukin (IL)-1b, irradiation, and reactive xygen intermediates (H2O2)." SIGNOR-249517 TLR4 protein O00206 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "up-regulates activity" binding 10090 22664090 t gcesareni "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-252067 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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-252064 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT up-regulates binding 9606 11544529 t fstefani "Mal (myd88-adapter-like) is required for toll-like receptor-4 signal transduction." SIGNOR-110337 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT "up-regulates activity" binding 10090 22664090 t gcesareni "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-252066 TLR5 protein O60602 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000727 24709011 f miannu "These studies demonstrate a novel function of Toll-like receptor-5 (TLR5) in a human multiple myeloma (MM) cell line, KMS28BM. These cells express high levels of both TLR5 mRNA and protein. When cells were treated with the specific TLR5 ligand flagellin, proliferation was increased, and the secretion of IgG λ antibody and the expression of the pro-inflammatory cytokine IL-6 were increased via NF-κB activation through PI3K/AKT and p38 signaling." SIGNOR-259868 TLRs proteinfamily SIGNOR-PF20 SIGNOR Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20404851 f lperfetto "TLR signaling pathways can be largely classified as either MyD88-dependent pathways, which drive the induction of inflammatory cytokines, or TRIF-dependent pathways, which are responsible for the induction of type I interferon as well as inflammatory cytokines3." SIGNOR-216310 TLRs proteinfamily SIGNOR-PF20 SIGNOR MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 10090 22664090 t miannu "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-260151 TLRs proteinfamily SIGNOR-PF20 SIGNOR NLRP3 protein Q96P20 UNIPROT "up-regulates quantity by expression" 28531279 f lperfetto "The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3" SIGNOR-256428 TLRs proteinfamily SIGNOR-PF20 SIGNOR TICAM1 protein Q8IUC6 UNIPROT "up-regulates activity" binding 10090 22664090 t gcesareni "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-252095 TLRs proteinfamily SIGNOR-PF20 SIGNOR TICAM2 protein Q86XR7 UNIPROT "up-regulates activity" binding 9606 20404851 t lperfetto "These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways" SIGNOR-216307 TLRs proteinfamily SIGNOR-PF20 SIGNOR TIRAP protein P58753 UNIPROT "up-regulates activity" binding 9606 20404851 t lperfetto "These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways" SIGNOR-216298 TLX1 protein P31314 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-259097 TLX1 protein P31314 UNIPROT PPP2CA protein P67775 UNIPROT "down-regulates activity" binding 9606 BTO:0000661 15897879 t 2 miannu "HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade." SIGNOR-240719 TLX1 protein P31314 UNIPROT PPP2CB protein P62714 UNIPROT "down-regulates activity" binding 9606 BTO:0000661 15897879 t 2 miannu "HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade." SIGNOR-240722 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 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 TMED10 protein P49755 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 16641999 t gcesareni "Here we report that tmp21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage" SIGNOR-146364 TMED5 protein Q9Y3A6 UNIPROT TMED10 protein P49755 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19948005 t Sara "P28 forms hetero-oligomeric complexes with p23. p23 is a major determinant for efficient targeting of p28 to the ERGIC" SIGNOR-261298 TMOD1 protein P28289 UNIPROT TPM3 protein P06753 UNIPROT "down-regulates activity" binding 9606 BTO:0000516 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 TMPRSS2 protein O15393 UNIPROT S protein P0DTC2 UNIPROT "up-regulates activity" cleavage 9606 BTO:0004299 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. The Cellular Serine Protease TMPRSS2 Primes SARS-2- S for Entry, and a Serine Protease Inhibitor Blocks SARS-CoV-2 Infection of Lung Cells" SIGNOR-260736 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 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 TNC protein P24821 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "up-regulates activity" binding 9606 BTO:0000801;BTO:0001336 24241034 t lperfetto "Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C." SIGNOR-253312 TNFAIP3 protein P21580 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 15258597 t "The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation." SIGNOR-259978 TNF protein P01375 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 11287630 f lperfetto "Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase" SIGNOR-106593 TNF protein P01375 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 11287630 f lperfetto "Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase" SIGNOR-106596 TNF protein P01375 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 11287630 f lperfetto "Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase" SIGNOR-244458 TNF protein P01375 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-252285 TNF protein P01375 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-261034 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 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 TNF protein P01375 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004914 22190977 f "Exposure of RA FLSs to TNF-α (10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels." SIGNOR-253605 TNF protein P01375 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 other 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 TNF protein P01375 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-260258 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 TNF protein P01375 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 11287630 f gcesareni "Irs-1 tyrosine phosphorylation by tnf was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mtor), a downstream target of akt. these results suggest that tnf impairs insulin signaling through irs-1" SIGNOR-106599 TNF protein P01375 UNIPROT JAG2 protein Q9Y219 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-253608 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16106106 f Regulation miannu "TNF-α and IL-6 inhibit lipoprotein lipase" SIGNOR-251855 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9609 3063839 f "Regulation of expression" miannu "Cytokines, notably TNF and IL-1, suppress synthesis of lipoprotein lipase which decreases the rate of TGFA clearance." SIGNOR-251853 TNF protein P01375 UNIPROT LZTR1 protein Q8N653 UNIPROT "down-regulates quantity by destabilization" 9606 16356934 f "Induction of Apoptosis by Staurosporine, TNFŒ±, and TRAIL Induces Degradation of LZTR-1 by Caspase- and Proteasome-dependent Pathways" SIGNOR-253612 TNF protein P01375 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 16813528 f lperfetto "These observations suggest that tnf-alpha activates p38 map kinase during the inflammatory response at the injured growth plate, and tnf-alpha-p38 signaling seems to be required for marrow mesenchymal cell proliferation and migration at the growth plate injury site and in cell culture." SIGNOR-147369 TNF protein P01375 UNIPROT MC1R protein Q01726 UNIPROT "down-regulates activity" "transcriptional regulation" 9606 BTO:0000847 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-252381 TNF protein P01375 UNIPROT NOTCH1 protein P46531 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-253606 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 TNF protein P01375 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" 10090 10485710 f lperfetto "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)." SIGNOR-70616 TNF protein P01375 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates 9606 10485710 f gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)." SIGNOR-70619 TNF protein P01375 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates 9606 10485710 f gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)" SIGNOR-70622 TNF protein P01375 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 10485710 t gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)" SIGNOR-70625 TNF protein P01375 UNIPROT REL protein Q04864 UNIPROT up-regulates 9606 BTO:0000782 10823840 f miannu "C-rel emerges as the main nf-kb family member stimulated by tnf_ in the context of physiologic activation of resting t cells." SIGNOR-77547 TNF protein P01375 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003355 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 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 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-253493 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 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-253484 TNF protein P01375 UNIPROT SCN11A protein Q9UI33 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-253492 TNF protein P01375 UNIPROT SCN11A protein Q9UI33 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-253483 TNF protein P01375 UNIPROT SCN1A protein P35498 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-253487 TNF protein P01375 UNIPROT SCN1A protein P35498 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-253478 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 TNF protein P01375 UNIPROT SCN3A protein Q9NY46 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-253485 TNF protein P01375 UNIPROT SCN4A protein P35499 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-253490 TNF protein P01375 UNIPROT SCN4A protein P35499 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. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253481 TNF protein P01375 UNIPROT SCN5A protein Q14524 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-253486 TNF protein P01375 UNIPROT SCN5A protein Q14524 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-253477 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 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-253491 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 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-253482 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 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 TNF protein P01375 UNIPROT SCNN1A protein P37088 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0005760 16877633 f "Regulation of expression" miannu "TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na(+) channel (ENaC) by approximately 70% in alveolar epithelial cells." SIGNOR-251954 TNF protein P01375 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-254809 TNF protein P01375 UNIPROT SNAI2 protein O43623 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 20509143 f miannu "we show that TNFα treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-κB/HIF1α signaling, which is strongly enhanced by p53 inactivation." SIGNOR-255152 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 10634209 t lperfetto "TNF-induced apoptosis is mediated primarily through the activation of type I receptors" SIGNOR-226676 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 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 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 23070005 t miannu "For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling." SIGNOR-199091 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT "up-regulates activity" binding 9606 12040173 t lperfetto "The binding of tnf to tnf-r1 triggers a series of intracellular events that ultimately result in the activation of two major transcription factors, nuclear factor kb (nf-kb) and c-jun." SIGNOR-88216 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT "up-regulates activity" binding 14732063 t "[...] 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-253594 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT "up-regulates activity" binding 17151142 t "These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling" SIGNOR-253592 TNF protein P01375 UNIPROT TNFRSF21 protein O75509 UNIPROT up-regulates binding 9606 BTO:0000142 9714541 t gcesareni "We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain." SIGNOR-59745 TNFRSF10A protein O00220 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 t amattioni "Fadd binds to ligated trailr1 or trail-r2" SIGNOR-97869 TNFRSF10C protein O14798 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 BTO:0000671 20103630 t amattioni "Albeit on binding the ligand, dcr1 and dcr2 do not transduce the apoptogenic signal," SIGNOR-163611 TNFRSF10D protein Q9UBN6 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 9382840 t amattioni "One function of trail-r4 may be inhibition of trail cytotoxicy. Dcr2 functions as an inhibitory apo2l receptor." SIGNOR-53447 TNFRSF11A protein Q9Y6Q6 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 9606 10075662 f miannu "RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation." SIGNOR-253047 TNFRSF11A protein Q9Y6Q6 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 BTO:0000968 17572386 f miannu "Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation" SIGNOR-253043 TNFRSF13C protein Q96RJ3 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 BTO:0000776 24432023 f lperfetto "Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures." SIGNOR-204361 TNFRSF13C protein Q96RJ3 UNIPROT Lymphoma phenotype SIGNOR-PH14 SIGNOR up-regulates 9606 BTO:0000776 24432023 f lperfetto "Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures." SIGNOR-204364 TNFRSF13C protein Q96RJ3 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000776;BTO:0000785 20889926 t lperfetto "Activation of br3 induces recruitment and degradation of traf3." SIGNOR-168199 TNFRSF17 protein Q02223 UNIPROT ELK1 protein P19419 UNIPROT up-regulates 9606 10903733 f miannu "Bcma overexpression activates elk-1 nuclear factor" SIGNOR-79486 TNFRSF17 protein Q02223 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates jnk" SIGNOR-79492 TNFRSF17 protein Q02223 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79495 TNFRSF17 protein Q02223 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79498 TNFRSF17 protein Q02223 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79501 TNFRSF17 protein Q02223 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79504 TNFRSF17 protein Q02223 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates jnk" SIGNOR-79489 TNFRSF17 protein Q02223 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates jnk" SIGNOR-79507 TNFRSF17 protein Q02223 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 10903733 f miannu "Bcma overexpression induces nf-kb activation" SIGNOR-79510 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 10090 BTO:0000165 17151142 f lperfetto "These results indicate that TNF-alpha regulates myogenesis and muscle regeneration as a key activator of p38." SIGNOR-235370 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000567 11672426 f lperfetto "Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MAPK) or p38 MAPK activities in a time-dependent manner." SIGNOR-226637 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 17151142 f "[...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation" SIGNOR-253600 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 20887952 f "These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs" SIGNOR-253602 TNFRSF1A protein P19438 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" 10090 BTO:0002572;BTO:0000801 21232017 f lperfetto "Tnfr1-induced phosforylation and degradarionn of ikb are almost completely abolished in tradd-deficient mefs,these hallmarks of classical nf-kn signaling are only attenuated in tradd-deficient macrophage." SIGNOR-235789 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT "up-regulates activity" binding 10090 BTO:0002572;BTO:0000801 21232017 t miannu "TRADD and RIP1 contain a C‐terminal death domain which mediates binding to the death domain of TNFR1. Upon association with ligated TNFR1, TRADD further recruits the adapter protein TRAF2 via its N‐terminal TRAF‐binding domain" SIGNOR-245029 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 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 7758105 t lperfetto "We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed." SIGNOR-32739 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 17151142 f "[...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation" SIGNOR-253601 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 20887952 f "These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs" SIGNOR-253603 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates 9606 8069916 f gcesareni "Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2." SIGNOR-33843 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 8069916 t gcesareni "Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2." SIGNOR-33133 TNFRSF1B protein P20333 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 9606 8069916 t lperfetto "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." SIGNOR-34645 TNFRSF25 protein Q93038 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 t amattioni "Dr3 induces apoptosis by tradd-mediated recruitment of fadd and caspase-8" SIGNOR-100480 TNFRSF6B protein O95407 UNIPROT FASLG protein P48023 UNIPROT down-regulates binding 9606 BTO:0001271;BTO:0000661 BTO:0000763 10318773 t amattioni "Tr6 specifically binds fas ligand. Tr6 may play a regulatory role for suppressing in fasl- mediated cell death." SIGNOR-67434 TNFRSF6B protein O95407 UNIPROT TNFSF15 protein O95150 UNIPROT down-regulates binding 9606 BTO:0000782 11911831 t amattioni "Tl1a, is a ligand for dr3 and decoy receptor tr6/dcr3. Tr6-fc protein antagonizes nf-kappab activation and apoptosis induced by tl1a" SIGNOR-116256 TNFSF10 protein P50591 UNIPROT TNFRSF10A protein O00220 UNIPROT up-regulates binding 9606 14585074 t amattioni "Trail interacts with tril-r1 and trail-r2 and activetes them" SIGNOR-101082 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 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 BTO:0000150;BTO:0000551;BTO:0000785 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 TNFSF11 protein O14788 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 BTO:0000968 17572386 f miannu "Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation" SIGNOR-253044 TNFSF11 protein O14788 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT "up-regulates activity" binding 9606 12897775 t miannu "RANKL, a member of the tumour necrosis factor superfamily, is most abundantly expressed as a cell-surface protein by bone-marrow stromal cells. It interacts with its receptor RANK (which is encoded by Tnfrsf11a) on macrophages and mature osteoclasts." SIGNOR-253042 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 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 BTO:0000007 10956646 t gcesareni "Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys." SIGNOR-81360 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 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 15851487 t lperfetto "Baff specifically binds baff receptor" SIGNOR-135713 TNFSF13 protein O75888 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 BTO:0000007 10956646 t gcesareni "Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys." SIGNOR-81308 TNFSF13 protein O75888 UNIPROT TNFRSF17 protein Q02223 UNIPROT up-regulates binding 9606 BTO:0000782 10973284 t gcesareni "April is involved in stimulation of b and t cell function. April functions via binding to bcma and taci and competes with tall-i for receptor binding." SIGNOR-81386 TNFSF14 protein O43557 UNIPROT TNFRSF14 protein Q92956 UNIPROT up-regulates binding 9606 BTO:0000763 10894944 t gcesareni "A member of the tumor necrosis factor (tnf) superfamily, human tnfsf14 (htnfsf14)/hvem-l (herpes virus entry mediator ligand) was isolated as a cellular ligand for hvem/tr2 and human lymphotoxin beta receptor (ltbetar). Tnfsf14 induces apoptosis and suppresses tumor formation" SIGNOR-79328 TNFSF4 protein P23510 UNIPROT TNFRSF4 protein P43489 UNIPROT up-regulates binding 9606 BTO:0000007 9488716 t gcesareni "Activation of nf-kappab in ox40-transfected hsb-2 cells was detected by electrophoretic mobility shift assay within 30 min after the binding of the ligand gp34." SIGNOR-54927 TNIK protein Q9UKE5 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates phosphorylation Ser177 QALKDARsPSPAHIV 9606 BTO:0000586 20530691 t llicata "Here, we report that tnik is an activating kinase for tcf4 and essential for colorectal cancer growth. Tnik, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of tcf4." SIGNOR-165946 TNK2 protein Q07912 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Tyr176 EKATGRYyAMKILKK 10090 BTO:0002021 20333297 t gcesareni "Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation." SIGNOR-252446 TNK2 protein Q07912 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr176 EKATGRYyAMKILKK 10090 BTO:0002021 20333297 t gcesareni "Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation." SIGNOR-252457 TNK2 protein Q07912 UNIPROT SNX9 protein Q9Y5X1 UNIPROT up-regulates phosphorylation 9606 16316319 t 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." SIGNOR-142569 TNKS2 protein Q9H2K2 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates ubiquitination 9606 19759537 t gcesareni "Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway." SIGNOR-188036 TNKS2 protein Q9H2K2 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates quantity by destabilization" 9606 BTO:0000007 19759537 t "Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway." SIGNOR-261248 TNKS protein O95271 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 19759537 t lperfetto "Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway." SIGNOR-187972 TNKS protein O95271 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 19759537 t lperfetto "Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway." SIGNOR-187975 TNKS protein O95271 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates quantity by destabilization" 9606 BTO:0000007 19759537 t "Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway." SIGNOR-261249 Tocilizumab antibody DB06273 DRUGBANK IL6R protein P08887 UNIPROT "down-regulates activity" binding 9606 other 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 tofacitinib chemical CHEBI:71200 ChEBI JAK3 protein P52333 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-258302 tolazoline chemical CHEBI:28502 ChEBI ADRA2A protein P08913 UNIPROT "down-regulates activity" "chemical inhibition" 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-258912 tolazoline chemical CHEBI:28502 ChEBI ADRA2B protein P18089 UNIPROT "down-regulates activity" "chemical inhibition" 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-258913 tolazoline chemical CHEBI:28502 ChEBI ADRA2C protein P18825 UNIPROT "down-regulates activity" "chemical inhibition" 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-258914 tolbutamide chemical CHEBI:27999 ChEBI CFTR protein P13569 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000944 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 tolcapone chemical CHEBI:63630 ChEBI COMT protein P21964 UNIPROT "down-regulates activity" "chemical inhibition" 10090 26919286 t miannu "The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice." SIGNOR-258475 tolcapone chemical CHEBI:63630 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-261091 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 TOMM70 protein O94826 UNIPROT HSP90AA1 protein P07900 UNIPROT "up-regulates activity" binding 9543 BTO:0000298 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 TOMM70 protein O94826 UNIPROT HSPA1A protein P0DMV8 UNIPROT "up-regulates activity" binding 9543 BTO:0000298 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-261380 TOP2A protein P11388 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 15942022 f lperfetto "Down-regulation of DNA topoisomerase IIalpha leads to prolonged cell cycle transit in G2 and early M phases and increased survival to microtubule-interacting agents" SIGNOR-242537 TOP2B protein Q02880 UNIPROT CDH13 protein P55290 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-242302 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 TOP2B protein Q02880 UNIPROT EPHA7 protein Q15375 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-242311 TOP2B protein Q02880 UNIPROT PBX3 protein P40426 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-242308 TOP2B protein Q02880 UNIPROT RELN protein P78509 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-242207 TOP2B protein Q02880 UNIPROT SST protein P61278 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-242305 TOP2B protein Q02880 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 24463367 f lperfetto "Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells" SIGNOR-242533 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 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 TOPORS protein Q9NS56 UNIPROT TP53 protein P04637 UNIPROT up-regulates sumoylation 9606 19473992 t 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-185844 topotecan chemical CHEBI:63632 ChEBI TOP1MT protein Q969P6 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000526 11166732 t miannu "Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma." SIGNOR-259318 topotecan chemical CHEBI:63632 ChEBI TOP1 protein P11387 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000526 11166732 t miannu "Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma." SIGNOR-259317 TOR1AIP1 protein Q5JTV8 UNIPROT VIM protein P08670 UNIPROT "up-regulates activity" binding 9606 BTO:0000452 16361107 t Sara "Co-immune precipitation studies revealed association between vimentin and torsinA in a complex. these studies suggest that mutant torsinA interferes with cytoskeletal events involving vimentin, possibly by restricting movement of these particles/filaments, and hence may affect development of neuronal pathways in the brain." SIGNOR-261313 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 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206313 torkinib chemical CHEBI:90679 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-258269 Tosedostat chemical CID:15547703 PUBCHEM ANPEP protein P15144 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207372 Tosedostat chemical CID:15547703 PUBCHEM LAP3 protein P28838 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207417 "tositumomab and iodine i 131 tositumomab" antibody DB00081 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0001690 14748653 t miannu "Tositumomab is an immunoglobulin G murine monoclonal antibody that binds to the CD20 antigen on the surface of normal and malignant human B-cells. Tositumomab is linked covalently with iodine-131 to produce the radioimmunoconjugate iodine-131 tositumomab (Bexxar). The iodine-131 tositumomab regimen was approved by the US Food and Drug Administration in June 2003 for the treatment of patients with CD20-positive, follicular non-Hodgkin's lymphoma, both with and without transformation, whose disease is refractory to rituximab (Rituxan) and has relapsed following chemotherapy." SIGNOR-259903 TP53BP1 protein Q12888 UNIPROT H4C1 protein P62805 UNIPROT unknown binding 9606 17190600 t gcesareni "Here we demonstrate that this link occurs through direct binding of 53bp1 and crb2 to histone h4." SIGNOR-151654 TP53BP1 protein Q12888 UNIPROT RIF1 protein Q5UIP0 UNIPROT "up-regulates activity" binding 10090 23333305 t miannu "RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination." SIGNOR-259058 TP53BP2 protein Q13625 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates binding 9606 8549741 t gcesareni "The phosphorylase phosphatase activity of pp1 was inhibited by p53bp2 at nanomolar concentrations." SIGNOR-39666 TP53BP2 protein Q13625 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 11839776 t gcesareni "53bp2 interacts with the tumour suppressor p53 and enhances p53-mediated activation of transcription, possibly by facilitating the dephosphorylation of one or more sites on p53" SIGNOR-114762 TP53INP1 protein Q96A56 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 22421968 t gcesareni "In this work, we show that tp53inp1 is also able to interact with atg8-family proteins and to induce autophagy-dependent cell death. mammalian cells contain multiple atg8 orthologs belonging to three subfamilies: microtubule-associated protein 1 light chain 3, -aminobutyric acid receptor-associated protein (gabarap) and -aminobutyric acid receptor-associated protein like 2 (gabarapl2)." SIGNOR-196667 TP53INP1 protein Q96A56 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 22421968 t gcesareni "Tp53inp1 is also able to interact with atg8-family proteins" SIGNOR-196664 TP53INP1 protein Q96A56 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22421968 t gcesareni "Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir)." SIGNOR-196670 TP53INP1 protein Q96A56 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates binding 9606 22421968 t gcesareni "Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir)" SIGNOR-196673 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 TP53INP2 protein Q8IXH6 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 19056683 t gcesareni "Tp53inp2 binds to lc3 as well as to lc3-related proteins gabarap and gabarap-like2." SIGNOR-182611 TP53INP2 protein Q8IXH6 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 19056683 t gcesareni "Tp53inp2 is a scaffold protein that recruits lc3 and/or lc3-related proteins to the autophagosome membrane by interacting with the transmembrane protein vmp1" SIGNOR-182614 TP53 protein P04637 UNIPROT ABCB1 protein P08183 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-255435 TP53 protein P04637 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-254482 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 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7834749 f "Nuclear p53" amattioni "Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis" SIGNOR-33922 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9122197 f gcesareni "P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis" SIGNOR-47541 TP53 protein P04637 UNIPROT BBC3 protein Q9BXH1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 16151013 f amattioni "Nuclear p53 caused expression of puma, which then displaced p53 from bcl-xl, allowing p53 to induce mitochondrial permeabilization." SIGNOR-140245 TP53 protein P04637 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 19007744 t "Cytosolic p53" lperfetto "Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis" SIGNOR-99712 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 TP53 protein P04637 UNIPROT BIRC5 protein O15392 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11965534 f acerquone "Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53." SIGNOR-117328 TP53 protein P04637 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates binding 9606 10207072 t gcesareni "Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo." SIGNOR-66956 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21524151 t lperfetto "p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting G1/S entry." SIGNOR-173425 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 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 8242752 t lperfetto "The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents." SIGNOR-37145 TP53 protein P04637 UNIPROT CDKN1A protein P38936 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-254484 TP53 protein P04637 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 24212651 f miannu "P53 is a nuclear transcription factor with a pro-apoptotic function" SIGNOR-256664 TP53 protein P04637 UNIPROT CRYAB protein P02511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21556774 t miannu "Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53" SIGNOR-253638 TP53 protein P04637 UNIPROT CTSD protein P07339 UNIPROT "up-regulates quantity by expression" "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-255434 TP53 protein P04637 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by expression" "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-255430 TP53 protein P04637 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" binding 9606 14586398 t miannu "We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53." SIGNOR-254087 TP53 protein P04637 UNIPROT FAS protein P25445 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 9841917 t "Nuclear p53" amattioni "In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene," SIGNOR-62376 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 TP53 protein P04637 UNIPROT FNTA protein P49354 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-242408 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 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 TP53 protein P04637 UNIPROT HR protein O43593 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15489903 f miannu "P53 may downregulate HR through multiple mechanisms including the reported associations with the Rad51 and Rad54 recombinases, and the BLM and WRN helicases." SIGNOR-255436 TP53 protein P04637 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 24737129 f "simone vumbaca" "We have identified a novel role for p53 that is specific to the regulation of several pro-inflammatory genes in human macrophages, including IL-6, IL-8 and CXCL1. Importantly, NF-κB co-activation is essential for this regulation" SIGNOR-255969 TP53 protein P04637 UNIPROT LRBA protein P50851 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15064745 f miannu "We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA." SIGNOR-253847 TP53 protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 7958853 f gcesareni "The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop." SIGNOR-34962 TP53 protein P04637 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-255437 TP53 protein P04637 UNIPROT MLH1 protein P40692 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000567 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-257605 TP53 protein P04637 UNIPROT MMP2 protein P08253 UNIPROT "up-regulates quantity by expression" "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-255432 TP53 protein P04637 UNIPROT NDRG1 protein Q92597 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15377670 f miannu "We isolated a p53-regulated gene named ndrg1 (n-myc down-regulated gene 1). Its expression is induced by dna damage in a p53-dependent fashion." SIGNOR-129183 TP53 protein P04637 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16990795 t gcesareni "P52 cooperates with p53 to regulate other known p53 target genes." SIGNOR-149811 TP53 protein P04637 UNIPROT NLRC4 protein Q9NPP4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001938;BTO:0000018 15580302 f miannu "Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53. Overexpression of p53 by transfection in U2OS and A549 cells increased Ipaf mRNA levels." SIGNOR-255439 TP53 protein P04637 UNIPROT NOXA1 protein Q86UR1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19879762 f lperfetto "As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5." SIGNOR-209687 TP53 protein P04637 UNIPROT PERP protein Q96FX8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10733530 f gcesareni "Perp induction is linked to p53-dependent apoptosis, including in response to e2f-1-driven hyperproliferation. Furthermore, analysis of the perp promoter suggests that perp is directly activated by p53." SIGNOR-75877 TP53 protein P04637 UNIPROT PMAIP1 protein Q13794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10807576 f "Nuclear p53" amattioni "Expression of noxa was dependent on p53. Noxa represent a mediator of p53-dependent apoptosis." SIGNOR-76152 TP53 protein P04637 UNIPROT PMAIP1 protein Q13794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14500851 f gcesareni "Apoptosis provoked by dna damage requires the p53 tumor suppressor, but which of the many p53-regulated genes are required has remained unknown. Two genes induced by this transcription factor, noxa and puma (bbc3), stand out, because they encode bh3-only proteins, proapoptotic members of the bcl-2 family required to initiate apoptosis. 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 TP53 protein P04637 UNIPROT PMS2 protein P54278 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000567 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 TP53 protein P04637 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f "P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts" SIGNOR-255669 TP53 protein P04637 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates binding 9606 15073170 t gcesareni "Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb." SIGNOR-124038 TP53 protein P04637 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates binding 9606 15073170 t gcesareni "Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb." SIGNOR-252816 TP53 protein P04637 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14985507 f 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 TP53 protein P04637 UNIPROT TBXAS1 protein P24557 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14586398 f miannu "We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription." SIGNOR-254086 TP53 protein P04637 UNIPROT THBS1 protein P07996 UNIPROT "up-regulates quantity by expression" "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-255433 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14585074 f "Nuclear p53" amattioni "Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53" SIGNOR-113707 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15964798 f gcesareni "Reduction in p53 expression also blocks p65 binding to the intronic region of the dr5 gene, indicating cooperation between p53 and p65 in dr5 expression. (articolo-abstract)" SIGNOR-138293 TP53 protein P04637 UNIPROT VCAN protein P13611 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12438652 f miannu "By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53." SIGNOR-255441 TP53 protein P04637 UNIPROT ZDHHC5 protein Q9C0B5 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000526 28775165 t "Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y" SIGNOR-261150 TP53RK protein Q96S44 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17712528 t gcesareni "The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of prpk to cos-7 cells. Prpk was shown to bind to p53 and to phosphorylate p53 at ser-15." SIGNOR-157471 TP63 protein Q9H3D4 UNIPROT PERP protein Q96FX8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21965674 f miannu "SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding." SIGNOR-255136 TP73 protein O15350 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 17700533 f miannu "Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death." SIGNOR-255473 TP73 protein O15350 UNIPROT BBC3 protein Q96PG8 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-255467 TP73 protein O15350 UNIPROT CDKN1A protein P38936 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-255468 TPR protein P12270 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates binding 9606 BTO:0000567 18981471 t miannu "Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20)." SIGNOR-181918 TRAC protein P01848 UNIPROT 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 CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε 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 αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ" SIGNOR-255297 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 8565075 t lperfetto "The strong interaction between tradd and fadd occurs via their death domains." SIGNOR-39951 TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 8612133 t lperfetto "We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process." SIGNOR-40043 TRADD protein Q15628 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 10629108 t amattioni "Tradd mediates recruitment of traf1/2" SIGNOR-73913 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 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 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 TRADD protein Q15628 UNIPROT TRAF5 protein O00463 UNIPROT up-regulates binding 9606 19632174 t gcesareni "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." SIGNOR-187058 TRAF1 protein Q13077 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates binding 9606 8069916 t gcesareni "Traf1 and traf2 can form homo- and heterotypic dimers." SIGNOR-34768 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 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT "up-regulates activity" binding 9606 BTO:0000459 18621737 t lperfetto "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." SIGNOR-179449 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18621737 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-179452 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 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 20385093 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-164785 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0000785 15084608 t lperfetto "We report here that one important mechanism of nik regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (traf3). Traf3 physically associates with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome." SIGNOR-124233 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT "up-regulates activity" binding 9606 9020361 t lperfetto "NIK binds to Traf2 and stimulates NF-kappaB activity." SIGNOR-46215 TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10346818 t amattioni "Oligomerization of the traf2 effector domain results in specific binding to mekk1, a protein kinase capable of jnk, p38, and ikk activation" SIGNOR-67552 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 TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" binding 9606 10688666 t lperfetto "Tnf receptor (tnfr) associated factor 2 (traf2), an adapter protein that couples tnfrs to the sapks and p38s, can activate ask1 in vivo and can interact in vivo with the amino- and carboxyl-terminal noncatalytic domains of the ask1 polypeptide" SIGNOR-75334 TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" binding 9606 9774977 t lperfetto "Traf2 is a strong activator of ask1" SIGNOR-60747 TRAF2 protein Q12933 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" ubiquitination Lys158 ALIHRDLkPPNLLLV 9606 BTO:0000007 20038579 t lperfetto "Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment." SIGNOR-162638 TRAF2 protein Q12933 UNIPROT MAP4K2 protein Q12851 UNIPROT up-regulates binding 9606 9712898 t gcesareni "Both full-lenght gck and the gck-ctd can form complexes in vivo with traf2." SIGNOR-59685 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 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 10090 BTO:0002572;BTO:0000801 21232017 t gcesareni "Rip1 is known to directly interact with traf2" SIGNOR-245032 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 10090 BTO:0002572;BTO:0000801 21232017 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-235407 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 8702708 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-42984 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 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 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000459 18621737 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-179456 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 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 TRAF3 protein Q13114 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000906 16306937 f miannu "TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines." SIGNOR-256077 TRAF3 protein Q13114 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0000785 15084608 t lperfetto "Traf3 is physically associated with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome." SIGNOR-124236 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 TRAF6 protein Q9Y4K3 UNIPROT ECSIT protein Q9BQ95 UNIPROT "down-regulates activity" ubiquitination 10090 21525932 t Giorgia "Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation" SIGNOR-260370 TRAF6 protein Q9Y4K3 UNIPROT MAP3K14 protein Q99558 UNIPROT "up-regulates activity" binding 9606 10075662 t miannu "RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK." SIGNOR-253048 TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 BTO:0002181 18758450 t lperfetto "Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6." SIGNOR-236071 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 TRAF6 protein Q9Y4K3 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 BTO:0000968 17572386 f miannu "TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation." SIGNOR-253046 TRAF6 protein Q9Y4K3 UNIPROT TAB1 protein Q15750 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-205455 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 TRAF6 protein Q9Y4K3 UNIPROT TAB3 protein Q8N5C8 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-205461 TRAF6 protein Q9Y4K3 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT "up-regulates activity" binding 9606 10075662 t miannu "TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation." SIGNOR-253045 TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" ubiquitination 9606 18758450 t lperfetto "Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis." SIGNOR-180562 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 TRAF7 protein Q6Q0C0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15001576 f miannu "Overexpression of traf7 induced caspase-dependent apoptosis." SIGNOR-123218 TRAF7 protein Q6Q0C0 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 15001576 f miannu "Overexpression of traf7 induced caspase-dependent apoptosis." SIGNOR-256666 TRAF7 protein Q6Q0C0 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates binding 9606 15001576 t miannu "Traf7 specifically interacts with and activates mekk3." SIGNOR-123221 TRAM-34 chemical CHEBI:34990 ChEBI KCNN4 protein O15554 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-207426 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000848 26347206 t miannu "Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation." SIGNOR-259447 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192823 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000848 26347206 t miannu "Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation." SIGNOR-259448 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192826 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000848 26347206 t miannu "Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation." SIGNOR-259446 trandolapril chemical CHEBI:9649 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." SIGNOR-258427 TRBC1 protein P01850 UNIPROT 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 CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε 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 αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ" SIGNOR-255298 "trichostatin A" chemical CHEBI:46024 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-258011 "trichostatin A" chemical CHEBI:46024 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-257942 "trichostatin A" chemical CHEBI:46024 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-258015 "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 "trichostatin A" chemical CHEBI:46024 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-258012 "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 "trichostatin A" chemical CHEBI:46024 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-258017 orantinib chemical CHEBI:91088 ChEBI FGFR1 protein P11362 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207435 "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 "trichostatin A" chemical CHEBI:46024 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-257937 "trichostatin A" chemical CHEBI:46024 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-258018 "trichostatin A" chemical CHEBI:46024 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-258014 "trichostatin A" chemical CHEBI:46024 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-257939 "trichostatin A" chemical CHEBI:46024 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-258013 "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 "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 TRIM11 protein Q96F44 UNIPROT PHOX2B protein Q99453 UNIPROT down-regulates ubiquitination 9606 22307522 t miannu "The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b." SIGNOR-195878 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 TRIM24 protein O15164 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19909775 t miannu "We found that trim24/transcriptional intermediary factor 1alpha (tif1alpha), which is known as a ligand-dependent nuclear receptor co-regulator, interacts with ar and enhances transcriptional activity of ar" SIGNOR-189113 TRIM24 protein O15164 UNIPROT TP53 protein P04637 UNIPROT down-regulates ubiquitination 9606 19844164 t miannu "New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation" SIGNOR-188726 TRIM27 protein P14373 UNIPROT Apoptosis phenotype SIGNOR-PH2 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-102019 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 TRIM27 protein P14373 UNIPROT MAPK11 protein Q15759 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-102022 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 TRIM27 protein P14373 UNIPROT MAPK13 protein O15264 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-102028 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 TRIM27 protein P14373 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu "Rfp expression in hek 293 cells activated jnk1" SIGNOR-102034 TRIM27 protein P14373 UNIPROT PIK3C2B protein O00750 UNIPROT down-regulates ubiquitination 9606 BTO:0000782 22128329 t miannu "We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity." SIGNOR-177935 TRIM27 protein P14373 UNIPROT WASHC1 protein A8K0Z3 UNIPROT "up-regulates activity" ubiquitination Lys220 DAPLSISkREQLEQQ 9606 23452853 t miannu "Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport." SIGNOR-253514 TRIM28 protein Q13263 UNIPROT ALDOA protein P04075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17900823 f miannu "We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor." SIGNOR-255628 TRIM28 protein Q13263 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16107876 t 2 miannu "we present evidence that MDM2 interacts with the nuclear corepressor KAP1. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation." SIGNOR-240405 TRIM33 protein Q9UPN9 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" binding S715 GYRQDDPSYRSFHSG 9606 BTO:0000007 25639486 t Luana "Tumour suppressor TRIM33 targets nuclear β-catenin degradation" SIGNOR-260896 TRIM33 protein Q9UPN9 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" binding 9606 BTO:0000574;BTO:0002625;BTO:0000414 16751102 t lperfetto "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. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses." SIGNOR-236064 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 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 TRIM63 protein Q969Q1 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR "up-regulates activity" 10090 25549588 f areggio "Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX), are markedly induced in almost all types of atrophy." SIGNOR-254993 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 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-258647 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM2 protein P08172 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-258649 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 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-258648 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 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-258646 trimetrexate chemical CHEBI:9737 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000797 7981057 t miannu "We examined the cytotoxicity and biochemical effects of the lipophilic antifol trimetrexate (TMQ) in two human colon carcinoma cell lines, SNU-C4 and NCI-H630, with different inherent sensitivity to TMQ. Dihydrofolate reductase (DHFR) and thymidylate synthase were quantitatively and qualitatively similar in both lines. During drug exposure, DHFR catalytic activity was inhibited by > or = 85% in both cell lines" SIGNOR-258482 trimipramine chemical CHEBI:9738 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 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 FBXW11 protein Q9UKB1 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates ubiquitination 9606 16885021 t gcesareni "Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbetatrcp ubiquitin ligase." SIGNOR-148438 TRIO protein O75962 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-260579 TRIP11 protein Q15643 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 9256431 t miannu "Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity." SIGNOR-50348 TRIP11 protein Q15643 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 9256431 t miannu "Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity." SIGNOR-50421 triprolidine chemical CHEBI:84116 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-258870 triptorelin chemical CHEBI:63633 ChEBI GNRH1 protein P01148 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001033 22416801 t miannu "The comparative effects of degarelix and GnRH agonists were assessed in two studies in a rat model of prostate cancer.14 In a 2‐month study, rats receiving the GnRH agonist, triptorelin (0.5 mg/kg daily), experienced an initial testosterone surge, followed by suppression to castration levels by day 28, which was maintained for the remainder of the study." SIGNOR-259158 TRPC6 protein Q9Y210 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 12032305 t "Members of the transient receptor potential channel (TRPC) family have been characterized as molecular substrates mediating receptor-activated cation influx" SIGNOR-253339 TRPC6 protein Q9Y210 UNIPROT PPP3CA protein Q08209 UNIPROT "up-regulates activity" 9606 27383564 f gcesareni "TRPC6 channel-dependent [Ca2+]i elevation and sequential activation of the calcineurin." SIGNOR-253328 TRPM6 protein Q9BX84 UNIPROT TRPM6 protein Q9BX84 UNIPROT "down-regulates activity" phosphorylation T1851 FNQVKPQTIPYTPRF 9606 BTO:0000007 18258429 t Manara "Autophosphorylation of Threonine1851 in the Kinase Domain Is Essential for the Inhibitory Effect of RACK1" SIGNOR-260922 TRPM7 protein Q96QT4 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser5 sEFLKQAW 9606 24103589 t lperfetto "Trpm7 was responsible for phosphorylation of the serine 5 (ser5) residue [29]. In 2009, the study focused on an association between anxa1 and trpm7 confirmed the presence of a trpm7/annexin a1/mg2_+ complex, suggesting a novel pathway in bradykinin signaling, dependent on pkc and c-src [30]. Even though that pathway is not fully characterized, the same team that discovered the ser5 phosphorylation of anxa1 also reported crucial relevance of this modification for anxa1 membrane binding and especially for the interaction between annexin a1 and its known partner, the calcium binding protein s100a11" SIGNOR-202804 TRPM7 protein Q96QT4 UNIPROT EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser78 SSGSPANsFHFKEAW 9606 21112387 t gcesareni "Here, we show that under conditions where cell growth is limited by mg(2+) availability, trpm7 via its kinase mediates enhanced thr56 phosphorylation of eef2." SIGNOR-170134 TRPS1 protein Q9UHF7 UNIPROT GDF5 protein P43026 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0005092 18363966 f "Regulation of expression" miannu "Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1." SIGNOR-251866 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 TRPV4 protein Q9HBA0 UNIPROT UCP1 protein P25874 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-253096 TSC1 protein Q92574 UNIPROT MTOR protein P42345 UNIPROT "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. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mtor)-mediated signaling to eukaryotic initiation factor 4e-binding protein 1 (4e-bp1) and ribosomal protein s6 kinase 1 (s6k1)." SIGNOR-93130 TSC1 protein Q92574 UNIPROT RHEB protein Q15382 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 20006481 t lperfetto "Tsc1 and tsc2 proteins, which together inhibit rheb through the gap activity of tsc2." SIGNOR-162096 TSC1 protein Q92574 UNIPROT TSC1/TSC2 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 TSC1/TSC2 complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 15340059 t lperfetto "Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb." SIGNOR-235895 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 TSC22D3 protein Q99576 UNIPROT NFKB2 protein Q00653 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 11468175 t "GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits." SIGNOR-253298 TSC22D3 protein Q99576 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" binding 9606 BTO:0000007 11468175 t "GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits." SIGNOR-253299 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 TSC22D3 protein Q99576 UNIPROT RELA protein Q04206 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 11468175 t "GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits." SIGNOR-253297 TSC2 protein P49815 UNIPROT MTOR protein P42345 UNIPROT "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-93133 TSC2 protein P49815 UNIPROT RHEB protein Q15382 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000142 15340059 t lperfetto "Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb." SIGNOR-128432 TSC2 protein P49815 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 9606 12172553 f gcesareni "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)." SIGNOR-91395 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 TSC2 protein P49815 UNIPROT TSC1/TSC2 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 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14623893 t miannu "I– uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane" SIGNOR-251995 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by stabilization" 9606 14623893 f miannu "Uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane" SIGNOR-251994 TSHB protein P01222 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 t gcesareni "Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners." SIGNOR-88653 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 TSPAN12 protein O95859 UNIPROT NDP protein Q00604 UNIPROT up-regulates 9606 19837033 f "Genetic Interaction" gcesareni "Tspan12 genetically interacts with norrin or lrp5" SIGNOR-188661 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000938 16923168 t "The effect has been demonstrated using P10636-8" lperfetto "Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation." SIGNOR-148966 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000938 16923168 t "The effect has been demonstrated using P10636-8" lperfetto "Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation." SIGNOR-148970 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000938 16923168 t "The effect has been demonstrated using P10636-8" lperfetto "Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation." SIGNOR-148974 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser739 GSIDMVDsPQLATLA 9606 BTO:0000938 16923168 t "The effect has been demonstrated using P10636-8" lperfetto "Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation." SIGNOR-148978 TTBK2 protein Q6IQ55 UNIPROT KIF2A protein O00139 UNIPROT "down-regulates activity" phosphorylation S135 SSAQQNGSVSDISPV 9534 BTO:0000298 26323690 t Manara "TTBK2 phosphorylates KIF2A primarily at growing MT ends and counteracts the depolymerization activity of KIF2A" SIGNOR-260926 TTC3 protein P53804 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000944 20059950 t gcesareni "TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus" SIGNOR-252436 TTC3 protein P53804 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000944 20059950 t gcesareni "TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus" SIGNOR-252459 TTF2 protein Q9UNY4 UNIPROT CDC5L protein Q99459 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 12927788 t miannu "HLodestar/HuF2 associates with CDC5L in cell lysates and HeLa nuclear extracts. It is possible that during the cell division cycle, hLodestar/HuF2’s associates with transcription/splicing complexes in order to inhibit transcription/splicing prior to the start of mitosis and/or functions in stabilizing nuclear complexes containing splicing factors (e.g., the CDC5L complex) so that these are available for re-initiation of splicing at the end of mitosis when gene expression is re-established in cells." SIGNOR-224460 TTK protein P33981 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto "Ttk phosphorylation of thr735 was associated with partial inhibition of nuclear targeting of c-abl." SIGNOR-181064 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation 9606 18243099 t amattioni "Direct phosphorylation of the aurora b regulator borealin by mps1 enhances aurora b activity and is essential for chromosome alignment" SIGNOR-160604 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 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 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 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr94 ATADLDItEINKLTA 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-186155 TTK protein P33981 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 15618221 t lperfetto "Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage" SIGNOR-132665 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Ser65 IDLGTTNsCVAVMEG 9606 17573779 t lperfetto "Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin" SIGNOR-156181 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Thr62 VVGIDLGtTNSCVAV 9606 17573779 t lperfetto "Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin" SIGNOR-156185 TTK protein P33981 UNIPROT MAD2L1 protein Q13257 UNIPROT "up-regulates activity" phosphorylation 18541701 t lperfetto "Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2." SIGNOR-252036 FGF2 protein P09038 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 15765505 f gcesareni "Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development." SIGNOR-134512 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr675 ANQMQPDtTSVVKDS 9606 18680479 t miannu "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / mutation of thr675 to alanine increased mps1 catalytic domain activity, and this was reduced to wt levels by mutation to aspartate" SIGNOR-179904 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr806 NQMAKGTtEEMKYVL 9606 18680479 t miannu "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / t806d mps1 was significantly less active than t806a, demonstrating a potential negative correlation between phosphorylation and activity at this site." SIGNOR-179908 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser582 LNKLQQHsDKIIRLY 9606 18680479 t miannu "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / autophosphorylation outside the activation segment was also important for activity in vitro, since s582a/s582d and y811f mutants exhibited decreased activity" SIGNOR-179896 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser677 QMQPDTTsVVKDSQV 9606 19120698 t llicata "Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity" SIGNOR-183022 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser742 QQIINQIsKLHAIID 9606 18680479 t gcesareni "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity after expression in bacteria or in cultured human cells." SIGNOR-179900 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr676 NQMQPDTtSVVKDSQ 9606 19120698 t llicata "Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity" SIGNOR-183026 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr686 VKDSQVGtVNYMPPE 9606 19120698 t llicata "Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity, autophosphorylation at the p+1 loop (t686) is associated with the active kinase." SIGNOR-183030 TTL protein Q8NG68 UNIPROT TUBA1A protein Q71U36 UNIPROT 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-176912 TTL protein Q8NG68 UNIPROT TUBA1B protein P68363 UNIPROT 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-176915 TTL protein Q8NG68 UNIPROT TUBA1C protein Q9BQE3 UNIPROT 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-176918 TTL protein Q8NG68 UNIPROT TUBA3C protein Q13748 UNIPROT 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-176921 TTL protein Q8NG68 UNIPROT TUBA3E protein Q6PEY2 UNIPROT 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-176924 TTL protein Q8NG68 UNIPROT TUBA4A protein P68366 UNIPROT 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-176927 TTL protein Q8NG68 UNIPROT TUBA8 protein Q9NY65 UNIPROT 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-176930 TTN protein Q8WZ42 UNIPROT TCAP protein O15273 UNIPROT unknown phosphorylation Ser157 GALRRSLsRSMSQEA 10090 BTO:0000165 9804419 t lperfetto "These data indicate that the activation of titin kinase in differentiating myocytes and the resulting phosphorylation of telethonin are involved in the reorganization of the cytoskeleton during myofibrillogenesis." SIGNOR-246925 "tubastatin A" chemical CHEBI:94186 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207450 TUBB1 protein Q9H4B7 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10116 17118269 f lperfetto "However, evidence suggests that the detyrosination/tyrosination cycle of alpha-tubulin may be linked in some cell types to cell division and proliferationNF-Y" SIGNOR-242138 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 TUBB protein P07437 UNIPROT SMAD3 protein P84022 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-154319 "Tuberoinfundibular peptide of 39 residues" smallmolecule CHEBI:80275 ChEBI PTH2R protein P49190 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-257576 TUBG1 protein P23258 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 19029337 f miannu "It has been reported that NEDD1 directly interacts with and recruits the γ-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly" SIGNOR-261423 TWIST1 protein Q15672 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-255510 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 TWIST1 protein Q15672 UNIPROT CD44 protein P16070 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-255512 TWIST1 protein Q15672 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255157 TWIST1 protein Q15672 UNIPROT CSNK2A1 protein P68400 UNIPROT down-regulates 9606 22975381 f amattioni "Ck2-mediated phosphorylation at ser392 of p53 was attenuated in the presence of recombinant twist1" SIGNOR-192064 TWIST1 protein Q15672 UNIPROT CTPS1 protein P17812 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-255518 TWIST1 protein Q15672 UNIPROT F2R protein P25116 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-255520 TWIST1 protein Q15672 UNIPROT FAP protein Q12884 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255523 TWIST1 protein Q15672 UNIPROT FN1 protein P02751 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255521 TWIST1 protein Q15672 UNIPROT FOS protein P01100 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-255526 TWIST1 protein Q15672 UNIPROT GDF15 protein Q99988 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-255527 TWIST1 protein Q15672 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255522 TWIST1 protein Q15672 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-255515 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 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 TWIST1 protein Q15672 UNIPROT NF1 protein P21359 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-255530 TWIST1 protein Q15672 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-255531 TWIST1 protein Q15672 UNIPROT PFDN4 protein Q9NQP4 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-255532 TWIST1 protein Q15672 UNIPROT RAP1A protein P62834 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-255533 TWIST1 protein Q15672 UNIPROT RBL2 protein Q08999 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-255535 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 TWIST1 protein Q15672 UNIPROT SNAI2 protein O43623 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 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 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 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 TWIST2 protein Q8WVJ9 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-255499 TWIST2 protein Q8WVJ9 UNIPROT CD44 protein P16070 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-255517 TWIST2 protein Q8WVJ9 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 19581928 f miannu "we showed aberrant IL-6 production and STAT3 activation in MCF-7 cells that constitutively express Twist, a metastatic regulator and direct transcriptional repressor of E-cadherin." SIGNOR-255536 TWIST2 protein Q8WVJ9 UNIPROT CTPS1 protein P17812 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-255500 TWIST2 protein Q8WVJ9 UNIPROT F2R protein P25116 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-255502 TWIST2 protein Q8WVJ9 UNIPROT FOS protein P01100 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-255503 TWIST2 protein Q8WVJ9 UNIPROT GDF15 protein Q99988 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-255496 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 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 TWIST2 protein Q8WVJ9 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-255513 TWIST2 protein Q8WVJ9 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-255495 TWIST2 protein Q8WVJ9 UNIPROT NF1 protein P21359 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-255505 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 TWIST2 protein Q8WVJ9 UNIPROT PFDN4 protein Q9NQP4 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-255507 TWIST2 protein Q8WVJ9 UNIPROT RAP1A protein P62834 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-255508 TWIST2 protein Q8WVJ9 UNIPROT RBL2 protein Q08999 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-255509 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 TWIST2 protein Q8WVJ9 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-255497 TXK protein P42681 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 BTO:0000782 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 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 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-44665 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 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 TYK2 protein P29597 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates phosphorylation Tyr138 SPTLVIAyLMMRQKM 9606 17785772 t lperfetto "Phosphorylation of vhr at tyr(138) was required for its phosphatase activity toward stat5. In addition, the src homology 2 domain of stat5 was required for the effective dephosphorylation of stat5 by vhr. The tyrosine kinase tyk2, which mediates the phosphorylation of stat5, was also responsible for the phosphorylation of vhr at tyr(138)." SIGNOR-157655 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 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT "up-regulates activity" phosphorylation Tyr481 PSSSIDEyFSEQPLK 9606 7526154 t lperfetto "In this report, we demonstrate that the alpha subunit of the type I IFN receptor (IFN-R) corresponds to the product of a previously cloned receptor subunit cDNA and, further, that the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit.These data support the hypothesis that the Tyk2 protein functions as part of a receptor complex to initiate intracellular signaling in response to type I IFNs" SIGNOR-246939 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 TYK2 protein P29597 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t lperfetto "Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity." SIGNOR-246943 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 10542297 t lperfetto "Stat3 activation requires kinase function of tyk2." SIGNOR-71781 TYK2 protein P29597 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-256255 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 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT "up-regulates activity" phosphorylation Tyr1055 VPEGHEYyRVREDGD 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-43092 TYSND1 protein Q2T9J0 UNIPROT ACOX1 protein Q15067 UNIPROT "up-regulates activity" cleavage -1 17255948 t miannu "Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1." SIGNOR-261057 TYSND1 protein Q2T9J0 UNIPROT SCP2 protein P22307 UNIPROT "up-regulates activity" cleavage -1 17255948 t miannu "Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1." SIGNOR-261055 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 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 9873633 t gcesareni "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2." SIGNOR-62892 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 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. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2." SIGNOR-104939 U0126 chemical CHEBI:90693 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 9873633 t gcesareni "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. U0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2." SIGNOR-62895 U0126 chemical CHEBI:90693 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. U0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2." SIGNOR-104942 U0126 chemical CHEBI:90693 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates 9606 11782488 f gcesareni "Bmk1activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2." SIGNOR-113782 U0126 chemical CHEBI:90693 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 and neuronal survival. Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2." SIGNOR-104945 U0126 chemical CHEBI:90693 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 9873633 t lperfetto "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2." SIGNOR-244958 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207606 U0126.EtOH chemical CHEBI:90692 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244961 U2AF1 protein Q01081 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR "form complex" binding 9606 8647433 t miannu "The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35)." SIGNOR-41945 U2AF2 protein P26368 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR "form complex" binding 9606 8647433 t miannu "The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35)." SIGNOR-41948 U2AF2 protein P26368 UNIPROT ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR "form complex" binding 9606 9237760 t miannu "Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35." SIGNOR-50173 U50488 chemical CHEBI:73358 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-258666 U50488 chemical CHEBI:73358 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-258826 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 UBAP2 protein Q5T6F2 UNIPROT ANXA2 protein P07355 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0002181 27121050 t Sara "UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination" SIGNOR-261314 UBASH3B protein Q8TF42 UNIPROT CBL protein P22681 UNIPROT down-regulates binding 9606 15159412 t gcesareni "Sts-1 and sts-2 contain sh3 domains that interacted with cbl, ub-associated domains, which bound directly to mono-ub or to the egfr/ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of sts-1/2. Ligand-induced recruitment of sts-1/sts-2 into activated egfr complexes led to inhibition of receptor internalization, reduction in the number of egfr-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways." SIGNOR-124897 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 UBE2A protein P49459 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination Lys164 AVVISCAkDGVKFSA 9606 12226657 t gcesareni "Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18." SIGNOR-92737 UBE2A protein P49459 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination Lys164 AVVISCAkDGVKFSA 9606 19706603 t gcesareni "Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18." SIGNOR-187761 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 UBE2D1 protein P51668 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" 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-253022 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 UBE2I protein P63279 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates activity" sumoylation Lys161 ALRPLVIkQEPREED -1 12511558 t miannu "C/EBPalpha interacts directly with the E2 SUMO-conjugating enzyme Ubc9 and can be SUMOylated in vitro using purified recombinant components. Our results indicate that SUMO modification of SC motifs provides a means to rapidly control higher order interactions among transcription factors and suggests that SUMOylation may be a general mechanism to limit transcriptional synergy." SIGNOR-256334 UBE2I protein P63279 UNIPROT ETV5 protein P41161 UNIPROT down-regulates sumoylation 9606 15857832 t miannu "Here we show that erm interacts with the sumo-conjugating enzyme ubc9 and is modified by sumo. We further show that sumo modification of this ets transcription factor affects its ability to activate transcription." SIGNOR-135850 UBE2I protein P63279 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates sumoylation Lys25 PETGRTVkEPEGPPP 9606 19744555 t miannu "Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2" SIGNOR-187901 UBE2I protein P63279 UNIPROT MITF protein O75030 UNIPROT down-regulates ubiquitination Lys308 SEARALAkERQKKDN 9606 10673502 t lperfetto "Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo." SIGNOR-75117 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 UBE2I protein P63279 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation Lys113 KNELKHVkYCQYAFD 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-98993 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 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT "down-regulates activity" sumoylation Lys417 TSPVTQkVkDEAAAQP 9606 BTO:0000007 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-256130 UBE2N protein P61088 UNIPROT H2AX protein P16104 UNIPROT up-regulates ubiquitination 9606 18077395 t gcesareni "In an h2ax- and mdc1-dependent manner , rnf8/ubc13 complexes go to sites of dna damage through their fha domain and initiate the synthesis of k63 polyubiquitin chains on chromatin that recruit the brca1 a complex through the uim domains of rap80." SIGNOR-159880 UBE2N protein P61088 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000785 14713952 t lperfetto "Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38." SIGNOR-121274 UBE2N protein P61088 UNIPROT UBE2V1 protein Q13404 UNIPROT "up-regulates activity" binding 9606 20551964 t lperfetto "Ubc13, the partner of rnf8 and rnf168, usually cooperates with an e2-like protein, uev1 (also known as ube2v1) or mms2 (also known as ube2v2), for the synthesis of lys63-linked polyubiquitin chains." SIGNOR-166177 UBE2O protein Q9C0C9 UNIPROT SMAD6 protein O43541 UNIPROT down-regulates ubiquitination Lys173 LLLEQELkTVTYSLL 9606 23455153 t gcesareni "We showed that ube2o functions as an e2-e3 hybrid to monoubiquitinate smad6 at lysine 174" SIGNOR-192255 UBE2V1 protein Q13404 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11057907 t lperfetto "We find that traf6, a ring domain protein, functions together with ubc13/uev1a to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (k63) of ubiquitin" SIGNOR-83603 UBE3A protein Q05086 UNIPROT LAMTOR1 protein Q6IAA8 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000601 30020076 t "Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity" SIGNOR-256145 UBIAD1 protein Q9Y5Z9 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" binding 9606 BTO:0000362 30518913 t miannu "This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells." SIGNOR-256206 UBIAD1 protein Q9Y5Z9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000362 30518913 f miannu "This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells." SIGNOR-256205 UBR1 protein Q8IWV7 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 t miannu "The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells" SIGNOR-128169 UBR2 protein Q8IWV8 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 t miannu "The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells" SIGNOR-128214 UBTF protein P17480 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-260077 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 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-217610 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates deubiquitination 9606 16027725 t gcesareni "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-138876 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 UCHL5 protein Q9Y5K5 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 16027725 t gcesareni "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-138879 UCHL5 protein Q9Y5K5 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates quantity by stabilization" binding 9606 17052192 t gcesareni "Smad7 can act as an adaptor able to recruit uch37 to the type i tgf-beta receptor. Consequently, uch37 dramatically up-regulates tgf-beta-dependent gene expression by de-ubiquitinating and stabilizing the type i tgf-beta receptor." SIGNOR-150135 UDP(3-) smallmolecule CHEBI:58223 ChEBI P2RY6 protein Q15077 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-257565 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 UFD1 protein Q92890 UNIPROT CD4 protein P01730 UNIPROT "down-regulates quantity by destabilization" binding 9606 20442859 t miannu "These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L." SIGNOR-252421 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t lperfetto "Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability" SIGNOR-77705 FOXO1 protein Q12778 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 20577053 f gcesareni "Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner." SIGNOR-166352 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 12093740 t lperfetto "Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability" SIGNOR-90274 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 9606 10880969 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. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1." SIGNOR-78895 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 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. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1." SIGNOR-143485 UHMK1 protein Q8TAS1 UNIPROT PIMREG protein Q9BSJ6 UNIPROT up-regulates phosphorylation Ser131 GAQKGSGsPTHSLSQ 9606 23419774 t lperfetto "Cats is a substrate of kis and mapped the phosphorylation site to cats serine 131 (s131). Kis enhances the transcriptional repressor activity of cats" SIGNOR-192702 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser80 PPNPEDRsPSPEPIY 9606 16420481 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-143837 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 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 16420481 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-143841 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 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-199797 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 UHMK1 protein Q8TAS1 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser438 GSHGQTPsPGALPLG 9606 10880969 t lperfetto "We also identified a tryptic peptide of synapsin i phosphorylated by kis" SIGNOR-78899 UHRF1 protein Q96T88 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0005192 20037778 f miannu "we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter." SIGNOR-254224 ULBP2 protein Q9BZM5 UNIPROT KLRK1 protein P26718 UNIPROT up-regulates binding 9606 BTO:0000782 10894171 t gcesareni "Here we describe a family of gpi-anchored cell surface proteins that function as ligands for the mouse activating nkg2d receptor. These molecules are encoded by the retinoic acid early inducible (rae-1) and h60 minor histocompatibility antigen genes on mouse chromosome 10 and show weak homology with mhc class i." SIGNOR-79233 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 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 23863160 f lperfetto "In mammals, two protein complexes, namely the ULK1/Atg13/FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin/Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation." SIGNOR-209907 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23863160 f lperfetto "Cellular energy and nutrient status will dictate whether mTORC1 takes over and drives cell growth or conversely whether AMPK becomes active once again to drive consecutive waves of autophagy thorough ULK1." SIGNOR-209925 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" phosphorylation 9606 23863160 t lperfetto "Raptor phosphorylation by ULK1 was sufficient to completely block Rheb-induced mTORC1 activity in cells as well as mTORC1 kinase activity invitro" SIGNOR-209910 ULK1 protein O75385 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates phosphorylation 9606 20921139 t gcesareni "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-168292 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 ULK1 protein O75385 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19211835 t gcesareni "Ulks directly phosphorylate atg13" SIGNOR-183957 ULK1 protein O75385 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 BTO:0000567;BTO:0000938 BTO:0000142 11146101 t gcesareni "N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions" SIGNOR-85614 ULK1 protein O75385 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 SIGNOR-C15 21460634 t lperfetto "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity." SIGNOR-173047 ULK1 protein O75385 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "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-173050 ULK1 protein O75385 UNIPROT PRKAG3 protein Q9UGI9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity phosphorylation of ampk by ulk1 represents a negative feedback circuit." SIGNOR-173053 ULK1 protein O75385 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates phosphorylation 9606 19597335 t gcesareni "Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks." SIGNOR-186992 ULK1 protein O75385 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR "form complex" binding 9606 23863160 t lperfetto "In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation." SIGNOR-209890 ULK2 protein Q8IYT8 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates phosphorylation 9606 21460634 t lperfetto "We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I" SIGNOR-217487 ULK2 protein Q8IYT8 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19225151 t gcesareni "Ulks directly phosphorylates atg13." SIGNOR-184126 ULK2 protein Q8IYT8 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t miannu "We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I" SIGNOR-173089 ULK2 protein Q8IYT8 UNIPROT PRKAB1 protein Q9Y478 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity" SIGNOR-173092 ULK2 protein Q8IYT8 UNIPROT PRKAG3 protein Q9UGI9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity." SIGNOR-173095 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT "up-regulates activity" phosphorylation S300 KKDQEGDSAAALS 9606 BTO:0000007 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 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT "up-regulates activity" phosphorylation S350 AEELKAIVSSSNQALL 9606 BTO:0000007 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-260794 UMPS protein P11172 UNIPROT "orotic acid" smallmolecule CHEBI:16742 ChEBI "down-regulates quantity" "small molecule catalysis" 9606 18020427 t miannu "Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate)." SIGNOR-253580 UMPS protein P11172 UNIPROT "orotidine 5'-phosphate" smallmolecule CHEBI:15842 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 18020427 t miannu "Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate)." SIGNOR-253581 UMPS protein P11172 UNIPROT Pyrimidine_nucleotide_metabolic_process phenotype SIGNOR-PH85 SIGNOR up-regulates 26059768 f miannu "The bifunctional enzyme UMP synthase leads to the synthesis of uridine 5′-monophosphate (UMP). UMP could be considered one of the hub molecules in pyrimidine metabolism because it is the precursor of other pyrimidine nucleotides." SIGNOR-253582 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 Unii-2ewn8Z05CN chemical CID:129138801 PUBCHEM EIF4A1 protein P60842 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000815 32470302 t "Simone Vumbaca" "Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase" SIGNOR-261120 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 UNII-XH2662798I chemical CID:16156006 PUBCHEM H3-3A protein P84243 UNIPROT down-regulates 9606 20068082 f gcesareni "Pf-00477736 also significantly enhances docetaxel efficacy in vitro and in vivo, in association with decreased cdc25c cytoplasmic phosphorylation (ser216) and histone h3 phosphorylation (ser10)(42)." SIGNOR-163130 URB597 chemical CID:1383884 PUBCHEM FAAH protein O00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207615 "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 "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 "Urotensin II" smallmolecule CHEBI:80244 ChEBI UTS2R protein Q9UKP6 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-257590 USF1 protein P22415 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 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 USF1 protein P22415 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-254814 USF1 protein P22415 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0004116 7862113 f irozzo "Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study." SIGNOR-255702 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 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 USF1 protein P22415 UNIPROT MYH9 protein P35579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 11467950 f miannu "we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies." SIGNOR-222554 USF1 protein P22415 UNIPROT POMC protein P01189 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19389701 f gcesareni "Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes" SIGNOR-185575 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 USF2 protein Q15853 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-254656 USF2 protein Q15853 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-255594 USF2 protein Q15853 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-254883 USF2 protein Q15853 UNIPROT MYH9 protein P35579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 11467950 f miannu "we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies." SIGNOR-222608 USO1 protein O60763 UNIPROT GOLGB1 protein Q14789 UNIPROT "up-regulates activity" binding 9606 23555793 t miannu "The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane." SIGNOR-261237 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 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 USP13 protein Q92995 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0002181 SIGNOR-C242 21962518 t Giulio "Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)" SIGNOR-260295 USP24 protein Q9UPU5 UNIPROT DDB2 protein Q92466 UNIPROT up-regulates deubiquitination 9606 23159851 t miannu "Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation" SIGNOR-199731 USP28 protein Q96RU2 UNIPROT MYC protein P01106 UNIPROT up-regulates deubiquitination 9606 BTO:0000150 17558397 t esanto "Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc." SIGNOR-155590 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 USP6 protein P35125 UNIPROT MMP10 protein P09238 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20418905 f miannu "In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock." SIGNOR-164943 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT "up-regulates quantity by stabilization" deubiquitination Lys501 ADDISLLk 9606 BTO:0003704 27302062 t irozzo "Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501." SIGNOR-259101 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 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 USP8 protein P40818 UNIPROT RNF41 protein Q9H4P4 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0002181 23750007 t irozzo "Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins." SIGNOR-259105 USP9X protein Q93008 UNIPROT EPS15 protein P42566 UNIPROT "down-regulates activity" deubiquitination 9606 26748853 t gcesareni "We identify the endocytic protein Eps15 as one of the critical substrates of USP9X" SIGNOR-245052 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 10090 BTO:0000165 20016939 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-236855 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 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 22298955 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-195697 USP9X protein Q93008 UNIPROT SMN1 protein Q16637 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 23112048 t lperfetto "Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron" SIGNOR-253113 UTS2R protein Q9UKP6 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-257426 UTS2R protein Q9UKP6 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-257051 UTS2R protein Q9UKP6 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-257164 UTS2R protein Q9UKP6 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-256922 UTS2R protein Q9UKP6 UNIPROT GNAS protein Q5JWF2 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-256779 UTS2R protein Q9UKP6 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-257319 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR EDN1 protein P05305 UNIPROT up-regulates 9606 BTO:0000667 9767234 f miannu "UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes." SIGNOR-252383 "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 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR IL1A protein P01583 UNIPROT up-regulates 9606 BTO:0000667 9767234 f miannu "UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes." SIGNOR-252384 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR IL1B protein P01584 UNIPROT up-regulates 9606 BTO:0000667 9767234 f miannu "UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes." SIGNOR-252382 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR MC1R protein Q01726 UNIPROT up-regulates 9606 BTO:0000847 9767234 f miannu "Melanocyte-stimulating hormone (MSH) receptor binding activity and melanocortin-1 receptor (MC1-R) gene expression on normal human melanocytes have been studied as responses to the effects of ultraviolet B (UVB), interleukin-1 (IL-1), endothelin-1 (ET-1) and tumour necrosis factor-alpha (TNF-alpha), which are known as UV sensitive regulators of melanocytic function. 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-252388 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR PAH protein P00439 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-252207 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR TNF protein P01375 UNIPROT up-regulates 9606 BTO:0000667 19005488 f miannu "UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts." SIGNOR-252208 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 UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17106237 t lperfetto "UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis." SIGNOR-150825 UVRAG protein Q9P2Y5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 18843052 t lperfetto "Although both human atg14 and uvrag interact with beclin 1 and vps34." SIGNOR-181554 UVRAG protein Q9P2Y5 UNIPROT "Vps34 Complex II" complex SIGNOR-C241 SIGNOR "form complex" binding -1 30397185 t lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260322 "UV stress" stimulus SIGNOR-ST7 SIGNOR RRM2B protein Q7LG56 UNIPROT up-regulates 9606 BTO:0001061 14583450 f miannu "Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3." SIGNOR-259362 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 VAC14 protein Q08AM6 UNIPROT "PAS complex" complex SIGNOR-C190 SIGNOR "form complex" binding 9606 BTO:0000007 17556371 t miannu "Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels." SIGNOR-253530 vadimezan chemical CHEBI:75934 ChEBI NQO1 protein P15559 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191397 "valproic acid" chemical CHEBI:39867 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 11742974 t Federica "Here we show that VPA inhibits corepressor-associated HDACs at therapeutically employed concentrations and acts as a potent inducer of differentiation in several types of transformed cells." SIGNOR-261078 valrubicin chemical CHEBI:135876 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000096 16019763 t miannu "Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis." SIGNOR-259383 valrubicin chemical CHEBI:135876 ChEBI TOP2B protein Q02880 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000096 16019763 t miannu "Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis." SIGNOR-259384 valsartan chemical CHEBI:9927 ChEBI AGTR1 protein P30556 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001260 8577935 t miannu "The binding characteristics of the angiotensin AT1 receptor antagonist valsartan were investigated in different animal species and tissues." SIGNOR-258489 VAMP3 protein Q15836 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-253082 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 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 vandetanib chemical CHEBI:49960 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207624 vandetanib chemical CHEBI:49960 ChEBI RET protein P07949 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-258307 Varespladib chemical CID:155815 PUBCHEM PLA2G1B protein P04054 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207633 VARLITINIB chemical CID:42642648 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189900 VARLITINIB chemical CID:42642648 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189903 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1A protein P37288 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-257461 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1B protein P47901 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-257462 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR2 protein P30518 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-257463 vatalanib chemical CHEBI:90620 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207645 vatalanib chemical CHEBI:90620 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207648 VAV1 protein P15498 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000782 9200440 t gcesareni "Hese data imply that c-cbl is a molecular adapter that regulates the function of vav" SIGNOR-49188 VAV1 protein P15498 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 9013873 f lperfetto "Vav may link gp130 activation to downstream mapk activation in hematopoietic cells." SIGNOR-244640 VAV1 protein P15498 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 7809090 t gcesareni "Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation." SIGNOR-33840 VAV1 protein P15498 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0001271 9209406 t gcesareni "Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7." SIGNOR-49362 VAV1 protein P15498 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 9013873 f gcesareni "Vav may link gp130 activation to downstream mapk activation in hematopoietic cells." SIGNOR-46064 VAV1 protein P15498 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates 9606 BTO:0000782 10725744 f lperfetto "Vav synergizes with protein kinase c theta to mediate il-4 gene expression in response to cd28 costimulation in t cells" SIGNOR-75827 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 7227 23525006 t "We identify the GTP exchange factor (GEF) Vav as a key regulator of Rac activity downstream of RTKs in a developmentally regulated cell migration event" SIGNOR-259081 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 VAV1 protein P15498 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-260580 VAV1 protein P15498 UNIPROT SYK protein P43405 UNIPROT up-regulates binding 9606 11331248 t lperfetto "Vav interacts with the tyrosine kinase syk" SIGNOR-107049 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 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 10982832 t miannu "Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases." SIGNOR-81645 VAV2 protein P52735 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-260582 VCP protein P55072 UNIPROT DERL1 protein Q9BUN8 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15215856 t miannu "VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97." SIGNOR-261372 VCP protein P55072 UNIPROT NPLOC4 protein Q8TAT6 UNIPROT "up-regulates activity" binding 9606 20442859 t miannu "These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes." SIGNOR-252423 VCP protein P55072 UNIPROT UFD1 protein Q92890 UNIPROT "up-regulates activity" binding 9606 20442859 t miannu "These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes." SIGNOR-252424 VDAC1 protein P21796 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10365962 f lperfetto "Our results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis." SIGNOR-249615 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 VDR protein P11473 UNIPROT CYP3A4 protein P08684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 12147248 f miannu "Expression of cytochrome P450 3A4 (CYP3A4) is induced by 1,25-dihydroxyvitamin D(3)(1,25(OH)(2)D(3)) in Caco-2 cells. However, since a typical vitamin D responsive element has not been found in the 5(')-flanking region of the CYP3A4 gene, the mechanism of 1,25(OH)(2)D(3)-induced CYP3A4 mRNA expression is poorly understood. In the present study, we demonstrated that vitamin D receptor (VDR) is a critical factor for the induction using the antisense oligonucleotide technique." SIGNOR-255600 VDR protein P11473 UNIPROT HLA-DRB1 protein P01912 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 19956544 f "The promoter sequence analysis of HLA-DRB1 0301 showed presence of VDRE involved in higher expression of HLA-DRB1 030, which was confirmed by flow cytometry and real time PCR analysis| The data shows an average of 1.79±0.28 (mean±S.D. of three independent experiments) fold increase in the HLA-DRB1 transcripts from B-LCL treated with calcitriol as compared to the vehicle control." SIGNOR-253978 VEGFA protein P15692 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 16301830 f "VEGF as a key mediator of angiogenesis in cancer." SIGNOR-256597 VEGFA protein P15692 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-252275 VEGFA protein P15692 UNIPROT DLL4 protein Q9NR61 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22426001 f gcesareni "Activation triggered by vegf-a (also known as vegf) has been shown to induce expression of thenotchligand dll4 in angiogenic vessels." SIGNOR-196736 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 VEGFA protein P15692 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 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-157100 VEGFB protein P49765 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-252276 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 VEGFC protein P49767 UNIPROT FLT4 protein P35916 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni "Vegf-c, was isolated as a ligand for the tyrosine kinase vegfr-3 (flt4)" SIGNOR-55205 VEGFC protein P49767 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni "Vegf-c is also a ligand for vegfr-2 (12), but the functional significance of this potential interaction in vivo is unknown" SIGNOR-55208 VEGFC protein P49767 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t gcesareni "The functional importance of the interaction of np2 with the lymphangiogenic growth factors was demonstrated by cointernalization of np2 along with vegfr-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with vegf-c or vegf-d." SIGNOR-147611 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 vemurafenib chemical CHEBI:63637 ChEBI BRAF protein P15056 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000848 23094782 t miannu "Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents; ipilimumab, a humanized, IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and vemurafenib , a BRAF (v-raf murine sarcoma viral oncogene homolog B1) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene." SIGNOR-259281 venlafaxine chemical CHEBI:9943 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9608 BTO:0000837 20378347 t Luana "The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD)." SIGNOR-257835 venlafaxine chemical CHEBI:9943 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001585 20378347 t Luana "The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD)." SIGNOR-257836 VEPH1 protein Q14D04 UNIPROT LATS1 protein O95835 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 r8" SIGNOR-177074 VEPH1 protein Q14D04 UNIPROT LATS2 protein Q9NRM7 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-177077 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 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 Verdinexor chemical CID:71492799 PUBCHEM XPO1 protein O14980 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000018 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 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-257603 VHL protein P40337 UNIPROT CDKN1C protein P49918 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000037 15824735 f miannu "three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL." SIGNOR-255601 VHL protein P40337 UNIPROT DAB2 protein P98082 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000037 15824735 f miannu "three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL." SIGNOR-255602 VHL protein P40337 UNIPROT HIF1A protein Q16665 UNIPROT 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 VHL protein P40337 UNIPROT KLF10 protein Q13118 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003781 18359287 f lperfetto "In this study, we show that both TGFBI and KLF10 are down-regulated by VHL in 786-0 cells, and that KLF10 may serve as a transactivator of the TGFBI promoter." SIGNOR-253213 VHL protein P40337 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000037 15824735 f miannu "three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL." SIGNOR-255603 VHL protein P40337 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 16678111 t "Here we found that pVHL directly associates with and stabilizes p53 by suppressing Mdm2-mediated ubiquitination and nuclear export of p53." SIGNOR-256594 vilanterol chemical CHEBI:75037 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 20462258 t Luana "A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. | Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo" SIGNOR-257843 "vincaleukoblastine sulfate" chemical CHEBI:9984 ChEBI TUBA1A protein Q71U36 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-259255 "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 FSTL3 protein O95633 UNIPROT MSTN protein O14793 UNIPROT down-regulates binding 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 t gcesareni "Fstl3 inhibits myostatin via its n-terminal domain." SIGNOR-199063 "vincaleukoblastine sulfate" chemical CHEBI:9984 ChEBI TUBD1 protein Q9UJT1 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-259257 "vincaleukoblastine sulfate" chemical CHEBI:9984 ChEBI TUBE1 protein Q9UJT0 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-259258 "vincaleukoblastine sulfate" chemical CHEBI:9984 ChEBI TUBG1 protein P23258 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-259259 "vincaleukoblastine sulfate" chemical CHEBI:9984 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "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-259260 "Vincristine sulfate" chemical CHEBI:79401 ChEBI MMP10 protein P09238 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000145 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-259253 "Vincristine sulfate" chemical CHEBI:79401 ChEBI TUBB4A protein P04350 UNIPROT "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-259250 "Vincristine sulfate" chemical CHEBI:79401 ChEBI TUBB protein P07437 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000143 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-259251 "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 "vinorelbine L-tartrate" chemical CHEBI:32296 ChEBI TUBB protein P07437 UNIPROT "down-regulates activity" binding 9606 BTO:0000356;BTO:0000762 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 VIP protein P01282 UNIPROT VIPR1 protein P32241 UNIPROT up-regulates binding 9606 11897681 t gcesareni "Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip)." SIGNOR-116122 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX1 protein Q92499 UNIPROT up-regulates 10090 21703541 f miannu "We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA." SIGNOR-260190 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX58 protein O95786 UNIPROT up-regulates 9606 19052324 t miannu "Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ." SIGNOR-260141 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 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 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR IFIH1 protein Q9BYX4 UNIPROT up-regulates 9606 19052324 t miannu "Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ." SIGNOR-260142 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271 21041712 t gcesareni "Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date." SIGNOR-169194 vorapaxar chemical CHEBI:82702 ChEBI F2R protein P25116 UNIPROT "down-regulates activity" "chemical inhibition" -1 18447380 t Luana "The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. " SIGNOR-257792 FURIN protein P09958 UNIPROT VWF protein P04275 UNIPROT "up-regulates activity" cleavage BTO:0001538 8218226 t Giorgia "Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine" SIGNOR-260368 vorinostat chemical CHEBI:45716 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-257921 vorinostat chemical CHEBI:45716 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-257950 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 vorinostat chemical CHEBI:45716 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-257951 vorinostat chemical CHEBI:45716 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-257916 vorinostat chemical CHEBI:45716 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-257948 vorinostat chemical CHEBI:45716 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-257922 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 vorinostat chemical CHEBI:45716 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-257918 vorinostat chemical CHEBI:45716 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-257949 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 vorinostat chemical CHEBI:45716 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-257917 VPS11 protein Q9H270 UNIPROT EZR protein P15311 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 21148287 t Sara "The interaction between the full-length Vps11 and ezrin was confirmed by immunoprecipitation and GST-pull down. ERM proteins and the HOPS complex are required for the transition from early to late endosomes" SIGNOR-261311 VPS11 protein Q9H270 UNIPROT RDX protein P35241 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 21148287 t Sara "Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. 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-261312 "Vps34 Complex I" complex SIGNOR-C242 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 30397185 f lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260323 "Vps34 Complex I" complex SIGNOR-C242 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260325 "Vps34 Complex II" complex SIGNOR-C241 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 30397185 f lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260324 "Vps34 Complex II" complex SIGNOR-C241 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260326 VPS39 protein Q96JC1 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "down-regulates quantity" binding 9543 BTO:0001538 12941698 t miannu "Overexpression of TLP blocks TGF-β-induced formation of Smad3/4 complexes while it does not alter Smad2/4 complex levels." SIGNOR-261378 VPS39 protein Q96JC1 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" relocalization 9543 BTO:0001538 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 VPS4A protein Q9UN37 UNIPROT CHMP2A protein O43633 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-260846 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 VRK1 protein Q99986 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser62 FGPARNDsVIVADQT 9606 15105425 t gcesareni "Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level." SIGNOR-124330 VRK1 protein Q99986 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr73 ADQTPTPtRFLKNCE 9606 15105425 t gcesareni "Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level." SIGNOR-124334 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 VRK1 protein Q99986 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-143285 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr2 tTSQKHRD 9606 16495336 t lperfetto "Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. 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" SIGNOR-144787 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 VRK1 protein Q99986 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 15378002 t flangone "Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription" SIGNOR-127073 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 VRK1 protein Q99986 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10951572 t gcesareni "Vrk1 phosphorylates murine p53 in threonine 18. This threonine is within the p53 hydrophobic loop (residues 13-23) required for the interaction of p53 with the cleft of its inhibitor mdm-2." SIGNOR-81222 VRK2 protein Q86Y07 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-144795 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 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr2 tTSQKHRD 9606 16495336 t lperfetto "Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. 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" SIGNOR-144799 VRK2 protein Q86Y07 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-144803 VRK2 protein Q86Y07 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates phosphorylation Ser31 PQDELDFsILFDYEY 9606 23105117 t gcesareni "We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain." SIGNOR-199263 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 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 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT "up-regulates activity" binding 9606 23020315 t miannu "Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF" SIGNOR-251967 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 VX-745 chemical CHEBI:90528 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 11892915 t gcesareni "Vx-745 was reported to be active against several isotypes of p38 mapk, including p38alpha, p38beta and p38gamma" SIGNOR-115782 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR1 protein Q9HB89 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-257591 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR2 protein Q9GZQ4 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-257592 WASF1 protein Q92558 UNIPROT "WRC complex" complex SIGNOR-C191 SIGNOR "form complex" binding 9606 21107423 t miannu "WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems." SIGNOR-253572 WASHC4 protein Q2M389 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-261018 WASHC5 protein Q12768 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-261019 "WASH complex" complex SIGNOR-C258 SIGNOR 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-261006 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 WAS protein P42768 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-261001 HSPA1A protein P0DMV8 UNIPROT FLCN protein Q8NFG4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 27353360 t "These data suggest that inhibition of Hsp70 does not lead to an increase in misfolded FLCN but instead to its degradation." SIGNOR-256506 WAY-600 chemical CID:25229526 PUBCHEM MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor mTOR" gcesareni SIGNOR-207788 WDR24 protein Q96S15 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-255302 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 WDR5 protein P61964 UNIPROT HMT complex SIGNOR-C19 SIGNOR "form complex" binding 9606 17500065 t lperfetto "The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes." SIGNOR-154766 WDR5 protein P61964 UNIPROT KMT2A/WDR5 complex SIGNOR-C57 SIGNOR "form complex" binding 9606 15960975 t miannu "The mll1-wdr5 complex is enzymatically active" SIGNOR-138251 WDR5 protein P61964 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-204828 WDR83 protein Q9BRX9 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates binding 9606 15118098 t gcesareni "Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex." SIGNOR-124470 WDR83 protein Q9BRX9 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates binding 9606 15118098 t gcesareni "Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex." SIGNOR-124473 WDR83 protein Q9BRX9 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates binding 9606 15118098 t lperfetto "Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex." SIGNOR-244964 WDR83 protein Q9BRX9 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15118098 t gcesareni "Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex." SIGNOR-124476 WEE1 protein P30291 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 16096060 t gcesareni "The wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (cdk1), thereby delaying entry into mitosis until appropriate conditions have been met" SIGNOR-139491 WEE1 protein P30291 UNIPROT CDK2 protein P24941 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 BTO:0000567 11029659 t gcesareni "Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases." SIGNOR-83139 WFS1 protein O76024 UNIPROT ATP1B1 protein P05026 UNIPROT "up-regulates quantity" binding 9534 BTO:0000298 17947299 t SARA "Sodium-potassium ATPase 1 Subunit Is a Molecular Partner of Wolframin, an Endoplasmic Reticulum Protein Involved in ER Stress|We conclude that the interaction may be important for Na+/K+ ATPase beta1 subunit maturation" SIGNOR-260999 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 WKYMVm chemical CID:457933 PUBCHEM FPR2 protein P25090 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-257493 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 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Thr185 TRNKVRKtFVGTPCW 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-151663 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 WNK1 protein Q9H4A3 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates phosphorylation Thr991 SAYTYERtLMMEQRS 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-187564 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 16083423 t gcesareni "Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1)" SIGNOR-253553 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 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-151667 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 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 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-151671 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 9606 BTO:0000007 BTO:0000671 16083423 t gcesareni "Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1)" SIGNOR-160846 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 17190791 t gcesareni "We finally establish that full-length wnk1, wnk2 and wnk3, but not wnk4, are capable of directly phosphorylating ser382 of wnk1 in vitro. This supports the notion that t-loop phosphorylation of wnk isoforms is controlled by trans-autophosphorylation." SIGNOR-151675 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 BTO:0000007 BTO:0000671 18270262 t gcesareni "We demonstrate that wnk1 is rapidly activated and phosphorylated at multiple residues after exposure of cells to hyperosmotic conditions and that activation is mediated by the phosphorylation of its t-loop ser382 residue, possibly triggered by a transautophosphorylation reaction." SIGNOR-160850 WNK2 protein Q9Y3S1 UNIPROT WNK1 protein Q9H4A3 UNIPROT "up-regulates activity" phosphorylation S382 ASFAKSVIGTPEFM 9606 BTO:0000007 22032326 t Manara "WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). | We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro." SIGNOR-260790 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT "down-regulates activity" phosphorylation S96 IEDLSQNSITGEHSQ 9606 BTO:0000007 24043619 t Manara "WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. " SIGNOR-260911 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT "down-regulates activity" phosphorylation T1048 YQEKVHMTWTKDKYM 9606 BTO:0000007 24043619 t Manara "WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. " SIGNOR-260910 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT "down-regulates activity" phosphorylation T991 SAYTYERTLMMEQRS 9606 BTO:0000007 24043619 t Manara "WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. " SIGNOR-260912 WNK3 protein Q9BYP7 UNIPROT WNK1 protein Q9H4A3 UNIPROT "up-regulates activity" phosphorylation S382 ASFAKSVIGTPEFM 9606 BTO:0000007 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 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 WNT10A protein Q9GZT5 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-131622 WNT10B protein O00744 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 12055200 f fspada "We have identified wnt10b as a potent inhibitor of adipogenesis that must be suppressed for preadipocytes to differentiate in vitro" SIGNOR-89131 WNT10B protein O00744 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 f fspada "We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b" SIGNOR-176190 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT "up-regulates activity" binding 9606 19008118 t FFerrentino "In mesenchymal precursor cells, Wnt10b (and Wnt10a) binding to frizzled (FZD1)" SIGNOR-253511 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates binding 9606 12055200 t fspada "Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6" SIGNOR-89134 WNT10B protein O00744 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates binding 9606 12055200 t fspada "Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 7" SIGNOR-89137 WNT10B protein O00744 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-131625 WNT10B protein O00744 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 12055200 t fspada "Inhibition of adipogenesis by wnt10b is likely mediated by‚ wnt‚ receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 8" SIGNOR-210164 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 WNT10B protein O00744 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-131631 WNT11 protein O96014 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000887 22309736 f 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-195963 WNT11 protein O96014 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "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-253127 WNT11 protein O96014 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-131634 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 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-141428 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 WNT11 protein O96014 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 7227 10862746 t gcesareni "Consistent with this, xfz7 biochemically and functionally interacts with xwnt11" SIGNOR-78406 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 WNT11 protein O96014 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 BTO:0000887 23151663 t gcesareni "Musk has an extracellular region with homology to the frizzled crd,binding of which by wnt11 stimulates a pcp-like pathway during neuromuscolar development. Here, we show that in vivo, wnt11r and wnt4a initiate musk translocation from muscle membranes to recycling endosomes 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-199641 WNT11 protein O96014 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-195966 WNT16 protein Q9UBV4 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000887 22309736 f 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-195969 WNT16 protein Q9UBV4 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-131674 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 WNT1 protein P04628 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 10090 BTO:0000887 16936075 t lperfetto "Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)" SIGNOR-253126 WNT1 protein P04628 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-255649 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT "up-regulates activity" binding 10090 BTO:0000887 16936075 t lperfetto "Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)" SIGNOR-217827 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 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-131568 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 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 WNT1 protein P04628 UNIPROT FZD6 protein O60353 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 bcatenin pathway." SIGNOR-198846 WNT1 protein P04628 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 11448771 t gcesareni "Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd)" SIGNOR-109250 WNT1 protein P04628 UNIPROT LRP5 protein O75197 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-131574 WNT1 protein P04628 UNIPROT LRP5 protein O75197 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-169645 WNT1 protein P04628 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-131577 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 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 22944199 f gcesareni "In explant cultures of mouse paraxial mesoderm, Wnt1 induced expression of the MRF Myf5, whereas Wnt7a or Wnt6 preferentially activated the MRF MyoD" SIGNOR-198849 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni "Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5" SIGNOR-60285 WNT1 protein P04628 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-176572 WNT1 protein P04628 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 t lperfetto "Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth" SIGNOR-129577 WNT2B protein Q93097 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-131777 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 WNT2 protein P09544 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-131727 WNT2 protein P09544 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-131730 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 WNT3A protein P56704 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" 9606 BTO:0000007 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." SIGNOR-180803 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 WNT3A protein P56704 UNIPROT FZD1 protein Q9UP38 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.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-169651 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 WNT3A protein P56704 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates binding 9606 19910923 t gcesareni "It was also shown that wnt5a inhibits the beta-catenin pathway by competing with wnt3a for binding to fz2, and that the impairment of clathrin-mediated internalization does not affect this wnt5a inhibitory action." SIGNOR-189117 WNT3A protein P56704 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21078818 t 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-169654 WNT3A protein P56704 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 10601008 t gcesareni "Here we focus on the role of Wnts, their putative receptors Frizzled and the soluble antagonist Frzb1 in regulating mammalian myogenesis. Although it is becoming evident that the signaling downstream of Frizzled receptors is much more complex than anticipated, it is conceivable that it may lead to transcriptional activation of Myf5 and MyoD and to initiation of myogenesis." SIGNOR-73039 WNT3A protein P56704 UNIPROT LRP5 protein O75197 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-131826 WNT3A protein P56704 UNIPROT LRP5 protein O75197 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.All the frizzled genes studied have" SIGNOR-169657 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 WNT3A protein P56704 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.All the frizzled genes studied have" SIGNOR-169660 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000568 16890161 t gcesareni "Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin." SIGNOR-148671 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 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 WNT4 protein P56705 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-131832 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 WNT4 protein P56705 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni "Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60370 WNT4 protein P56705 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni "Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60373 WNT5A protein P41221 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "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-253129 WNT5A protein P41221 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-255651 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 19910923 t gcesareni "Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway.Wnt5a Internalized fz2 probably with ror1 or ror2 through the clathrin-mediated route, whereas wnt5a competed with wnt3a for binding to fz2 to inhibit the beta-catenin pathway." SIGNOR-189120 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 2808370 t gcesareni "Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway." SIGNOR-23441 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 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 BTO:0000393 21903638 t gcesareni "It has been shown that wnt5a activates the calcium signaling pathway in the presence of receptor fz2, 3, 4, 6 and receptor fz 5." SIGNOR-176579 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 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-141434 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 WNT5A protein P41221 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 9054360 t gcesareni "These results identify hfz5 as a receptor for wnt-5a." SIGNOR-46897 WNT5A protein P41221 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-141437 WNT5A protein P41221 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates 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-227958 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 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 WNT5A protein P41221 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-131841 WNT5A protein P41221 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni "Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60376 WNT5A protein P41221 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni "Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60379 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 BTO:0000938 22343533 t gcesareni "Ror1 and ror2 bind wnt5a." SIGNOR-196133 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 t gcesareni "Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis." SIGNOR-173331 WNT5A protein P41221 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 t gcesareni "Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis." SIGNOR-199647 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 WNT5B protein Q9H1J7 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-131882 WNT5B protein Q9H1J7 UNIPROT FZD6 protein O60353 UNIPROT up-regulates 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-141443 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 WNT5B protein Q9H1J7 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-131888 WNT5B protein Q9H1J7 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 19577541 f fspada "Wnt5b additionally appears to be a potent enhancer of adipogenic capacity by stimulation of ppargamma" SIGNOR-186625 WNT6 protein Q9Y6F9 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 f fspada "We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b" SIGNOR-176193 WNT6 protein Q9Y6F9 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-131891 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 WNT6 protein Q9Y6F9 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni "Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60415 WNT6 protein Q9Y6F9 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni "In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-198916 WNT6 protein Q9Y6F9 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni "In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60418 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 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 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 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 9606 BTO:0002314 BTO:0001103 23290138 t apalma "Our previous work has demonstrated that ligation of Wnt7a to Fzd7 activates the planar cell polarity (PCP) pathway […] Therefore, we conclude that the Fzd7/Sdc4 co-receptor complex binds both Wnt7a and FN." SIGNOR-255845 CDK5R1 protein Q15078 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR "form complex" binding 9606 11331872 t lperfetto "Induced p35 forms a complex with Cdk5 and activates its kinase activity" SIGNOR-250682 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 WNT7A protein O00755 UNIPROT LRP5 protein O75197 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-131900 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 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 22944199 f gcesareni "In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Here we report that cells expressing wnt1 will preferentially activate myf5 while cells expressing wnt7a will preferentially activate myod" SIGNOR-198922 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni "Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5" SIGNOR-60471 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 WNT7A protein O00755 UNIPROT SPRY4 protein Q9C004 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002058 15705594 f miannu "In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity." SIGNOR-253034 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 WNT7B protein P56706 UNIPROT FZD1 protein Q9UP38 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-137931 WNT7B protein P56706 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-131978 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763;BTO:0001260 15923619 t flangone "These studies point to an important interaction between wnt7b, lrp5, and fzd1 and fzd10." SIGNOR-137937 WNT7B protein P56706 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni "In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod." SIGNOR-198925 WNT8A protein Q9H1J5 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-131984 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 WNT8B protein Q93098 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-132024 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 WNT9A protein O14904 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-195972 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 WNT9A protein O14904 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-132073 WNT9A protein O14904 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-132076 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 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 WNT9B protein O14905 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-132111 WNT9B protein O14905 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-132114 WNT9B protein O14905 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20093360 t gcesareni "We find that wnt9b binds to a different part of the lrp6 extracellular domain" SIGNOR-163552 Wnt proteinfamily SIGNOR-PF40 SIGNOR CTNNB1 protein P35222 UNIPROT "up-regulates quantity by stabilization" 17081971 f "The central player in the canonical Wnt cascade is β-catenin, a cytoplasmic protein whose stability is regulated by the destruction complex." SIGNOR-256240 Wnt proteinfamily SIGNOR-PF40 SIGNOR Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 9606 23290138 t miannu "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-256173 Wnt proteinfamily SIGNOR-PF40 SIGNOR LPR5/6 complex SIGNOR-C219 SIGNOR "up-regulates activity" binding 9606 23209147 t miannu "FZD and LRP5/6 transduce Wnt signal via engaging downstream cytoplasmic components, among which two scaffolding proteins, Dishevelled and Axin, have prominent roles." SIGNOR-256174 wortmannin chemical CHEBI:52289 ChEBI MYLK protein Q15746 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207791 wortmannin chemical CHEBI:52289 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 8162590 t gcesareni "The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase." SIGNOR-252666 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 wortmannin chemical CHEBI:52289 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates "chemical inhibition" 9534 BTO:0001444 22253445 t lperfetto "From these results, we conclude that LY294002 and wortmannin inhibit SARS pseudovirus entry by targeting PI4KB and that PI4KB is involved in SARS-CoV S-mediated entry into VeroE6 cells." SIGNOR-260730 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT 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-26677 WT1 protein P19544 UNIPROT AREG protein P15514 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10490105 t lperfetto "The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin" SIGNOR-251745 WT1 protein P19544 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000007 23042785 f irozzo "Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression." SIGNOR-255904 WT1 protein P19544 UNIPROT NPHS1 protein O60500 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000671 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 WT1 protein P19544 UNIPROT PAX2 protein Q02962 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000671 7720589 t "A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis" SIGNOR-252298 WT1 protein P19544 UNIPROT PODXL protein O00592 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000671 11719225 t "Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself." SIGNOR-252300 WT1 protein P19544 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo "Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation." SIGNOR-255705 WT1 protein P19544 UNIPROT RBM4 protein Q9BWF3 UNIPROT down-regulates binding 9606 16934801 t miannu "Wilm's tumor protein 1 (wt1), a protein implicated in various cancers and developmental disorders, consists of two major isoforms: wt1(-kts), a transcription factor, and wt1(+kts), a post-transcriptional regulator that binds to rna and can interact with splicing components. Here we show that wt1 interacts with the novel splicing regulator rbm4. / we conclude that the (+kts) form of wt1 is able to inhibit the effect of rbm4 on alternative splicing." SIGNOR-149166 WT1 protein P19544 UNIPROT REN protein P00797 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 18496514 t "Here, we show that a splice variant of the Wilms' tumor protein lacking three amino acids WT1(-KTS) suppresses renin gene transcription" SIGNOR-252296 WT1 protein P19544 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9867871 f miannu "The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments." SIGNOR-253898 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 WT1 protein P19544 UNIPROT Urogenital_tract phenotype SIGNOR-PH71 SIGNOR "up-regulates activity" 10090 BTO:0000671 10101119 f "The Wilms' Tumour gene WT1 has important functions during development. Knock-out mice were shown to have defects in the urogenital system and to die at embryonic day E13.5, probably due to heart failure." SIGNOR-252302 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT "up-regulates activity" relocalization 9606 BTO:0005493 15221015 t lperfetto "we found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor." SIGNOR-126578 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0005493 15221015 t lperfetto "Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor." SIGNOR-227466 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 15221015 t gcesareni "Wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor." SIGNOR-126128 WWP1 protein Q9H0M0 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates ubiquitination 9606 15221015 t gcesareni "Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7" SIGNOR-126581 WWTR1 protein Q9GZV5 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-199208 WWTR1 protein Q9GZV5 UNIPROT ASNS protein P08243 UNIPROT "down-regulates quantity by repression" "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-255608 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 WWTR1 protein Q9GZV5 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 22153608 t "Activation of Wnt signaling induces the hyperphosphorylation of Dishevelled (DVL), and this, via a poorly understood mechanism, ultimately leads to a rise in beta-Catenin levels and to the activation of beta-Catenin target genes." gcesareni "Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation." SIGNOR-195212 WWTR1 protein Q9GZV5 UNIPROT LTBR protein P36941 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-255604 WWTR1 protein Q9GZV5 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 BTO:0000222;BTO:0001946 BTO:0000887;BTO:0001103 20466877 t gcesareni "Taz physically interacts with myod through the ww domain and activates myod-dependent gene transcription." SIGNOR-165414 WWTR1 protein Q9GZV5 UNIPROT NKX2-1 protein P43699 UNIPROT up-regulates binding 9606 BTO:0000887 16397409 t gcesareni "Taz also binds to the transcription factor ttf-1 that is involved in formation and differentiation of the lungs and respiratory epithelia, and stimulates the production of pulmonary surfactant." SIGNOR-143472 WWTR1 protein Q9GZV5 UNIPROT PAX3 protein P23760 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 16300735 t gcesareni "These results indicate that pax3 specifically interacts with taz both in vitro and in vivo." SIGNOR-236879 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 WWTR1 protein Q9GZV5 UNIPROT PPARG protein P37231 UNIPROT down-regulates binding 9606 22153608 t gcesareni "Kmp also enhanced the association of taz with ppar_, thereby suppressing the gene transcription of ppar_ targets and resulting in diminished adipocyte differentiation." SIGNOR-195215 WWTR1 protein Q9GZV5 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-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-199211 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 WWTR1 protein Q9GZV5 UNIPROT SMAD2 protein Q15796 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-169838 WWTR1 protein Q9GZV5 UNIPROT SMAD2 protein Q15796 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-169835 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 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 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 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-255607 WWTR1 protein Q9GZV5 UNIPROT TEAD1 protein P28347 UNIPROT up-regulates binding 9606 23431053 t "YAP/TAZ mainly bind to the transcription factors TEAD1?????_?4 to regulate genes involved in cell proliferation and cell death." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead1?_?_?4." SIGNOR-192768 WWTR1 protein Q9GZV5 UNIPROT TEAD2 protein Q15562 UNIPROT up-regulates binding 9606 23431053 t "YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201382 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 XAF1 protein Q6GPH4 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates binding 9606 17613533 t gcesareni "Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3." SIGNOR-156843 XAF1 protein Q6GPH4 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates binding 9606 17613533 t gcesareni "Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3" SIGNOR-155288 XAF1 protein Q6GPH4 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 17613533 t gcesareni "Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3." SIGNOR-155637 XAV939 chemical CHEBI:62878 ChEBI AXIN1 protein O15169 UNIPROT up-regulates 9606 19759537 f gcesareni "Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2" SIGNOR-188045 XAV939 chemical CHEBI:62878 ChEBI AXIN2 protein Q9Y2T1 UNIPROT up-regulates 9606 19759537 f gcesareni "Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2" SIGNOR-188048 XAV939 chemical CHEBI:62878 ChEBI CTNNB1 protein P35222 UNIPROT down-regulates 9606 19759537 f amattioni "Xav939 selectively inhibits beta-catenin-mediated transcription. Xav939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex." SIGNOR-188051 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT "down-regulates activity" "chemical inhibition" -1 20565110 t "We report two crystal structures of the PARP domain of human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling." SIGNOR-259995 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates "chemical inhibition" 9606 19759537 t gcesareni "Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2." SIGNOR-188057 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207833 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT "down-regulates activity" "chemical inhibition" -1 19759537 t "In biochemical activity assays, XAV939 strongly inhibited TNKS1 and TNKS2, with half-maximal inhibitory concentration values of 0.011 and 0.004 μM, respectively, but displayed much weaker effects on PARP1 and PARP2" SIGNOR-259994 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates "chemical inhibition" 9606 19759537 t gcesareni "Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2." SIGNOR-188054 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207830 XBP1 protein P17861 UNIPROT B-Lymphocyte_diff phenotype SIGNOR-PH113 SIGNOR "up-regulates activity" 9606 BTO:0000392 11460154 f "XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells." SIGNOR-259957 XBP1 protein P17861 UNIPROT NPPB protein P16860 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20170659 f miannu "The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1." SIGNOR-255609 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 XBP-1S protein P17861_P17861-2 UNIPROT "Chaperone-mediated protein folding" phenotype SIGNOR-PH120 SIGNOR up-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-260185 XBP-1S protein P17861_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 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 XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT "down-regulates quantity by destabilization" binding -1 11583623 t lperfetto "Xiap is an endogenous inhibitor of caspase-7" SIGNOR-110840 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 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates quantity by destabilization" binding 9606 11242052 t lperfetto "A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis" SIGNOR-105702 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 XIAP protein P98170 UNIPROT DIABLO protein Q9NR28 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 15749826 t lperfetto "Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis." SIGNOR-134504 XL147 chemical CHEBI:71957 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207854 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000551 22722787 t "XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations." 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-197959 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207857 XL-647 chemical CID:10458325 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000551 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 XL-647 chemical CID:10458325 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207860 XL765 chemical CHEBI:71958 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207869 XL765 chemical CHEBI:71958 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252660 XL765 chemical CHEBI:71958 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207872 XL765 chemical CHEBI:71958 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207875 XL765 chemical CHEBI:71958 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207878 XL765 chemical CHEBI:71958 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207881 XPA protein P23025 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 9606 BTO:0001109 30327428 f "A coordinated repair process mediated by the xeroderma pigmentosum complementation group proteins (XPs), which include XPA through XPG. XPA is indispensable in this pathway and has reported functions in DNA damage verification, stabilization of repair intermediates and positioning of NER factors" SIGNOR-258984 XPO1 protein O14980 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates relocalization 9606 11074002 t gcesareni "We demonstrate that inhibition of crm1-mediated nuclear export by treatment of cells with leptomycin b results in endogenous smad4 accumulating very rapidly in the nucleus." SIGNOR-84247 XPO1 protein O14980 UNIPROT TP53 protein P04637 UNIPROT "down-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-260067 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 XRCC5 protein P13010 UNIPROT Ku70/Ku80/DNA-PK complex SIGNOR-C107 SIGNOR "form complex" binding 9606 BTO:0002419 17308091 t miannu "complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established" SIGNOR-226019 XRCC5 protein P13010 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0002284 16166097 t miannu "The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome." SIGNOR-225537 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation 9606 17573348 t gcesareni "Here we show in vitro that lkb1 phosphorylates and activates mark2" SIGNOR-156126 XRCC6 protein P12956 UNIPROT Ku70/Ku80/DNA-PK complex SIGNOR-C107 SIGNOR "form complex" binding 9606 BTO:0002419 17308091 t miannu "complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established" SIGNOR-226023 XRCC6 protein P12956 UNIPROT PRKDC protein P78527 UNIPROT up-regulates relocalization 9606 19133841 t gcesareni "Ku and dna-pkcs only interact in the presence of dna and recruitment of dna-pkcs to sites of dna damage in vivo is ku-dependent. Inward translocation of ku allows dna-pkcs to interact with the extreme termini of the dna, allowing two dna-pkcs molecules to interact across the dsb in a so-called synaptic complex . This interaction stimulates the kinase activity of dna-pkcs, promoting phosphorylation in trans across the dsb (discussed in more detail below). Once assembled at the dna ends, the dna-pkcs-ku-dsb complex serves to tether the ends of the dsb together and protects the dna ends from nuclease attack." SIGNOR-183276 Y-27632 chemical CHEBI:75393 ChEBI ROCK2 protein O75116 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207893 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 YAP1 protein P46937 UNIPROT BMP4 protein P12644 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression." SIGNOR-199066 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 YAP1 protein P46937 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000562 23607968 t gcesareni "Additionally, the hippo and wnts also cooperate in the nucleus, where yap interacts with beta-catenin and induces the expression of canonical wnt target genes, such as sox2 and snai2 in mouse heart tissue." SIGNOR-201939 YAP1 protein P46937 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 23178811 t gcesareni "Yap restricts elevated wnt independently of the axinapcgsk-3beta complex partly by limiting the activity of dishevelled (dvl)." SIGNOR-199806 YAP1 protein P46937 UNIPROT FBXO32 protein Q969P5 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "The downregulation of fbox32 expression by high yap activity in activated satellite cells may contribute to sustaining high levels of myod in activated satellite cells." SIGNOR-199069 YAP1 protein P46937 UNIPROT FSTL3 protein O95633 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression." SIGNOR-199072 YAP1 protein P46937 UNIPROT MYF6 protein P23409 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "Myf6 (mrf4) is repressed by hyap1 s127a overexpression." SIGNOR-199075 YAP1 protein P46937 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-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-199217 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 14765127 t "Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation." gcesareni "Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner." SIGNOR-121803 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 22153608 t "Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation." gcesareni "Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner." SIGNOR-195221 YAP1 protein P46937 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 23431053 t "YAP can specifically recognize the phosphorylated SMAD linker sequence containing the PY motif, and its presence is required for efficient transcription of BMP target genes." gcesareni "Yap binds to the phosphorylated smad1 to activate gene transcription." SIGNOR-201462 YAP1 protein P46937 UNIPROT TEAD1 protein P28347 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201465 YAP1 protein P46937 UNIPROT TEAD2 protein Q15562 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201468 YAP1 protein P46937 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201471 YAP1 protein P46937 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201474 YAP1 protein P46937 UNIPROT TEAD proteinfamily SIGNOR-PF22 SIGNOR "up-regulates activity" binding 9606 23431053 t miannu "YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death" SIGNOR-230719 YAP1 protein P46937 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 21808241 t "The WW domain of YAP binds to PPXY-containing p73 family members." gcesareni "Yap also interacts with p73, a p53 family pro-apoptotic transcription factor, to induce expression of genes such as bax, puma and pml." SIGNOR-175934 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001023 17072343 f miannu "YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C." SIGNOR-255614 YBX1 protein P67809 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001023 17072343 f miannu "YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C." SIGNOR-255610 YBX1 protein P67809 UNIPROT TYMS protein P04818 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001023 17072343 f miannu "YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C." SIGNOR-255613 YES1 protein P07947 UNIPROT CDK4 protein P11802 UNIPROT down-regulates phosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 BTO:0000567 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 YES1 protein P07947 UNIPROT YES1 protein P07947 UNIPROT "up-regulates activity" phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 9794236 t lperfetto "Autophosphorylation of Src and Yes blocks their inactivation by Csk phosphorylation" SIGNOR-247014 yohimbine chemical CHEBI:10093 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-258682 YWHAB protein P31946 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-252396 YWHAB protein P31946 UNIPROT SRPK2 protein P78362 UNIPROT down-regulates binding 9606 BTO:0000938 BTO:0000142 phosphorylation:Tyr492 Y>491 19592491 t lperfetto "14-3-3 interacts with akt-phosphorylated srpk2 and blocks its nuclear translocation" SIGNOR-186767 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 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 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 YWHAG protein P61981 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-252400 YWHAQ protein P27348 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-88300 YWHAQ protein P27348 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 BTO:0000887 11433030 t gcesareni "14-3-3tau associates with and activates the mef2d transcription factor during muscle cell differentiation." SIGNOR-109139 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 YWHAQ protein P27348 UNIPROT PRKD1 protein Q15139 UNIPROT down-regulates -1 BTO:0000782 10092600 f lperfetto "14-3-3tau strongly down-regulates pkcmu kinase activity in vitro" SIGNOR-65951 YWHAZ protein P63104 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-252397 YY1 protein P25490 UNIPROT ACTC1 protein P68032 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 9171244 f miannu "Expression of YY1 inhibited cardiac alpha-actin promoter activity, whereas coexpression of Nkx-2.5 and SRF was able to partially reverse YY1 repression." SIGNOR-255616 YY1 protein P25490 UNIPROT ATP2C1 protein P98194 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 15955096 f miannu "when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter." SIGNOR-255193 YY1 protein P25490 UNIPROT ATP6V1A protein P38606 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001007 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 YY1 protein P25490 UNIPROT COX7C protein P15954 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9092564 f miannu "Mutation of both YY1 sites eliminates most of the promoter activity. Mutation at the upstream YY1 site significantly reduces the efficiency of transcript initiation at the major start site and thus plays the dominant role in COX7C regulation." SIGNOR-255617 YY1 protein P25490 UNIPROT FCER1A protein P12319 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000732 11971001 f "Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells" SIGNOR-254290 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 YY1 protein P25490 UNIPROT HOXB13 protein Q92826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001130 19013255 f miannu "Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers." SIGNOR-254233 YY1 protein P25490 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15291746 f miannu "These results designate YY1 as the factor responsible for the intron 1-mediated boost of the HSD3B2 gene basal promoter activity." SIGNOR-255619 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 YY1 protein P25490 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates activity" binding 9606 BTO:0000664 12913000 t "Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling." SIGNOR-251654 YY1 protein P25490 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "down-regulates activity" binding 9606 BTO:0000664 12913000 t "Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling." SIGNOR-254305 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 Zalospirone chemical CID:163925 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-258864 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr334 QAEEEAVyEEPPEQE 9606 BTO:0000782 14557276 t lperfetto "We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling." SIGNOR-118691 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr344 PPEQETFyEQPPLVQ 9606 BTO:0000782 14557276 t lperfetto "We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling." SIGNOR-118695 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 ZAP70 protein P43403 UNIPROT GAB2 protein Q9UQC2 UNIPROT "up-regulates activity" phosphorylation Tyr614 KSTGSVDyLALDFQP 9606 BTO:0000782 11572860 t lperfetto "In the present study, we found that gab2 is phosphorylated by zap-70, associates with the tcr signaling complex, and acts as an inhibitory adaptor molecule via recruitment of shp-2 following tcr ligation." SIGNOR-110731 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr156 ADEDEDDyHNPGYLV 9606 BTO:0000782 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-247018 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr161 DDYHNPGyLVVLPDS 9606 BTO:0000782 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-247022 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 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-247026 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 BTO:0000782 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-247030 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr255 EEEGAPDyENLQELN 9606 BTO:0000782 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 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT "up-regulates activity" phosphorylation Tyr113 SSFEEDDyESPNDDQ 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-102507 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 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 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-42956 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 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-42960 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 9047237 t lperfetto "Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient." SIGNOR-46859 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 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr423 NSLNEEWyVSYITRP 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-42972 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr426 NEEWYVSyITRPEAE 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-42976 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr323 DEPVADPyDQSFESR 9606 BTO:0000782 15735648 t lperfetto "Thus, phosphorylation of tyr323 dependent on the tyrosine kinase lck and mediated by zap70 serves as an important mechanism for tcr activation of p38 in t cells." SIGNOR-134329 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 ZAP70 protein P43403 UNIPROT SH2B3 protein Q9UQQ2 UNIPROT up-regulates phosphorylation Tyr273 LEMPDNLyTFVLKVK 9606 BTO:0000782 9169414 t lperfetto "In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation." SIGNOR-48854 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 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 shc1 (iso2)." SIGNOR-59647 ZAP70 protein P43403 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 shc1 (iso2)." SIGNOR-59651 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 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 shc1 (iso2)." SIGNOR-59659 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr126 RDAMVRDyVRQTWKL 9606 BTO:0000661 7961936 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. By comparative two-dimensional phosphopeptide mapping, we show that ZAP-70 isolated from Jurkat T cells also autophosphorylates at Tyr-292 and Tyr-126" SIGNOR-247044 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr292 DTLNSDGyTPEPARI 9606 BTO:0000782;BTO:0000776 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-43324 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr315 MPMDTSVyESPYSDP 9606 BTO:0000661 11828374 t lperfetto "We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function." SIGNOR-247048 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr319 TSVYESPySDPEELK 9606 BTO:0000661 10037717 t lperfetto "We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function." SIGNOR-247053 ZBED1 protein O96006 UNIPROT GATA4 protein P43694 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 7227 BTO:0001138 22021382 f 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-239736 ZBTB14 protein O43829 UNIPROT ZBTB14 protein O43829 UNIPROT "up-regulates activity" binding 9606 10080939 t miannu "ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter, has the POZ domain at the amino-terminus and the Kruppel-type zinc finger domain at the carboxy-terminus. We demonstrated that the POZ domain has a function mediating homomeric protein-protein interaction and this interaction requires the zinc finger domain." SIGNOR-220534 ZBTB16 protein Q05516 UNIPROT miR-146a mirna MI0000477 miRBase "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000565 18568019 t miannu "In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation." SIGNOR-256309 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 ZBTB16 protein Q05516 UNIPROT ZBTB16/ZBTB32 complex SIGNOR-C80 SIGNOR "form complex" binding 9606 10572087 t miannu "We show that fazf is a transcriptional repressor and it readily forms heterodimers with plzf." SIGNOR-72377 ZBTB32 protein Q9Y2Y4 UNIPROT ZBTB16/ZBTB32 complex SIGNOR-C80 SIGNOR "form complex" binding 9606 10572087 t miannu "We show that fazf is a transcriptional repressor and it readily forms heterodimers with plzf." SIGNOR-72380 ZBTB43 protein O43298 UNIPROT BDP1 protein A6H8Y1 UNIPROT unknown binding 9606 16542149 t miannu "The zinc finger protein ZNF297B interacts with BDP1, a subunit of TFIIIB. Due to the essential role of BDP1 in Pol III transcription, we propose that ZNF297B may also regulate these transcriptional pathways." SIGNOR-225852 ZBTB47 protein Q9UFB7 UNIPROT CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR "form complex" binding 9606 BTO:0000007 20116376 t "Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex." SIGNOR-253957 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 ZC3H12A protein Q5D1E8 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 BTO:0000007 30842549 t "Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA" SIGNOR-259943 ZC3H12A protein Q5D1E8 UNIPROT TAL1 protein P17542 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 BTO:0000007 30842549 t "Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA" SIGNOR-259944 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 ZDHHC2 protein Q9UIJ5 UNIPROT AKAP5 protein P24588 UNIPROT "up-regulates activity" palmitoylation Cys36;Cys129 "KEKASMLcFKRRKKA; KSRLKIPcIKFPRGP" 10116 BTO:0004553 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 ZDHHC2 protein Q9UIJ5 UNIPROT Dlg4 protein P31016 UNIPROT "up-regulates activity" palmitoylation Cys3;Cys5 MDcLCIVTTK;MDCLcIVTTKKY 9606 BTO:0000007 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 ZDHHC5 protein Q9C0B5 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates activity" palmitoylation 9606 BTO:0000526 28775165 t "Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2." SIGNOR-261144 ZDHHC5 protein Q9C0B5 UNIPROT S1PR1 protein P21453 UNIPROT "up-regulates activity" palmitoylation 9606 BTO:0000793 29185452 t "We propose that DHHC5-mediated palmitoylation of S1P1R determines Gi coupling and its signalling in a spatio/temporal manner." SIGNOR-261140 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 ZDHHC9 protein Q9Y397 UNIPROT NRAS protein P01111 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-261355 ZEB1 protein P37275 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255158 ZEB1 protein P37275 UNIPROT EPCAM protein P16422 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000584 23667256 f miannu "We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter." SIGNOR-255622 ZEB1 protein P37275 UNIPROT GRHL2 protein Q6ISB3 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-255623 ZFHX3 protein Q15911 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11314020 f miannu "We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1." SIGNOR-254436 ZFHX3 protein Q15911 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14654895 f miannu "these results corroborated the previous reports that ATBF1 regulated AFP expression and inhibited transcription." SIGNOR-255625 ZFP36 protein P26651 UNIPROT "EIF4E2/GIGYF1 complex" complex SIGNOR-C256 SIGNOR "up-regulates activity" relocalization 9606 30917308 t lperfetto "A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs" SIGNOR-261014 ZFP36 protein P26651 UNIPROT "EIF4E2/GIGYF2 complex" complex SIGNOR-C257 SIGNOR "up-regulates activity" relocalization 9606 30917308 t lperfetto "A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs" SIGNOR-261015 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 ZFP91 protein Q96JP5 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates ubiquitination 9606 20682767 t gcesareni "Zfp91 interacts with and promotes the lys(63)-linked ubiquitination of nik and subsequent processing of p100 to p52." SIGNOR-167331 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 ZFPM1 protein Q8IX07 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9006 21853041 t miannu "GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1." SIGNOR-256061 ZFPM1 protein Q8IX07 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 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-259963 ZFPM2 protein Q8WW38 UNIPROT GATA4 protein P43694 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 9927675 t miannu "FOG-2 associates physically with the N-terminal zinc finger of GATA-4 both in vitro and in vivo. This interaction appears to modulate specifically the transcriptional activity of GATA-4 because overexpression of FOG-2 in both NIH 3T3 cells and primary rat cardiomyocytes represses GATA-4-dependent transcription from multiple cardiac-restricted promoters." SIGNOR-236959 ZFYVE9 protein O95405 UNIPROT SMAD2 protein Q15796 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-165786 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 9865696 t lperfetto "We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. 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-62874 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 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" relocalization 9606 9865696 t lperfetto "We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. 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-232126 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 BTO:0002181 11238441 f fspada "Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m)." SIGNOR-105494 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates relocalization 9606 11238441 t lperfetto "Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels" SIGNOR-105491 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates 9606 BTO:0002181 11238441 f fspada "Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m)." SIGNOR-105500 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates relocalization 9606 11238441 t lperfetto "Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels" SIGNOR-105497 ZIC3 protein O60481 UNIPROT GLI3 protein P10071 UNIPROT up-regulates binding 9606 17764085 t lperfetto "Zic3 functions as a transcriptional coactivator of gli3 when it physically associates with gli3" SIGNOR-157637 zileuton chemical CHEBI:10112 ChEBI ALOX5 protein P09917 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0001271 1848634 t miannu "5-lipoxygenase inhibitory activity of zileuton." SIGNOR-258363 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 ziprasidone chemical CHEBI:10119 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000601 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 ziprasidone chemical CHEBI:10119 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-258501 ziprasidone chemical CHEBI:10119 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-258502 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 ziprasidone chemical CHEBI:10119 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-258500 ZNF148 protein Q9UQR1 UNIPROT SOX18 protein P35713 UNIPROT "down-regulates quantity by repression" "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-254821 ZNF202 protein O95125 UNIPROT POMGNT1 protein Q8WZA1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22419172 f miannu "Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose β-1,2-N-acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83_-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202)." SIGNOR-255626 ZNF217 protein O75362 UNIPROT "CoREST-HDAC complex" complex SIGNOR-C105 SIGNOR "form complex" binding 9606 BTO:0000567 11171972 t miannu "Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function." SIGNOR-222118 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 ZNF318 protein Q5VUA4 UNIPROT AR protein P10275 UNIPROT "down-regulates activity" binding 512–663 >512662 9606 BTO:0001321 16469430 t Monia "Using different promoters and cells, we confirmed that AR-mediated transactivation was repressed by TZF in a dose-dependent manner (Fig. 1A and B). Endogenous ARmediated transactivation was also inhibited by expression of TZF; These results indicate that amino acid residues 512–663 are essential for the repressive effect of TZF on AR-mediated transactivation." SIGNOR-261187 ZNF423 protein Q2M1K9 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR "up-regulates activity" 10090 BTO:0000011 20200519 f "Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate." SIGNOR-255928 ZNF503 protein Q96F45 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity" "transcriptional repression" 10090 BTO:0000817 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 ZNF503 protein Q96F45 UNIPROT GATA3 protein P23771 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000093 28258171 f Monia "Intriguingly, ZPO2/ZNF503 levels were higher in breast cancer samples with WT GATA3 than in those with mutated GATA3 (Fig. 1B). We found that Zpo2 down-regulated GATA3 levels, whereas shRNA-mediated Zpo2 knockdown enhanced GATA3 expression" SIGNOR-261189 ZNF503 protein Q96F45 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000817 25538248 f Monia "Zpo2-overexpressing cells demonstrated high levels of pFAK compared with the control (Fig. 6A). Additionally, Western blot analysis indicated that, in response to Zpo2 expression, both EpH4.9 and PyMT cells increase FAK activity, as demonstrated by higher levels of pFAK staining (Fig. 6B)." SIGNOR-261191 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 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 GNAI1 protein P63096 UNIPROT PLD2 protein O14939 UNIPROT down-regulates binding 9606 BTO:0000938 9148895 t gcesareni "The results of this study suggest that membrane phospholipase d activity can be negatively regulated via gi" SIGNOR-48256 ZNHIT1 protein O43257 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 20473270 f gcesareni "We show that the srcap subunit named znhit1 or p18hamlet, which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation." SIGNOR-165613 ZNRD1 protein Q9P1U0 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 16373708 f miannu "ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells." SIGNOR-259907 ZNRD1 protein Q9P1U0 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 16373708 f miannu "ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells." SIGNOR-259908 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 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates relocalization 9606 23151663 t gcesareni "Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6." SIGNOR-199650 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates ubiquitination 9606 22575959 t gcesareni "Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6." SIGNOR-197417 ZNRF3 protein Q9ULT6 UNIPROT FZD4 protein Q9ULV1 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-260115 zolmitriptan chemical CHEBI:10124 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-258341 zotepine chemical CHEBI:32316 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 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 zotepine chemical CHEBI:32316 ChEBI DRD4 protein P21917 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 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-258555 zotepine chemical CHEBI:32316 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-258554 zotepine chemical CHEBI:32316 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-258550 zotepine chemical CHEBI:32316 ChEBI HTR1E protein P28566 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-258557 zotepine chemical CHEBI:32316 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-258552 zotepine chemical CHEBI:32316 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 20223878 t Luana "These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity." SIGNOR-257829 ZRSR2 protein Q15696 UNIPROT ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR "form complex" binding 9606 9237760 t miannu "Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35." SIGNOR-50176 ZSTK-474 chemical CHEBI:90545 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252646 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207935 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207938 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207941 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207944 STXBP4 protein Q6ZWJ1 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates activity" binding -1 31782549 t "WW domain‐containing protein STXBP4 inhibits YAP activity via LATS1‐mediated phosphorylation." SIGNOR-260013 GSK3B protein P49841 UNIPROT MNX1 protein P50219 UNIPROT down-regulates phosphorylation Ser77 ADRLRAEsPSPPRLL 9606 24425879 t miannu "Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9)." SIGNOR-203657 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB3 protein Q01970 UNIPROT up-regulates 23994464 t apalma "However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits" SIGNOR-255016 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 TG101209 chemical CHEBI:90304 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207260 IL22RA1 protein Q8N6P7 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 12087100 f gcesareni "Il-22 also induced serine phosphorylation of stat3 on ser(727)." SIGNOR-90162 FYN protein P06241 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Tyr18 MEDHAGTyGLGDRKD 9606 BTO:0000938 BTO:0000142 14999081 t lperfetto "In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn." SIGNOR-123099 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT up-regulates binding 9606 BTO:0000782 24352680 t fstefani "Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain" SIGNOR-203484 HSPA1A protein P0DMV8 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 21730050 t gcesareni "Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex" SIGNOR-251668 TNF protein P01375 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" 10090 10485710 f lperfetto "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)." SIGNOR-252733 GNB1 protein P62873 UNIPROT GNG2 protein P59768 UNIPROT "up-regulates activity" binding 10696571 t "GNB1 dissociates from the receptor, bound with GNG2 as stable dimer" SIGNOR-251105 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 TNFRSF21 protein O75509 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 t amattioni "Dr6 interacts with tradd" SIGNOR-100184 TNFSF15 protein O95150 UNIPROT TNFRSF25 protein Q93038 UNIPROT up-regulates binding 9606 14585074 t amattioni "The ligand of dr3 is tl1a" SIGNOR-103078 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 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK8 protein P45983 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189702 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Thr275 LVDSKAKtRSAGCAA 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-51211 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207302 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A13 protein Q9NSD5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207066 1038915-60-4 chemical CID:24958200 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194399 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 "4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid" chemical CHEBI:125628 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194527 BMP4 protein P12644 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 8006002 t fspada "Bmp-4 bound to alk-3 and alk-6 efficiently" SIGNOR-35763 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 BAX protein Q07812 UNIPROT VDAC1 protein P21796 UNIPROT "up-regulates activity" binding 10365962 t lperfetto "The recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC" SIGNOR-249613 GRB2 protein P62993 UNIPROT SOS2 protein Q07890 UNIPROT up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." SIGNOR-175180 1124329-14-1 chemical CID:56973724 PUBCHEM TTK protein P33981 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190137 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 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A1 protein P30531 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206960 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARG protein P13631 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-258030 alvocidib chemical CHEBI:47344 ChEBI CDK4 protein P11802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192038 alvocidib chemical CHEBI:47344 ChEBI CDK5 protein Q00535 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192104 alvocidib chemical CHEBI:47344 ChEBI CDK6 protein Q00534 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192385 alvocidib chemical CHEBI:47344 ChEBI CDK7 protein P50613 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192446 alvocidib chemical CHEBI:47344 ChEBI CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192449 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192458 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192461 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK4 protein P11802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192464 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK5 protein Q00535 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192467 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK6 protein Q00534 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192470 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192480 ERCC2 protein P18074 UNIPROT ERCC3 protein P19447 UNIPROT up-regulates binding 9606 10024882 t miannu "Xpd helps xpb in promoter opening and as such participates in the transcription reaction." SIGNOR-64672 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT "down-regulates activity" phosphorylation Ser518 KTVTPASsAKTSPAK 10116 BTO:0000938 15652488 t lperfetto "Ser-518 is also a potential phosphorylation site of CRMP-2 by GSK-3_." SIGNOR-133251 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 CDKN1A protein P38936 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 BTO:0000222 16982699 t gcesareni "Considering that akt1 phosphorylates p21, this dissociation likely results from phosphorylation of p21 and release of cdk2." SIGNOR-149711 COL6A2 protein P12110 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present." SIGNOR-254674 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190176 (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide chemical CHEBI:91449 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-204490 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide chemical CHEBI:49868 ChEBI PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190281 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline chemical CHEBI:91387 ChEBI BMPR1A protein P36894 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193642 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline chemical CHEBI:94782 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190919 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCA protein P17252 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191490 ADX-47273 chemical CID:11383075 PUBCHEM GRM5 protein P41594 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-189338 CCL2 protein P13500 UNIPROT CCR4 protein P51679 UNIPROT "up-regulates activity" binding 9606 17160712 t gcesareni "CCR2 and CCR4 are two cell surface receptors that bind CCL2" SIGNOR-237555 LAMC2 protein Q13753 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR "form complex" binding 9211848 t lperfetto "Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2." SIGNOR-253237 ABT-737 chemical CID:11228183 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189174 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 4-Iodo-3-nitrobenzamide chemical CID:9796068 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193474 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193534 AMHR2 protein Q16671 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 14746809 t gcesareni "See table2" SIGNOR-121593 CREBBP protein Q92793 UNIPROT MYBL1 protein P10243 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 9210395 t 2 miannu "CBP co-operates functionally with A-Myb" SIGNOR-240984 "BMS 794833" chemical CID:44155856 PUBCHEM MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190422 TAK-901 chemical CID:16124208 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207191 ATM protein Q13315 UNIPROT EXO1 protein Q9UQ84 UNIPROT up-regulates phosphorylation 9606 20019063 t gcesareni "The phosphorylation of exo1 by atm appears to regulate the activity of exo1 following resection, allowing optimal rad51 loading and the completion of hr repair." SIGNOR-162304 doramapimod chemical CHEBI:40953 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190332 ATG10 protein Q9H0Y0 UNIPROT ATG12 protein O94817 UNIPROT up-regulates binding 9606 18704115 t gcesareni "Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein." SIGNOR-180129 COL6A1 protein P12109 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present." SIGNOR-254673 WNT3A protein P56704 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 t gcesareni "Here, we report that ryk directly binds wnt-1 and wnt-3a via its wif domain and is required for the tcf." SIGNOR-129580 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000567 11583623 t amattioni "Xiap is an endogenous inhibitor of caspase-3" SIGNOR-110837 MAP3K1 protein Q13233 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000944 8131746 t lperfetto "Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity." SIGNOR-244881 ATM protein Q13315 UNIPROT PPM1G protein O15355 UNIPROT "up-regulates activity" phosphorylation Ser183 GTGEEPGsQGLNGEA -1 26324325 t "ATM indeed mediated PPM1G phosphorylation at S183, and mutation of this residue (S183A) abrogated detection with the phospho-specific antibody" SIGNOR-255591 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 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "NLRP3 inflammasome" complex SIGNOR-C225 SIGNOR "up-regulates quantity by expression" "transcriptional activation" 9606 28531279 f miannu "The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3" SIGNOR-260328 ATM protein Q13315 UNIPROT PPP1R2 protein P41236 UNIPROT down-regulates phosphorylation Ser44 DEELSKKsQKWDEMN 9606 18250156 t gcesareni "Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1." SIGNOR-160648 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 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 VAV2 protein P52735 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-260583 VAV3 protein Q9UKW4 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-260584 TGFBR1 protein P36897 UNIPROT SERPINE1 protein P05121 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 28520219 f miannu "The transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways." SIGNOR-260590 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 N protein P59595 UNIPROT SERPINE1 protein P05121 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000763 18055455 f 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." SIGNOR-260589 ORF4b protein K9N643 UNIPROT IKBKE protein Q14164 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-260592 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 FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" binding 9606 20156194 t miannu "We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself" SIGNOR-260629 FLNA protein P21333 UNIPROT MAP2K7 protein O14733 UNIPROT "up-regulates activity" binding 9606 20156194 t miannu "We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself" SIGNOR-260628 MAS1 protein P04201 UNIPROT AGTR1 protein P30556 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15809376 t miannu "our findings demonstrate that the protein encoded by the Mas proto-oncogene exhibits direct antagonistic properties on the AT1 receptor in vitro and that this oligomeric interaction may represent a natural state for these receptors in vivo in some tissues. the present findings in native tissues suggest that the Mas receptor can act as an in vivo functional antagonist of the AT1 receptor owing to formation of a hetero-oligomeric complex" SIGNOR-260626 MAS1 protein P04201 UNIPROT FLNA protein P21333 UNIPROT "up-regulates activity" binding 9606 26460884 t miannu "We further determined that GPCRs, AT1R, and MAS directly recruited FLNa and promoted its phosphorylation by cellular S/T kinases in an agonist-dependent manner. Our studies thus provide a structural framework for filamin in GPCR signaling, potentially regulating a variety of cellular responses. MAS likely binds filamin constitutively and hence leads to constitutive filamin phosphorylation. These results emphasize that it is the active receptor that mediates filamin phosphorylation by PKA or other cellular S/T kinases" SIGNOR-260627 MFGE8 protein Q08431 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 10116 BTO:0000801 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-260652 MFGE8 protein Q08431 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 "AP-3/clathrin vescicle" complex SIGNOR-C250 SIGNOR "Early Endosome" complex SIGNOR-C246 SIGNOR "up-regulates activity" relocalization 9606 23144738 t lperfetto "Rabip4' colocalized with AP-3 on a tubular subdomain of early endosomes and the extent of colocalization was increased by a dominant negative rab4 mutant. Knock-down of AP-3 had an ever more dramatic effect and caused accumulation of lysosomes in protrusions at the plasma membrane. The most peripheral lysosomes were localized beyond microtubules, within the cortical actin network. Our results uncover a novel function for AP-3 and rabip4' in regulating lysosome positioning through an interorganellar pathway." SIGNOR-260712 PI4KB protein Q9UBF8 UNIPROT "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 BTO:0001444 22253445 f lperfetto "PI4KB knockdown inhibits SARS-CoV S-mediated entry, whereas PI3KR1 knockdown increases SARS-CoV S-mediated entry" SIGNOR-260734 SACM1L protein Q9NTJ5 UNIPROT "phosphatidylinositol 4-phosphate" smallmolecule CHEBI:37530 ChEBI "down-regulates quantity" "small molecule catalysis" 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 SACM1L protein Q9NTJ5 UNIPROT "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR down-regulates 9534 BTO:0001444 22253445 f lperfetto "Ectopic Expression of Sac1 Phosphatase Inhibits SARS-CoV S-mediated Entry" SIGNOR-260735 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 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 "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 CSNK2A1 protein P68400 UNIPROT G3BP1 protein Q13283 UNIPROT "down-regulates activity" phosphorylation Ser149 VTEPQEEsEEEVEEP 9606 BTO:0001938 27920254 t miannu "We also show that casein kinase 2 phosphorylates G3BP1 at serine 149 in vitro and in cells. These data support a role for casein kinase 2 in regulation of protein synthesis by downregulating stress granule formation through G3BP1.CK2 regulates SG disassembly during stress recovery.G3BP1 is among the strongest SG nucleating proteins, and previous work indicated that G3BP1 phosphorylation at S149 restricts stress granule assembly by partly inhibiting G3BP1 oligomerization" SIGNOR-260748 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 E protein P59637 UNIPROT SDCBP protein O00560 UNIPROT "up-regulates activity" relocalization 9534 BTO:0001444 25122212 t Luana "Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation." SIGNOR-260752 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" binding 9606 25520508 t miannu "We show that G3BP1 can activate effectors of the innate immune transcriptional program, culminating in enhanced expression of a set of cytokines. We demonstrate that a subset of PKR is recruited to SGs, that close-proximity interactions between G3BP1 and PKR complexes increase in response to stress and PKR activation, that once activated PKR no longer associates with SGs, and that the PXXP domain of G3BP1 is essential for PKR recruitment to SGs and PKR activation in cells. Together, these findings suggest that G3BP1 plays an important role in the recruitment of PKR to SGs and suggest that activation of PKR can take place at the SG." SIGNOR-260750 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25520508 f miannu "Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactivated or coopted by many viruses to promote productive infection" SIGNOR-260747 3b protein P59633 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 BTO:0001950 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 AP1 complex SIGNOR-C154 SIGNOR CCL2 protein P13500 UNIPROT "up-regulates activity" "transcriptional regulation" 9606 BTO:0001950 21561061 t Luana "3b Potentiates AP-1-Dependent MCP-1 Promoter Activity" SIGNOR-260764 AP1 complex SIGNOR-C154 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR "up-regulates activity" 9606 21561061 f Luana "AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models." SIGNOR-260765 AP1 complex SIGNOR-C154 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR "up-regulates activity" 9606 31340499 f Luana "AP-1 Transcription Factors as Regulators of Immune Responses in Cancer" SIGNOR-260766 ULK3 protein Q6PHR2 UNIPROT GLI1 protein P08151 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 19878745 t Manara "We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro. | Our data suggest that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins." SIGNOR-260797 ULK3 protein Q6PHR2 UNIPROT GLI2 protein P10070 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 19878745 t Manara "We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro" SIGNOR-260798 ULK3 protein Q6PHR2 UNIPROT GLI3 protein P10071 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 19878745 t Manara "We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro" SIGNOR-260799 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT "up-regulates activity" phosphorylation S384 RLLAALEVASAAMAK 9606 BTO:0000007 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-260795 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT "up-regulates activity" phosphorylation S464 TLDKEGLSESVRSSCT 9606 BTO:0000007 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 CHK2 protein Q683Z8 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates activity" phosphorylation S364 EPLLSRMGSLRA 9606 BTO:0000093 12717439 t Manara "Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. | These results suggest that the Ser 364 site is phosphorylated by Chk2 and that anti-P-Ser 364 recognises the phosphorylated site in E2F-1." SIGNOR-260822 STK11 protein Q15831 UNIPROT SNRK protein Q9NRH2 UNIPROT "up-regulates activity" phosphorylation T173 QPGKKLTTSCGSLAY 9606 BTO:0000567 15733851 t Manara "We demonstrate that LKB1 activates SNRK by phosphorylating the T‐loop residue (Thr173)" SIGNOR-260824 TESK1 protein Q15569 UNIPROT TESK1 protein Q15569 UNIPROT "up-regulates activity" phosphorylation S220 EPLAVVGSPYWMAPE -1 10207045 t Manara "These results suggest that autophosphorylation of Ser-215 is an important step to positively regulate the kinase activity of TESK1." SIGNOR-260825 TSSK1B protein Q9BXA7 UNIPROT TSSK1B protein Q9BXA7 UNIPROT "up-regulates activity" phosphorylation T174 GRMALSKTFCGSP -1 15733851 t Manara "Electrospray Q‐TOF2 mass spectroscopy analysis of a trypsin digested TSSK1 purified from E. coli, revealed that it was phosphorylated at its T‐loop residue (Fig. 2D), indicating that TSSK1 as was previously shown for MELK [18], can autophosphorylate its T‐loop Thr residue." SIGNOR-260823 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT "up-regulates activity" phosphorylation S382 LKRASFAKSVIGTPE 9606 BTO:0000007 12374799 t Manara "Activation of WNKs requires autophosphorylation of at least one serine residue, serine 382 in WNK1, within the WNK activation loop." SIGNOR-260826 MAP4K3 protein Q8IVH8 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation Thr538 LGDAKTNtFCGTPDY 9606 BTO:0000782 21983831 t llicata "We report that the kinase glk (map4k3) directly activated pkc-? During tcr signaling." SIGNOR-176744 G3BP1 protein Q13283 UNIPROT G3BP2 protein Q9UN86 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 23279204 t miannu "Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli." SIGNOR-260862 G3BP2 protein Q9UN86 UNIPROT G3BP1 protein Q13283 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 23279204 t miannu "Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli." SIGNOR-260863 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 CCL7 protein P80098 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-260850 IL12A protein P29459 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 BTO:0000782 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-260966 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CXCL8 protein P10145 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001025 19185596 f miannu "S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection." SIGNOR-260974 TLR2 protein O60603 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 9606 BTO:0001025 19185596 f miannu "S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection." SIGNOR-260973 7a protein P59635 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 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 dabrafenib chemical CHEBI:75045 ChEBI CDK16 protein Q00536 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0005011 29112787 t Monia "We have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. We confirmed NEK9 to be a potent target of dabrafenib by in vitro kinase assays, with inhibition of NEK9 observed in the single-digit nanomolar range." SIGNOR-261073 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000661 7566123 t Monia "Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin." SIGNOR-261074 2-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine chemical CID:49830260 PUBCHEM VCP protein P55072 UNIPROT "down-regulates activity" "chemical inhibition" -1 23316025 t Luana "Inhibition of p97 by ML240 and ML241 is ATP competitive. To determine the mechanism by which ML240 and ML241 inhibited p97 ATPase, we evaluated rates of ATP hydrolysis at different concentrations of ATP. ML240 and ML241 inhibited p97competitively with respect to ATP with a Kivalues of 0.22 mm and 0.35 mm respectively." SIGNOR-261093 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 BTO:0002036 29764999 t Monia "DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells" SIGNOR-261095 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 BRD3 protein Q15059 UNIPROT "down-regulates quantity" "chemical inhibition" 9606 BTO:0002036 29764999 t Monia "DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells" SIGNOR-261096 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 BRD4 protein O60885 UNIPROT "down-regulates quantity" "chemical inhibition" 9606 BTO:0002036 29764999 t Monia "DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells" SIGNOR-261094 "Camostat mesylate" chemical CID:5284360 PUBCHEM TMPRSS2 protein O15393 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000195 32142651 t Monia "Ndeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells, efficiently blocked 2019-nCoV-S-driven entry into Caco-2 (TMPRSS2+) but not 293T (TMPRSS2- 110 ) cells while the CatB/L inhibitor E64d had the opposite effect" SIGNOR-261098 "CID 122201421" chemical CID:122201421 PUBCHEM BRD4 protein O60885 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000567 26035625 t Monia "Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4; These data confirmed that BRD4 is removed from the cell nuclei in a time dependent manner due to the presence of MZ1" SIGNOR-261097 "CID 132010322" chemical CID:132010322 PUBCHEM BRD2 protein P25440 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001321 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 "CID 132010322" chemical CID:132010322 PUBCHEM BRD3 protein Q15059 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001321 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-261104 "CID 132010322" chemical CID:132010322 PUBCHEM BRD4 protein O60885 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001321 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 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 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 BTO:0000007 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 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR MOV10 protein Q9HCE1 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 32496609 f miannu "Mov10 is a processing body (P-body) protein and an interferon-stimulated gene that can affect replication of retroviruses, hepatitis B virus, and hepatitis C virus (HCV)." SIGNOR-261137 MIPOL1 protein Q8TD10 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 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 MIPOL1 protein Q8TD10 UNIPROT RELA protein Q04206 UNIPROT "down-regulates activity" dephosphorylation 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 MOV10 protein Q9HCE1 UNIPROT IKBKE protein Q14164 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 27016603 t miannu "MOV10 enhances IRF3 activation and IRF3-mediated gene induction. This indicated that MOV10-mediated antiviral activity is most likely mediated through IKKε and not through TBK1. Involvement of IKKε was further established by examining the physical interaction of MOV10 and IKKε." SIGNOR-261138 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 CSDE1 protein O75534 UNIPROT FOS protein P01100 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 BTO:0000944 15314026 t "By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv" SIGNOR-261145 KLC1 protein Q07866 UNIPROT TOR1A protein O14656 UNIPROT "up-regulates activity" binding 10116 BTO:0001009 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 MPHOSPH10 protein O00566 UNIPROT IMP3 protein Q9NV31 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA." SIGNOR-261173 MPHOSPH10 protein O00566 UNIPROT IMP4 protein Q96G21 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA." SIGNOR-261174 MPHOSPH10 protein O00566 UNIPROT RPS5 protein P46782 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome." SIGNOR-261175 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 GTF2F2 protein P13984 UNIPROT GTF2F1 protein P35269 UNIPROT "up-regulates activity" binding 9543 BTO:0001538 11278533 t miannu "Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30." SIGNOR-261180 GTF2F2 protein P13984 UNIPROT POLR2E protein P19388 UNIPROT "up-regulates activity" binding 9543 BTO:0001538 11278533 t miannu "Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30." SIGNOR-261179 HSBP1 protein O75506 UNIPROT HSF1 protein Q00613 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 9649501 t Monia "HSBP1 is nuclear-localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock. During attenuation of HSF1 to the inert monomer, HSBP1 associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activity, and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. HSF1 interacts with HSBP1 in vivo and is a nuclear localized protein." SIGNOR-261181 LARP7 protein Q4G0J3 UNIPROT HEXIM1 protein O94992 UNIPROT "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-261183 RBM7 protein Q9Y580 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "up-regulates activity" relocalization 9606 BTO:0000007 30824372 t miannu "Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb) via its release from the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP). these findings establish that RBM7 binds 7SK snRNP and that genotoxic stress activates P-TEFb by relocating it from 7SK snRNP to the CTD of Pol II." SIGNOR-261182 ATM protein Q13315 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1083 ESERGSGsQSSVPSV 9606 18442975 t llicata "Ser-1083 phosphorylation is ir-inducible, depends on atm and nijmegen breakage syndrome 1 (nbs1), and is required for intra-s phase checkpoint." SIGNOR-178479 BAG5 protein Q9UL15 UNIPROT PRKN protein O60260 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15603737 t Monia "Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity Immunoprecipitation (IP) of GFP-parkin resulted in the coimmunoprecipitation of both Hsp70 and BAG5 or BAG5(DARA) (Figure 4A). Furthermore, IP of GFP-parkin resulted in the coimmunoprecipitation of BAG5 or BAG5 (DARA) in the absence of overexpressed Hsp70. Taken together, these data demonstrate that BAG5 can directly inhibit parkin-mediated autoubiquitinylation independently of Hsp70." SIGNOR-261198 HECTD1 protein Q9ULT8 UNIPROT HSP90AA1 protein P07900 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 22431752 t Monia "We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Identification of Hsp90 in both proteomic screens suggested that members of the Hsp90 superfamily may be substrates of Hectd1. Myc-Hectd1ANK and HA-Hsp90bd (the fragment identified in the yeast two-hybrid screen) bind in an in vitro binding assay (Fig. 3 D) and when coexpressed in HEK293T cells. Hectd1 is required for K63-linked Ubn of Hsp90. Together, these results demonstrate that Hectd1-dependent Ubn of Hsp90 targets it away from the membrane and the secretory pathway." SIGNOR-261199 MYCBP2 protein O75592 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" binding -1 9689053 t Monia "We have identified a large and highly conserved nuclear protein that interacts directly with the transcriptional activating domain of Myc (designated ‘‘protein associated with Myc’’ or Pam).Pam Binds to Myc but Not NMyc. the data indicate that the portion of Myc between amino acids 44 and 107 is essential for binding to Pam (Fig. 7B). We hypothesize that the binding of Pam plays a role in transcriptional activation by Myc, either as facilitator or regulator." SIGNOR-261201 MYCBP2 protein O75592 UNIPROT RAN protein P62826 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10090 26304119 t Monia "MYCBP2 Is a Nuclear GEF for Ran in DRG Neurons—Next, we studied whether or not MYCBP2 modulates the interaction between Ran/RanGAP1. MYCBP2 contains an N-terminal RCC1-like domain (Fig. 8C) (13), and RCC1 is a known GEF for Ran, indicating a potential functional interaction between MYCBP2 and Ran." SIGNOR-261204 SIRT5 protein Q9NXA8 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0003999 31608237 f Monia "In SIRT5 silenced Mero-14 cells, beclin-1 protein levels were downregulated upon rotenone and resveratrol treatment. In summary, in most cases, where significant effects were detected, SIRT1, SIRT3, and SIRT5 had positive effects on beclin1 and LC3II/LC3I ratio" SIGNOR-261206 BAG3 protein O95817 UNIPROT SIRT5 protein Q9NXA8 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0006301 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 SIRT5 protein Q9NXA8 UNIPROT GLS protein O94925 UNIPROT "up-regulates activity" binding 9606 BTO:0006301 30910998 t Monia "Immunoprecipitation assays of interaction between GLS and SIRT5 in HepG2 cells infected with lentivirus containing empty or BAG3 construct. Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. It has been reported that SIRT5 is responsible for desuccinylation of GLS35, immunoprecipitation (IP) was then performed." SIGNOR-261207 SIRT5 protein Q9NXA8 UNIPROT NFE2L2 protein Q16236 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0003575 31815138 f Monia "Western blot showed that Sirt5 overexpression upregulated Nrf2. Sirt5 attenuates apoptosis through Nrf2/HO-1 and Bcl-2." SIGNOR-261208 SIRT5 protein Q9NXA8 UNIPROT SIRT3 protein Q9NTG7 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001938 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 SIRT5 protein Q9NXA8 UNIPROT G6PD protein P11413 UNIPROT "up-regulates activity" "catalytic activity" 9606 BTO:0000007 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-261211 SIRT5 protein Q9NXA8 UNIPROT IDH2 protein P48735 UNIPROT "up-regulates activity" "catalytic activity" 9606 BTO:0000007 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 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 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR GOLGB1 protein Q14789 UNIPROT "down-regulates activity" cleavage Asp1882 D-->G 9606 BTO:0000567 14970262 t miannu "Giantin and syntaxin 5 are cleaved by caspase-3. Given that both giantin and syntaxin 5 are cleaved at an early stage during apoptosis, we anticipated that, at the very least, the delivery of ER-derived transport intermediates to the Golgi would be impaired in apoptotic cells." SIGNOR-261235 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR STX5 protein Q13190 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000567 14970262 t miannu "Giantin and syntaxin 5 are cleaved by caspase-3. Given that both giantin and syntaxin 5 are cleaved at an early stage during apoptosis, we anticipated that, at the very least, the delivery of ER-derived transport intermediates to the Golgi would be impaired in apoptotic cells." SIGNOR-261236 GGCX protein P38435 UNIPROT SMAD7 protein O15105 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10116 BTO:0004850 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 MAP4K4 protein O95819 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni "Hpk1 binds and phosphorylates mekk1 directly" SIGNOR-44040 AKAP5 protein P24588 UNIPROT Pka-C1 protein P12370 UNIPROT "up-regulates activity" relocalization 10116 BTO:0004553 10939335 t "In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150" SIGNOR-261292 AKAP5 protein P24588 UNIPROT PPP3CC protein P48454 UNIPROT "up-regulates activity" relocalization 10116 BTO:0004553 20694001 t "Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin" SIGNOR-261291 C9orf72 protein Q96LT7 UNIPROT RAB1A protein P62820 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 27334615 t miannu "C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation" SIGNOR-261297 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 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR RASSF1 protein Q9NS23 UNIPROT down-regulates binding 9606 21776416 t gcesareni "Basal inactivation of rassf1a is achieved by rassf1a self association and via 14-3-3 interactions (to isoforms s and e) at serine 175/178/179 of rassf1a." SIGNOR-175121 APOBEC3B protein Q9UH17 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-261331 APOBEC3C protein Q9NRW3 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-261326 APOBEC3D protein Q96AK3 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-261328 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 20663147 t gcesareni "Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation." SIGNOR-167152 APOBEC3A protein P31941 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-261332 DCTPP1 protein Q9H773 UNIPROT "dCMP 3'-end residue" smallmolecule CHEBI:53119 ChEBI "up-regulates quantity by expression" "small molecule catalysis" 10116 BTO:0003618 31377845 t lperfetto "Our data indicate that DCTPP1 is crucially involved in the provision of dCMP for thymidylate biosynthesis, introducing a new player in the regulation of pyrimidine dNTP levels and the maintenance of genomic integrity" SIGNOR-261333 "DNA polymerase alpha:primase complex" complex SIGNOR-C262 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 24043831 f 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-261344 "DNA primase complex" complex SIGNOR-C261 SIGNOR "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-261341 GLA protein P06280 UNIPROT 1,3-dichloro-7-hydroxy-9,9-dimethyl-9H-acridin-2-one smallmolecule CHEBI:52012 ChEBI "up-regulates quantity by expression" "small molecule catalysis" -1 31996391 t lperfetto "DDAOG is cleaved by -galactosidase ( Lindvall et al., 2009 ) in the Trpv1 cells to produce 7-hydroxy-9H(I,3-dichloro-9,9-dimethylacridin-2-one (DDAO)." SIGNOR-261334 IL17A protein Q16552 UNIPROT "IL17R complex" complex SIGNOR-C260 SIGNOR "up-regulates activity" binding 9606 BTO:0001946 32024054 t lperfetto "Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response." SIGNOR-261337 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI NR3C2 protein P08235 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-258714 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile chemical CHEBI:77397 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-257794 1-[4-[1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-pyrazolo[3,4-d]pyrimidinyl]phenyl]-3-methylurea chemical CHEBI:91364 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor mTOR" gcesareni SIGNOR-207800 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane chemical CHEBI:125354 ChEBI CXCR4 protein P61073 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206268 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 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 PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252657 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 1-[5-bromo-4-methyl-2-[[(2S)-2-morpholinyl]methoxy]phenyl]-3-(5-methyl-2-pyrazinyl)urea chemical CHEBI:124917 ChEBI CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193787 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI COMT protein P21964 UNIPROT up-regulates 9606 BTO:0000542 17612537 f "Regulation of expression" miannu "Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA." SIGNOR-251962 192927-92-7 chemical CID:11957576 PUBCHEM HTR1D protein P28221 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193814 "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI ITPR1 protein Q14643 UNIPROT "up-regulates activity" "chemical activation" 9606 24646566 t miannu "The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell." SIGNOR-256239 "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 18593525 t gcesareni "The hrh1 predominantly couples to g?q/11 proteins, leading to the activation of phospholipase c (plc) and subsequent release of the second messengers inositol trisphosphate (ip3) and diacylglycerol (dag) followed by the activation of pkc and the release of [ca2+]i." SIGNOR-179291 "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI AKT2 protein P31751 UNIPROT "up-regulates activity" binding 9606 21779497 t lperfetto "When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival." SIGNOR-175247 "1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate" smallmolecule CHEBI:16618 ChEBI AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 21779497 t gcesareni "When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival." SIGNOR-175250 "1-phospho-alpha-D-glucuronic acid" smallmolecule CHEBI:681 ChEBI DRD3 protein P35462 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.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1)." SIGNOR-258434 "(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid" chemical CHEBI:94640 ChEBI GRM2 protein Q14416 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-193728 "(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid" chemical CHEBI:94640 ChEBI GRM3 protein Q14832 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-193772 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 BTO:0001008 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 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile chemical CHEBI:95341 ChEBI JAK2 protein O60674 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001008 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-257832 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191021 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K2 protein P36507 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-258204 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191024 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline smallmolecule CHEBI:94276 ChEBI GLI1 protein P08151 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150;BTO:0001130 17494766 t gcesareni "Gant61 was able to efficiently block gli1 as well as gli2-induced transcription" SIGNOR-154753 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline smallmolecule CHEBI:94276 ChEBI GLI2 protein P10070 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150;BTO:0001130 17494766 t gcesareni "Gant61 was able to efficiently block gli1 as well as gli2-induced transcription" SIGNOR-154756 2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide chemical CHEBI:91367 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190245 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 "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191094 2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol chemical CHEBI:93773 ChEBI ARAF protein P10398 UNIPROT down-regulates "chemical inhibition" 9606 12970777 t gcesareni "At drug concentrations around the reported ic(50) for the raf inhibitor l-779,450, it suppressed dna synthesis and induced apoptosis in hematopoietic fdc-p1 cells transformed to grow in response to either raf-1 or a-raf (fd/deltaraf-1:er and fd/deltaa-raf:er)" SIGNOR-100355 "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 "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 "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 2-(hydroxymethyl)-4-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)phenol chemical CHEBI:64064 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "The affinity measurements (log KD values of −5.73, −9.26 and −6.33 for β1, β2 and β3, respectively), show that salmeterol has high affinity for the β2-adrenoceptor. " SIGNOR-257852 2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide chemical CHEBI:91331 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191103 (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 (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol chemical CHEBI:94701 ChEBI RRM1 protein P23921 UNIPROT "down-regulates activity" "chemical inhibition" -1 7048062 t miannu "In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase" SIGNOR-258404 (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol chemical CHEBI:94701 ChEBI RRM2 protein P31350 UNIPROT "down-regulates activity" "chemical inhibition" -1 7048062 t miannu "In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase" SIGNOR-258405 (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide chemical CHEBI:131158 ChEBI APP protein P05067 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206850 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 BTO:0001239 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 3-(4-Methylphenyl)-5-(1-propyl-3,6-dihydro-2H-pyridin-5-yl)-1,2-oxazole chemical CID:9817231 PUBCHEM SIGMAR1 protein Q99720 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000942 9144641 t Federica "PD144418 exhibited an affinity for ơ1 of 0.08nM(Ki) versusa Ki of 1377nM for ơ2 site." SIGNOR-261114 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide chemical CHEBI:91433 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195543 3b protein P59633 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0001950 21561061 f Luana "An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP" SIGNOR-260760 3b protein P59633 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001950 21561061 f Luana "An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP" SIGNOR-260761 "3-phenanthryl hydrogen sulfate" chemical CHEBI:37459 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" -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-258439 "3-phenanthryl hydrogen sulfate" chemical CHEBI:37459 ChEBI DRD3 protein P35462 UNIPROT "down-regulates activity" "chemical inhibition" -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-258438 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189984 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK3 protein Q00526 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189987 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189990 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK5 protein Q00535 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189993 "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 "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194518 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FGFR3 protein P22607 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-258105 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 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-258210 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 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-258776 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 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-258774 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine chemical CID:11617559 PUBCHEM CSF1R protein P07333 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-259743 [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 5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide chemical CHEBI:91333 ChEBI PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192991 58131-57-0 chemical CID:42640 PUBCHEM MDM4 protein O15151 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194856 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 5-methyltetrahydrofolate smallmolecule CHEBI:20612 ChEBI MTR protein Q99707 UNIPROT "up-regulates activity" "chemical activation" 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 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR "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-259241 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 6-[2-tert-butyl-5-(6-methyl-2-pyridinyl)-1H-imidazol-4-yl]quinoxaline chemical CHEBI:91391 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206715 6-(3,4-Dimethoxyphenyl)-3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole chemical CID:661498 PUBCHEM DCTPP1 protein Q9H773 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000093 28145708 t Federica "Here we report on thediscovery of a series of 3,6-disubstituted triazolothiadiazolesas potent dCTPase inhibitors." SIGNOR-261113 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 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 6 protein P59634 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" relocalization 9606 17108024 f miannu "ORF 6 protein inhibits the translocation of STAT1.SARS-CoV ORF 6 protein, but not ORF 3b or N protein, was able to inhibit the translocation of STAT1-GFP to the nucleus. A higher magnification of the image of ORF 6 protein in cells transfected with STAT1-GFP and treated with IFN-β shows that ORF 6 protein does not colocalize with STAT1, indicating that ORF 6 does not directly interact with STAT1" SIGNOR-260341 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one chemical CID:56593482 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-258321 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1A protein P35348 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190604 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1D protein P25100 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190642 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 8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one chemical CHEBI:91361 ChEBI PRKDC protein P78527 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194865 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A11 protein P48066 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206990 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A12 protein P48065 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207031 873837-23-1 chemical CID:46930994 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190467 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 8-hydroxy-5-[1-hydroxy-2-(propan-2-ylamino)butyl]-1H-quinolin-2-one chemical CHEBI:91585 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-257857 8-OH-DPAT chemical CHEBI:73364 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 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-258890 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RXRB protein P28702 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-259238 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RXRG protein P48443 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-259239 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR "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-259240 "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 "a7/b1 integrin" complex SIGNOR-C126 SIGNOR "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "down-regulates activity" 9925758 f lperfetto "These data indicate that alpha7 expression leads to the functional down regulation of alpha5beta1 integrin by decreasing ligand binding affinity and surface expression. In conclusion, the data reported establish the existence of a negative cooperativity between alpha7 and alpha5 integrins that may be important in determining functional regulation of integrins during myogenic differentiation." SIGNOR-253251 "A8/b1 integrin" complex SIGNOR-C165 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-257707 A-966492 chemical CID:16666333 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205698 AATF protein Q9NY61 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 23146908 f "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 "abiraterone acetate" chemical CHEBI:68639 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205573 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates phosphorylation Tyr153 RGNADLAyILSMEPC 9606 15657060 t gcesareni "C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9." SIGNOR-133260 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 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Y231 ANGEAVYCKFHYK 9606 BTO:0000007 12777400 t Manara "These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386" SIGNOR-260769 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr219 SIQGHNDyMCPATNQ 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-163562 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 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 ABL1 protein P00519 UNIPROT MTOR protein P42345 UNIPROT down-regulates phosphorylation 9606 10753870 t gcesareni "Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k)." SIGNOR-76562 ABL1 protein P00519 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates quantity by stabilization" phosphorylation Y1243 NGGSSLSYTNPAVAA 9606 BTO:0000567 16888623 t Manara "The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site. " SIGNOR-260830 ABL1 protein P00519 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" phosphorylation Y425 SDKYGLGYQLCDNSV 9606 BTO:0000007 27899378 t Manara "C-ABL can directly phosphorylate PLK1 and activate PLK1. | The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability." SIGNOR-260935 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity" phosphorylation Tyr108;Tyr102 SSISTPHyEDIPFTR;DLKLQEyQSAIKVE 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-255912 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Tyr432 KEGWMVHyTSKDTLR 9606 BTO:0000567 12637538 t gcesareni "Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity." SIGNOR-246211 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" phosphorylation Tyr315 ETRICKIyDSPCLPE 10090 BTO:0002883 11684015 t gcesareni "Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance" SIGNOR-247599 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 t "C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315" SIGNOR-251434 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 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT "up-regulates quantity by stabilization" phosphorylation Y149 SVTAPSPYAQPSSTF 9606 BTO:0000971 19783996 t Manara "In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters." SIGNOR-260934 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation 9606 BTO:0000149 15886098 t amattioni "Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations." SIGNOR-136958 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 BTO:0001271;BTO:0000017 21602891 t gcesareni "Rin1 binds to the abl sh3 and sh2 domains, and these interactions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl, inhibiting these cytoskeletal regulators by promoting intramolecular over intermolecular associations. the ability of crk to function as an adaptor protein is negatively regulated and terminated by phosphorylation on y221, which results in an intramolecular sh2-ptyr clamp, thereby resulting in the disassembly of crk-mediated signaling complexes" SIGNOR-173849 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 ACE2 protein Q9BYF1 UNIPROT AGT protein P01019 UNIPROT "up-regulates activity" cleavage Pro40 GDRVYIHpFHLVIHN -1 11815627 t miannu "The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus." SIGNOR-256315 ACE2 protein Q9BYF1 UNIPROT "Angiotensin 1-7" protein P01019_PRO_0000420660 UNIPROT "up-regulates quantity" cleavage 9606 32201502 f 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-260227 ACE2 protein Q9BYF1 UNIPROT Angiotensin-1 protein P01019_PRO_0000032457 UNIPROT "up-regulates activity" cleavage His42 RVYIHPFhLVIHNES -1 11815627 t miannu "The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus." SIGNOR-260221 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM2 protein P08172 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-258631 aclidinium chemical CHEBI:65346 ChEBI CHRM3 protein P20309 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-258151 ACOX1 protein Q15067 UNIPROT TP73 protein O15350 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0001154 31401980 t miannu "Downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. ACOX1 reduced p73 expression by destabilizing p73 protein. We also found that ACOX1 interacted with p73 protein" SIGNOR-261056 ACTB protein P60709 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 BTO:0000007 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-260608 ADAM10 protein O14672 UNIPROT CDH1 protein P12830 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-259846 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 adapalene chemical CHEBI:31174 ChEBI RARG protein P13631 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000404 30836068 t miannu "Adapalene, the third-generation synthetic retinoid,selectively bound to specific RAR, thus activating genes responsible forcellular differentiation. It showed greatest affinity for subtypes RARβ in dermal fibroblasts (Kd value 34 nM) and RARγ in the epidermis (Kdvalue 130 nM)" SIGNOR-258488 "AD/b2 integrin" complex SIGNOR-C172 SIGNOR VCAM1 protein P19320 UNIPROT "up-regulates activity" binding 9606 BTO:0000751 10438935 t lperfetto "These results indicate that VCAM-1 can bind to an I domain and that the binding of alpha D beta 2 to VCAM-1 may contribute to the trafficking of a subpopulation of leukocytes that express alpha D beta 2." SIGNOR-253375 ADCY1 protein Q08828 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI up-regulates "small molecule catalysis" 9606 17251915 t gcesareni "Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases." SIGNOR-152546 ADCY1 protein Q08828 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI up-regulates "small molecule catalysis" 9606 BTO:0000007 22863277 t milica "To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production." SIGNOR-198486 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 ADCYAP1 protein P18509 UNIPROT VIPR1 protein P32241 UNIPROT up-regulates binding 9606 11897681 t gcesareni "Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip)." SIGNOR-116066 "adenosine 5'-monophosphate" smallmolecule CHEBI:16027 ChEBI MLXIPL protein Q9NP71 UNIPROT "down-regulates activity" binding 10116 BTO:0000575 26984404 t "We discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3." SIGNOR-255668 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2A protein Q9BTU6 UNIPROT "down-regulates activity" "chemical inhibition" -1 21704602 t Luana "Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity" SIGNOR-258317 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2B protein Q8TCG2 UNIPROT "down-regulates activity" "chemical inhibition" -1 21704602 t Luana "Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity" SIGNOR-258316 ADGRG1 protein Q9Y653 UNIPROT ADGRG1 protein Q9Y653 UNIPROT "up-regulates activity" cleavage 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-253980 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 ADIPOQ protein Q15848 UNIPROT ADIPOR2 protein Q86V24 UNIPROT up-regulates binding 9606 BTO:0000142 16622416 t milica "Two adiponectin receptors, adipor1 and adipor2, have recently been identified." SIGNOR-146173 ADIPOQ protein Q15848 UNIPROT ADIPOR2 protein Q86V24 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 12802337 t acerquone "Expression of adipor1/r2 or suppression of adipor1/r2 expression by small-interfering rna supports our conclusion that they serve as receptors for globular and full-length adiponectin," SIGNOR-101809 ADIPOR1 protein Q96A54 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 BTO:0000142 16622416 t milica "Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin." SIGNOR-146212 ADIPOR2 protein Q86V24 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 BTO:0000142 16622416 t milica "Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin." SIGNOR-146215 ADORA2A protein P29274 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-257151 "ado-trastuzumab emtansine" antibody DB05773 DRUGBANK ERBB2 protein P04626 UNIPROT "down-regulates activity" binding 9606 BTO:0000150 19010901 t miannu "The anatomy of an antibody–cytotoxic drug conjugate can be divided into three general components: the antibody, the linker, and the cytotoxic drug. The efficacy of any such conjugate is dictated in part by the differential expression of the target antigen in tumor versus normal tissue. HER2 is a clinically validated target for the treatment of breast cancer. Trastuzumab and, more recently, lapatinib are approved for clinical use in women whose breast cancer overexpresses HER2. a trastuzumab conjugate, which simply uses HER2 as an address for the delivery of a potent cytotoxic agent, may offer promise as an effective therapeutic modality." SIGNOR-259882 ADP chemical CHEBI:16761 ChEBI P2RY13 protein Q9BPV8 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-257561 ADRA1B protein P35368 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-256950 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 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 ADRB3 protein P13945 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-256896 afatinib chemical CHEBI:61390 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000150 22418700 t gcesareni "Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members." SIGNOR-259442 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 AGO2 protein Q9UKV8 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR "form complex" binding 9606 23661684 t miannu SIGNOR-143102 agomelatine chemical CHEBI:134990 ChEBI HTR2C protein P28335 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189474 AGPAT3 protein Q9NRZ7 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI up-regulates "small molecule catalysis" 9606 12401205 t gcesareni "Pa can be generated by the acylation of lyso-pa by lyso-pa acyl transferases" SIGNOR-94864 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT "down-regulates activity" binding 9606 10318826 t miannu "AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor." SIGNOR-252380 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates binding 9606 BTO:0001253 9311920 t gcesareni "Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r, melanocortin receptor subtypes implicated in weight regulation." SIGNOR-51067 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" binding 9606 10318826 t miannu "AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor." SIGNOR-252379 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT down-regulates binding 9606 BTO:0001253 9311920 t gcesareni "Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r,." SIGNOR-51104 AGTR1 protein P30556 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-106932 AGTR1 protein P30556 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 21289285 t gcesareni "These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction." SIGNOR-171763 AHSA1 protein O95433 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates activity" binding 9606 BTO:0001519 16696853 t miannu "The interaction of GCH1 with Aha1 may recruit GCH1 into the eNOS/Hsp90 complex so as to support local changes in nitric oxide production by endothelial cells." SIGNOR-252213 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 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 AKAP8L protein Q9ULX6 UNIPROT DHX9 protein Q08211 UNIPROT "up-regulates activity" binding 9606 11402034 t miannu "We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA." SIGNOR-260950 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 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-252562 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 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser365 GQRDRSSsAPNVHIN 9606 BTO:0000007 10869359 t "Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo" SIGNOR-251471 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 AKT1 protein P31749 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates activity" phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 BTO:0000222 16982699 t gcesareni "Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction." SIGNOR-149702 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 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-167336 AKT1 protein P31749 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-158624 AKT1 protein P31749 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 f "PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype." SIGNOR-254371 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 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 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-175285 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21798082 t gcesareni "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-175291 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 AKT1 protein P31749 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 18394876 t lperfetto "The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity" SIGNOR-252582 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 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 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-252855 AKT1 protein P31749 UNIPROT HK1 protein P19367 UNIPROT up-regulates binding 9606 BTO:0000938 16027165 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-252480 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 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 AKT1 protein P31749 UNIPROT HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser199 SQRGRSGsGNFGGGR 9606 18562319 t gcesareni "Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199." SIGNOR-252519 AKT1 protein P31749 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000007 11154276 t lperfetto "Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1." SIGNOR-252465 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT "down-regulates activity" phosphorylation Ser400 EDQPRCQsLDSALLE 9606 BTO:0000661 12138205 t gcesareni "The regulation of NF-kappa B-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400)," SIGNOR-252553 AKT1 protein P31749 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 f lperfetto "Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1." SIGNOR-79335 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma "Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K" SIGNOR-255107 AKT1 protein P31749 UNIPROT 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-252575 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 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t gcesareni "These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor." SIGNOR-252555 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 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 AKT1 protein P31749 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Thr90 EARHRVPtTELCRPP 9606 BTO:0000782;BTO:0001271 15930267 t miannu "Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo." SIGNOR-252479 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 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 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 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 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 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-78689 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 t gcesareni "Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity" SIGNOR-123243 AKT2 protein P31751 UNIPROT 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 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-235960 AKT2 protein P31751 UNIPROT 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-249640 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE 9606 10377430 t lperfetto "Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus." SIGNOR-252872 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLPRPE 10090 BTO:0000944 11313479 t "Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity." SIGNOR-252873 AKT2 protein P31751 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 f gcesareni "Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu)." SIGNOR-157770 AKT2 protein P31751 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation Ser193 GLPERSVsLTGAPES 10116 17177604 t lperfetto "AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP’s ability to promote rapid mRNA decay." SIGNOR-151220 AKT2 protein P31751 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000150 12697749 t lperfetto "Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity" SIGNOR-100588 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 AKT2 protein P31751 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-201125 AKT3 protein Q9Y243 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser133 EILSRRPsYRKILND 9606 9829964 t gcesareni "When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp." SIGNOR-62257 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 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-183644 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT 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-183648 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 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-183652 AKT3 protein Q9Y243 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" binding Ser633 WRRKRKEsSNTDSAG 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-251625 AKT3 protein Q9Y243 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-164306 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 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-251469 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251470 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-137430 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244176 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT "down-regulates activity" binding 9606 BTO:0000222 16982699 t lperfetto "More importantly, the consequences of phosphorylation of either Thr145 or Ser146 are distinct. When p21 is phosphorylated on Thr145, it localizes to the nucleus and results in the disruption of the association between proliferating cell nuclear antigen and p21. Furthermore, phosphorylation of Thr145 promotes stabilization of p21" SIGNOR-244187 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT "down-regulates activity" phosphorylation Ser10 NVRVSNGsPSLERMD 9606 12042314 t lperfetto "Identification of p27kip1phosphorylation sites revealed that akt phosphorylated p27kip1at ser10(fig.4). Therefore, akt might participate in nuclear export of p27kip1as well as p27kip1degradation. Moreover, akt might be one of the unidentified ser10kinases." SIGNOR-244198 AKT proteinfamily SIGNOR-PF24 SIGNOR COPS6 protein Q7L5N1 UNIPROT up-regulates phosphorylation Ser60 DHWIRMRsQEGRPVQ 9606 23095642 t llicata "Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6." SIGNOR-199254 AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 EILSRRPsYRKILND 9606 9829964 t "The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. |When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP." SIGNOR-251474 AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser133 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-247992 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 AKT proteinfamily SIGNOR-PF24 SIGNOR EZH2 protein Q15910 UNIPROT "down-regulates activity" phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 t lperfetto "Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3" SIGNOR-244259 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "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" SIGNOR-183620 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni "Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9" SIGNOR-242578 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation 28712664 t "AKT phosphorylates and inhibits GSK3 in addition to many other substrates including TSC2, FOXO proteins, TBC1D4." SIGNOR-255488 AKT proteinfamily SIGNOR-PF24 SIGNOR H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t lperfetto "Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro" SIGNOR-244275 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-148675 AKT proteinfamily SIGNOR-PF24 SIGNOR HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto "Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212" SIGNOR-153323 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT "down-regulates activity" phosphorylation Ser400 EDQPRCQsLDSALLE 9606 BTO:0000661 12138205 t gcesareni "The regulation of NF-kappa B-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400)," SIGNOR-248019 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT "down-regulates activity" phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000661 12138205 t gcesareni "The regulation of NF-kappa B-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400)," SIGNOR-249666 AKT proteinfamily SIGNOR-PF24 SIGNOR NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 t lperfetto "Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype." SIGNOR-244318 AKT proteinfamily SIGNOR-PF24 SIGNOR NR4A1 protein P22736 UNIPROT "down-regulates activity" phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000782 11274386 t lperfetto "We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350" SIGNOR-105927 AKT proteinfamily SIGNOR-PF24 SIGNOR PHB2 protein Q99623 UNIPROT down-regulates binding 10090 15173318 t lperfetto "Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation" SIGNOR-234441 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 AKT proteinfamily SIGNOR-PF24 SIGNOR PPP1CA protein P62136 UNIPROT down-regulates phosphorylation Thr320 NPGGRPItPPRNSAK 9606 BTO:0000661 12202491 t lperfetto "Ir-induced pp1 activation in the nucleus may be a critical component in an atm-mediated pathway controlling checkpoint activation." SIGNOR-244330 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-99300 AKT proteinfamily SIGNOR-PF24 SIGNOR YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto "Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102" SIGNOR-182493 AKT proteinfamily SIGNOR-PF24 SIGNOR YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 t lperfetto "Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined." SIGNOR-244381 AKT proteinfamily SIGNOR-PF24 SIGNOR ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 15538381 t lperfetto "Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity." SIGNOR-244385 AKT proteinfamily SIGNOR-PF24 SIGNOR ZYX protein Q15942 UNIPROT down-regulates phosphorylation Ser142 PQPREKVsSIDLEID 9606 17572661 t lperfetto "Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation" SIGNOR-244389 "AL/b2 integrin" complex SIGNOR-C169 SIGNOR ICAM1 protein P05362 UNIPROT "up-regulates activity" binding 10090 BTO:0003104 12808052 t lperfetto "The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity." SIGNOR-253364 "albuterol sulfate" chemical CHEBI:2550 ChEBI ADRB2 protein P07550 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-206682 alectinib chemical CHEBI:90936 ChEBI ALK protein Q9UM73 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190961 aliskiren chemical CHEBI:601027 ChEBI REN protein P00797 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000131 18307734 t Luana "Aliskiren has a low bioavailality (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23–36 h)" SIGNOR-257771 ALK protein Q9UM73 UNIPROT PIK3R3 protein Q92569 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000762 27322022 t lperfetto "Subsequent studies revealed that ALK promoted cell migration through the P3K-AKT pathway via the p55γ regulatory subunit of PI3K." SIGNOR-253217 ALK protein Q9UM73 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000785 14968112 t gcesareni "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-122082 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RXRB protein P28702 UNIPROT "up-regulates activity" binding 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-256191 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RXRG protein P48443 UNIPROT "up-regulates activity" binding 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-256193 alogliptin chemical CHEBI:72323 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" -1 22475866 t Luana "Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization." SIGNOR-258333 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 17589504 t lperfetto "Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy" SIGNOR-156409 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 BTO:0000459 20921139 t lperfetto "we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2." SIGNOR-168252 AMHR2 protein Q16671 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 14746809 t gcesareni "See table2" SIGNOR-121596 amitriptyline chemical CHEBI:2666 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 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-258702 amitriptyline chemical CHEBI:2666 ChEBI CHRM4 protein P08173 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 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 amitriptyline chemical CHEBI:2666 ChEBI CHRM5 protein P08912 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 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-258701 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 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 AMOT protein Q4VCS5 UNIPROT YAP1 protein P46937 UNIPROT down-regulates relocalization 9606 21808241 t gcesareni "Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms." SIGNOR-175779 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 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 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 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0002572 21460634 t miannu "AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1." SIGNOR-216418 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" phosphorylation 9606 20083114 t lperfetto "A recent study revealed that ampk can inhibit mtorc1 independently of tsc2 by phosphorylating raptor at ser863." SIGNOR-216422 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 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto "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." SIGNOR-216647 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto "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." SIGNOR-216651 AMPK complex SIGNOR-C15 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t lperfetto "Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka." SIGNOR-216523 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 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-216568 AMPK complex SIGNOR-C15 SIGNOR ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 17097062 t lperfetto "Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp." SIGNOR-216519 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 26721223 f "Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity." SIGNOR-255493 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 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 Angiotensin-2 protein P01019_PRO_0000032458 UNIPROT AGTR1 protein P30556 UNIPROT "up-regulates activity" binding 9606 32201502 t MIANNU "Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways" SIGNOR-260238 (-)-anisomycin chemical CHEBI:338412 ChEBI FOSB protein P53539 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189629 ANKRD6 protein Q9Y2G4 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 20006983 t gcesareni "Our data thus demonstrate that diversin and dishevelled function together in a mutually dependent fashion in zebrafish gastrulation and organ formation" SIGNOR-162142 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 ANP32A protein P39687 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 12522243 t "PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation." SIGNOR-259082 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 21159646 t gcesareni "In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases." SIGNOR-170611 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK8 protein P45983 UNIPROT down-regulates "chemical inhibition" 9606 11717429 t gcesareni "We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm)." SIGNOR-111983 AP1 complex SIGNOR-C154 SIGNOR CXCL8 protein P10145 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000353 32446778 t 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 AP1 complex SIGNOR-C154 SIGNOR IL6 protein P05231 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 20086235 f "JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes" SIGNOR-254513 "AP-2 complex" complex SIGNOR-C245 SIGNOR ITSN1 protein Q15811 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 15496985 t Giorgia "Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples" SIGNOR-260397 AP2M1 protein Q96CW1 UNIPROT "AP-2 complex" complex SIGNOR-C245 SIGNOR "form complex" binding 31671891 t lperfetto "The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit" SIGNOR-260420 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 APC protein P25054 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "form complex" binding 9606 BTO:0000586 9734785 t lperfetto "Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level." SIGNOR-227296 APC protein P25054 UNIPROT ODC1 protein P11926 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000182 12112318 t "APC-dependent regulation of ornithine decarboxylase in human colon tumor cells|Upon induction of APC expression, ODC promoter activity and RNA levels were suppressed" SIGNOR-253670 APEX1 protein P27695 UNIPROT CYP11B2 protein P19099 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22652909 f miannu "We conclude that APEX1 is a novel transcriptional repressor of CYP11B2 and that differential APEX1 binding at -1651 of CYP11B2 results in altered gene expression." SIGNOR-253736 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 APOA1 protein P02647 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates 9606 BTO:0000443 20642861 t miannu "ApoA-I increases cholesterol release in mature human adipocytes." SIGNOR-252104 APOA5 protein Q6Q788 UNIPROT LPL protein P06858 UNIPROT "up-regulates activity" binding 9606 21773006 t Regulation miannu "Apo A5 binds to and enhances the activity of lipoprotein lipase (LPL) enzyme" SIGNOR-251845 Apoptosome complex SIGNOR-C230 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-256471 Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000567 9390557 t lperfetto "Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade." SIGNOR-256472 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 ARAP2 protein Q8WZ64 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-260454 ARAP2 protein Q8WZ64 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-260453 ARG1 protein P05089 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0000452 BTO:0001103 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-255545 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 ARHGAP21 protein Q5T5U3 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-260475 ARHGAP31 protein Q2M1Z3 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-260490 ARHGAP8 protein P85298 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-260463 ARHGEF12 protein Q9NZN5 UNIPROT RHOA protein P61586 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 BTO:0001271 11094164 t gcesareni "Here, we show that larg can activate rho in vivo" SIGNOR-84657 ARHGEF7 protein Q14155 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 21048939 t gcesareni "Arhgef7 is interacting with lrrk2 in vitro and in vivo. Gtpase activity of full-length lrrk2 increases in the presence of recombinant arhgef7. Arhgef7 might act as a guanine nucleotide exchange factor for lrrk2" SIGNOR-169217 ARHGEF1 protein Q92888 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-260528 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 ARHGEF25 protein Q86VW2 UNIPROT CDC42 protein P60953 UNIPROT up-regulates "guanine nucleotide exchange factor" 10090 BTO:0000165;BTO:0000222 16314529 t lperfetto "Exogenous expression of geft promotes myogenesis of c2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process." SIGNOR-235391 ARID1A protein O14497 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-132919 ARNTL protein O00327 UNIPROT PER3 protein P56645 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-253630 ARNT protein P27540 UNIPROT CA9 protein Q16790 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599;BTO:0001950 22387692 f lperfetto "The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX." SIGNOR-253706 AR protein P10275 UNIPROT AKR1C3 protein P42330 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 22971343 f miannu "Both AR antagonism and androgen deprivation can upregulate AKR1C3." SIGNOR-253737 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 AR protein P10275 UNIPROT ARG2 protein P78540 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321 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 AR protein P10275 UNIPROT SERPINB5 protein P36952 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16304843 f lperfetto "In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter" SIGNOR-253685 AR protein P10275 UNIPROT Survival phenotype SIGNOR-PH13 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-251539 ARRB2 protein P32121 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 16908539 t gcesareni "We demonstrate that _-arrestins mediate the activity-dependent interaction of smo and the kinesin motor protein kif3a." SIGNOR-148773 ARVCF protein O00192 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-252128 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 ASPSCR1 protein Q9BZE9 UNIPROT VCPKMT protein Q9H867 UNIPROT up-regulates binding 9606 23349634 t gcesareni "In the case of vcp, methylation by mettl21d was stimulated by the addition of the ubx cofactor aspscr1, which we show directly interacts with the methyltransferase." SIGNOR-200572 ASXL1 protein Q8IXJ9 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 26470845 t lperfetto "Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals" SIGNOR-241759 ASXL2 protein Q76L83 UNIPROT TET2 protein Q6N021 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001545 28516957 f miannu "Interestingly, this identified a number of genes known to promote leukemogenesis (either alone or in the context of AML1-ETO leukemia) as differentially expressed by ASXL2 loss. These include downregulation of TET2 as well as NOTCH2 with ASXL2 loss in human AML1-ETO-expressing cells, downregulation of which have been previously shown to functionally promote myeloid leukemogenesis when altered in expression" SIGNOR-260074 AT-406 chemical CID:25022340 PUBCHEM BIRC3 protein Q13489 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189957 AT9283 chemical CID:11696609 PUBCHEM ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190008 AT9283 chemical CID:11696609 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190011 AT9283 chemical CID:11696609 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190014 ATF4 protein P18848 UNIPROT DDIT3 protein P35638 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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-260170 ATF4 protein P18848 UNIPROT HSPA5 protein P11021 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16205636 f miannu "Suppression of ATF4 expression by small interfering RNA (siRNA) partially inhibited the celecoxib-dependent upregulation of GRP78." SIGNOR-253749 ATG101 protein Q9BSB4 UNIPROT ATG13 protein O75143 UNIPROT up-regulates binding 9606 19597335 t gcesareni "Furthermore, atg101 is important for the stability and basal phosphorylation of atg13 and ulk1" SIGNOR-186989 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 ATG12/5/16L1 complex SIGNOR-C109 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates -1 23321721 f lperfetto "Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation" SIGNOR-226702 ATG12 protein O94817 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR "form complex" binding 9606 BTO:0000007 18321988 t lperfetto "Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex)." SIGNOR-226689 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 ATM protein Q13315 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" 9606 BTO:0000887 18534819 f gcesareni "The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity." SIGNOR-161434 ATM protein Q13315 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0000887 18534819 f lperfetto "The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity." SIGNOR-244392 ATM protein Q13315 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser490 QSTEPALsQIVMAPS 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-137619 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 ATM protein Q13315 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates phosphorylation Thr434 TPPPSPNtQTPVQPP 9606 BTO:0000551 23108047 t miannu "Phosphorylation of ccdc6 at thr434 by atm during dna damage response prevents fbxw7-mediated ccdc6 degradation." SIGNOR-199276 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 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 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 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1404 EEIKSQNsQESTADE 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-90113 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 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto "These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination" SIGNOR-188412 ATM protein Q13315 UNIPROT PVR protein P15151 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000914 21406724 f "The up-regulation of PVR expression involves DNA-damage response (DDR)-dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker γH2AX." SIGNOR-253927 ATM protein Q13315 UNIPROT RAD17 protein O75943 UNIPROT unknown phosphorylation Ser646 ETWSLPLsQNSASEL 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-73520 ATM protein Q13315 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Thr367 IIYTQDFtVPGQVPE 9606 BTO:0000848 12234250 t gcesareni "We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo." SIGNOR-92873 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 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t gcesareni "The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells." SIGNOR-197622 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 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001938 15254178 t lperfetto "Although the stabilization of p53 was apparently concordant with its phosphorylation on N-terminal serine residues in HFFF-2 cells, it did not require the phosphorylation of Ser15 or Ser20 by ATM, a cellular kinase known to phosphorylate and promote the stabilization of p53 in response to DNA damage." SIGNOR-126757 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0002552 17967874 t gcesareni "The increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15." SIGNOR-158636 ATOH1 protein Q92858 UNIPROT MUC2 protein Q02817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17000673 f miannu "This study confirms the importance of HATH1 for the development of intestinal secretory cells. The results further suggest that HATH1 is an important factor in the up-regulation of MUC2 expression that occurs in mucinous cancers and signet ring carcinomas." SIGNOR-253755 atomoxetine chemical CHEBI:127342 ChEBI SLC6A2 protein P23975 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-259071 ATP13A1 protein Q9HD20 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0004093 other 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 atropine smallmolecule CHEBI:16684 ChEBI CHRM5 protein P08912 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-258393 ATR protein Q13535 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 17124492 t lperfetto "Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment" SIGNOR-150870 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 23422745 t gcesareni "The phosphorylation of atr and atm substrates, chk1, chk2, h2ax, and brca1 was significantly reduced or abrogated in mutant cells." SIGNOR-201050 ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 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-134716 ATR protein Q13535 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t lperfetto "Atm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.Substitution of thr68 with ala reduced the extent of phosphorylation and activation of chk2 in response to ir" SIGNOR-81442 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 ATR protein Q13535 UNIPROT RAD17 protein O75943 UNIPROT "up-regulates activity" phosphorylation Ser646 ETWSLPLsQNSASEL 9606 BTO:0000567 11687627 t lperfetto "Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival." SIGNOR-111248 ATR protein Q13535 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR 9606 19843584 t llicata "Atr phosphorylates s33 in response to replication stress" SIGNOR-188666 AURKA protein O14965 UNIPROT AURKA protein O14965 UNIPROT up-regulates phosphorylation Thr288 APSSRRTtLCGTLDY 9606 24867643 t lperfetto "The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability" SIGNOR-205106 AURKA protein O14965 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 16082213 t lperfetto "We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353" SIGNOR-139396 AURKA protein O14965 UNIPROT PIN1 protein Q13526 UNIPROT down-regulates 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 AURKA protein O14965 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 18615013 t gcesareni "We find that aurora a (aurka) can directly phosphorylate plk1 on thr 210;activation of plk1 requires phosphorylation of a conserved threonine residue (thr 210)." SIGNOR-179422 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Ser12 YSSSQRVsSYRRTFG -1 12686604 t lperfetto "We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro." SIGNOR-100107 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Ser60 VYQVSRTsGGAGGLG -1 12686604 t lperfetto "We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro." SIGNOR-100111 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Thr17 RVSSYRRtFGGAPGF -1 12686604 t lperfetto "We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro." SIGNOR-100115 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPATGGV 9606 21282660 t 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-171717 AURKB protein Q96GD4 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser278 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-198650 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser44 KPTFGKLsINKPTSE 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-165558 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 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser183 CPHHERCsDSDGLAP 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-197598 "Av/b1 integrin" complex SIGNOR-C175 SIGNOR UTF1 protein Q5T230 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001086 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 "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 AVPR1B protein P47901 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-257176 AXIN1 protein O15169 UNIPROT RNF111 protein Q6ZNA4 UNIPROT up-regulates binding 9606 16601693 t gcesareni "Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia." SIGNOR-145845 AXIN1 protein O15169 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates 9606 16601693 f gcesareni "Axin promotes smad3 phosphorylation;phosphorylated smad3 dissociates from the axin complex and then combines with smad4 to activate transcription in the nucleus." SIGNOR-145848 AXIN1 protein O15169 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates binding 9606 16601693 t gcesareni "Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia." SIGNOR-145851 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 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT "up-regulates activity" phosphorylation Tyr866 EVHPAGRyVLCPSTT -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-250593 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190224 "bafilomycin A1" chemical CHEBI:22689 ChEBI ATP6V1A protein P38606 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000968 9572882 t "Simone Vumbaca" "The macrolide antibiotic bafilomycin A1 is a very potent and specific inhibitor of V-ATPases." SIGNOR-261084 BAG1 protein Q99933 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 7834747 t lperfetto "Cloning and functional analysis of BAG-1: A novel Bcl-2-binding protein with anti-cell death activity|" SIGNOR-254118 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 baicalein chemical CHEBI:2979 ChEBI CYP2C9 protein P11712 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190236 BAK1 protein Q16611 UNIPROT DIABLO protein Q9NR28 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-118905 BAK1 protein Q16611 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-118908 BAX protein Q07812 UNIPROT DIABLO protein Q9NR28 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-87109 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 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 BAZ1B protein Q9UIG0 UNIPROT MDC1 protein Q14676 UNIPROT down-regulates 9606 20965415 f gcesareni "H2ax tyr142 is constitutively phosphorylated by the kinase wstf, a member of the baz/wal family of chromatin remodelling enzymes, and blocks mdc1 recruitment" SIGNOR-168831 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004911 20395365 f Regulation miannu "BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors." SIGNOR-251800 BCL2L11 protein O43521 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000972 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-260426 BCL2L11 protein O43521 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 22492984 t gcesareni "Bim, and puma bind with high affinity to all pro-survival proteins" SIGNOR-196932 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 10090 BTO:0000759 12242151 t lperfetto "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." SIGNOR-92939 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 BCL2 protein P10415 UNIPROT BAK/BAX complex SIGNOR-C96 SIGNOR "down-regulates activity" binding 9606 16243507 t lperfetto "Displacement model. BH3-only proteins are proposed to activate Bax and Bak by displacing them from the Bcl-2 pro-survival proteins that sequester their active forms" SIGNOR-209681 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 15208637 t amattioni "The transcriptional activity of beta-catenin depends on bcl-9. Bcl-9 functions in targeting beta-catenin to the nucleus and thus increases the transcriptional activity of beta-catenin" SIGNOR-126059 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 BCORL1 protein Q5H9F3 UNIPROT HDAC4 protein P56524 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17379597 t irozzo "BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor." SIGNOR-259112 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT "down-regulates activity" phosphorylation Y360 YSPRSFEDCGGGYTP 9606 BTO:0001538 9467953 t Manara "Thus, we propose that the phosphorylation of tyrosine 328 and 360 within Bcr by Bcr-Abl will drastically interfere with Bcr's kinase role in either signal transduction or some other cellular mechanism." SIGNOR-260828 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 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 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 11726515 t irozzo "However, direct binding of Grb2 to Bcr/Abl also facilitates its tyrosine phosphorylation, which we propose reflects activation of a physiological negative regulatory mechanism by this oncogenic tyrosine kinase.Direct binding of Grb2 to Bcr/Abl facilitates Grb2 phosphorylation." SIGNOR-255820 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr1007 "VLPQDKEyYKV KEPG" 10090 BTO:0002882 11593427 t irozzo "In this report, we show that Bcr–Abl forms a complex with Jak2, and induces tyrosine phosphorylation of Jak2; full phosphorylation requires the SH2 domain of Bcr–Abl. We found that Y1007 of Jak2 was phosphorylated in Bcr–Abl positive cells; phosphorylation of Jak2 Y1007 is known to be required for Jak2 kinase activation." SIGNOR-255812 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 t lperfetto "Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro." SIGNOR-114094 BDKRB1 protein P46663 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-257237 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 belinostat chemical CHEBI:61076 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-257960 belinostat chemical CHEBI:61076 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-257745 beta-Funaltrexamine chemical CHEBI:81527 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-258772 betamethasone chemical CHEBI:3077 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 17561562 t dermatitis gcesareni SIGNOR-251686 bexarotene chemical CHEBI:50859 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR "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-259233 BFAR protein Q9NZS9 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates binding 9606 BTO:0000093 11733517 t gcesareni "We also demonstrate that the mitochondrial protein bar, which has been shown to simultaneously bind caspase-8 and bcl-2" SIGNOR-112585 BIRC2 protein Q13490 UNIPROT CASP2 protein P42575 UNIPROT down-regulates binding 9606 16701639 t gcesareni "However, among hiap1, hiap2 and xiap, only hiap2 binds and inhibits caspase-2." SIGNOR-146738 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination 9606 16603398 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-145036 BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 18997794 t lperfetto "Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3." SIGNOR-182128 BIX-02188 chemical CID:66524294 PUBCHEM MAP2K5 protein Q13163 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190365 BKM120 chemical CHEBI:71954 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190383 BKM120 chemical CHEBI:71954 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190386 BKM120 chemical CHEBI:71954 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190389 BKM120 chemical CHEBI:71954 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190392 blinatumomab antibody DB09052 DRUGBANK CD33 protein P20138 UNIPROT "down-regulates activity" binding 9606 BTO:0001545 25883042 t miannu "Blinatumomab, a bispecific antibody construct targeting CD19, is the most advanced member of bispecific T-cell engager (BiTE®) molecules. all data strongly suggest CD33 as a suitable target antigen for BiTE® therapy in AML." SIGNOR-259889 BLOC-2 complex SIGNOR-C252 SIGNOR KIF13A protein Q9H1H9 UNIPROT "up-regulates activity" binding 9606 30404817 t lperfetto "Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis." SIGNOR-260702 BMI1 protein P35226 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000785 19884659 f gcesareni "Chromatin immunoprecipitation assays revealed the bmi-1 transcriptionally downregulated expression of the tumor suppressor pten in tumor cells through direct association with the pten locus." SIGNOR-189040 BMP10 protein O95393 UNIPROT ACVRL1 protein P37023 UNIPROT up-regulates binding 9606 17068149 t acerquone "Taken together, our results sug- gest that bmp9 and bmp10 are two spe- cific alk1 ligands that may physiologi- cally trigger the effects of alk1 on angiogenesis" SIGNOR-150201 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 BMP2 protein P12643 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates 9606 21793042 f gcesareni "Upon bmp binding to the bmpr-ii, bmpr-i is recruited to form an activated quaternary complex, which then phosphorylates and activates intracellular smad proteins. Receptor smads bind to a co-smad and translocate to the nucleus to serve as transcription factors." SIGNOR-175273 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR "up-regulates activity" binding 10090 BTO:0000165 11282024 t lperfetto "Bmp-4 and gdf-5 are known to bind to activin" SIGNOR-235376 BMP7 protein P18075 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003858 12734180 f miannu "In the present study we investigated the inhibitory effects of IGF-1 and OP-1 on MMP-13 expression in human chondrocytes. We found that the suppressive effect of IGF-1 and OP-1 on the MMP-13 promoter activity was dose-dependent at the transcriptional level with a corresponding decrease in the level of MMP-13 protein." SIGNOR-254801 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates phosphorylation 9606 18756288 t lperfetto "Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1." SIGNOR-217029 BMPR1A protein P36894 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR "form complex" binding 9606 7791754 t lperfetto "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)." SIGNOR-255257 BMPR1A protein P36894 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 10712517 t gcesareni "Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors" SIGNOR-75649 BMPR1A protein P36894 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 10090 10712517 t gcesareni "Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors" SIGNOR-75652 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR "up-regulates activity" phosphorylation 9606 "BTO:0000165;BTO:0002974; BTO:0002809" 9442019 f 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-255779 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 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-235622 BMPR2 protein Q13873 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR "form complex" 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-33437 BMPR2 protein Q13873 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 7791754 t gcesareni "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-33434 BMS-754807 chemical CHEBI:88339 ChEBI IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190497 "BMS 794833" chemical CID:44155856 PUBCHEM KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190419 BMX protein P51813 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 23716717 t llicata "Bmx phosphorylated focal adhesion kinase (fak) at tyr577 subsequent to its src-mediated phosphorylation at tyr576. Loss of bmx by rna interference or by genetic deletion in mouse embryonic fibroblasts (mefs) markedly impaired fak activity." SIGNOR-202139 BNIP2 protein Q12982 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 18678706 t lperfetto "Cdo-bnip-2-cdc42 complex stimulates cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation." SIGNOR-179861 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 bradykinin smallmolecule CHEBI:3165 ChEBI BDKRB1 protein P46663 UNIPROT up-regulates "chemical activation" 9606 BTO:0001130;BTO:0000189 17251915 t gcesareni "Neuropeptides such as grp, endothelin, bradykinin, neuromedin b (nmb), cholecystokinin (cck) and angiotensin ii activate their cognate gpcrs to stimulate cell proliferation in various cell types, and have a crucial role in many aggressive human cancers, including small-cell lung cancer (sclc), pancreatic cancer, hnscc and prostate cancer." SIGNOR-152588 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 BRCA1 protein P38398 UNIPROT HSPA5 protein P11021 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 18776923 f miannu "We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression." SIGNOR-253761 BRCA1 protein P38398 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR "up-regulates activity" binding 10426999 t lperfetto "BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50.| These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex." SIGNOR-251501 brimonidine chemical CHEBI:3175 ChEBI ADRA2B protein P18089 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-258901 brimonidine chemical CHEBI:3175 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-258900 BRIP1 protein Q9BX63 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" binding 9606 BTO:0000093;BTO:0003323 11301010 t irozzo "BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. Moreover, BACH1 likely contributes to the DNA repair function of BRCA1 []." SIGNOR-259185 BRSK1 protein Q8TDC3 UNIPROT CDC25B protein P30305 UNIPROT "down-regulates activity" phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567 15150265 t lperfetto "Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectively phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-107404 BRSK1 protein Q8TDC3 UNIPROT CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto "Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-124839 "BS-181 hydrochloride" chemical CID:49867928 PUBCHEM CDK7 protein P50613 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190783 BTF3 protein P20290 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by repression" "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-253950 BTF3 protein P20290 UNIPROT RRAS2 protein P62070 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003081 17312387 f miannu "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." SIGNOR-253766 BTF3 protein P20290 UNIPROT SSPN protein Q14714 UNIPROT "down-regulates quantity by repression" "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-253951 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT "up-regulates activity" phosphorylation Tyr503 EAHPNDLyVEGLPEN 9534 BTO:0004055 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 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 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 16371461 t lperfetto "Phosphorylated gli3 can bind beta-trcp directly both in vitro and in vivo, resulting in polyubiquitination of gli3 and processing through proteasome activity" SIGNOR-143171 BTRC protein Q9Y297 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates ubiquitination 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-160985 BTRC protein Q9Y297 UNIPROT PER1 protein O15534 UNIPROT down-regulates ubiquitination 9606 BTO:0000671 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 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Ser92 AAQMEVAsFLLSKEN 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-250608 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Thr157 VLYSQKAtPGSSRKT 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-250609 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 11208622 t ashma gcesareni SIGNOR-251687 BVES protein Q8NE79 UNIPROT VAMP3 protein Q15836 UNIPROT "up-regulates activity" binding -1 20057356 t llicata "Taken together, these data demonstrate that Bves interacts with VAMP3 and facilitates receptor recycling both in vitro and during early development." SIGNOR-237771 BZW2 protein Q9Y6E2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 BTO:0003897 30805927 f francesca "Overexpression (or silence) of BZW2 in HCC cells significantly stimulates (or decreases) the activation of the PI3K/AKT/mTOR signaling pathway" SIGNOR-261218 C25H27N5O4S chemical CID:66577011 PUBCHEM KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189711 Calcineurin complex SIGNOR-C155 SIGNOR 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-252324 Calcineurin complex SIGNOR-C155 SIGNOR 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-252332 Calcineurin complex SIGNOR-C155 SIGNOR 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-252329 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 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-252311 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P62158 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 t 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-235590 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2A protein Q9UQM7 UNIPROT "up-regulates activity" binding 15621017 t "It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK." SIGNOR-255491 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2D protein Q13557 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001103 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-255953 CALM1 protein P62158 UNIPROT PPP3CA protein Q08209 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-114098 CALM1 protein P62158 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 CALM1 protein P62158 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 CALM1 protein P62158 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 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 CAMK1G protein Q96NX5 UNIPROT EIF4G3 protein O43432 UNIPROT up-regulates phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 BTO:0000938 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 CAMK1 protein Q14012 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD -1 8663317 t llicata "Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site." SIGNOR-250611 CAMK2A protein Q9UQM7 UNIPROT CACNA1B protein Q00975 UNIPROT down-regulates phosphorylation Ser2120 ERRQPSSsSSEKQRF 9606 BTO:0000938 16982421 t gcesareni "Here, we report a direct modulation of ca(v)2.2 channel inactivation properties by 14-3-3, a family of signaling proteins involved in a wide range of biological processes.Wild-type gst fusion proteins containing the putative 14-3-3-binding motif (aa 2076__?2140) werein vitro phosphorylated at s2126 by either camkii or pka, as detected by thesequence- and phosphorylation-specific antibody, anti-ps2126 (middle panel). Phosphorylation of s2126 significantly increases its binding to recombinant 14-3-3?" SIGNOR-149684 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 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 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 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser282 NSLQRVPsYDSFDSE 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-96338 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 CAMK2A protein Q9UQM7 UNIPROT ITPKA protein P23677 UNIPROT up-regulates phosphorylation Thr311 EHAQRAVtKPRYMQW 9606 BTO:0000938 BTO:0000975;BTO:0000142 9155020 t lperfetto "D-myo-inositol 1,4,5-trisphosphate 3-kinase a is activated by receptor activation through a calcium:calmodulin-dependent protein kinase ii phosphorylation mechanism. the phosphorylated residue was thr311." SIGNOR-48387 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Ser270 SVRMLSGsKEKDRNL 9606 BTO:0000671 10908300 t gcesareni "The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization." SIGNOR-79682 CAMK2A protein Q9UQM7 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser19 KGFRRAVsELDAKQA 9606 BTO:0000142 1680128 t llicata "This increase in ser19 phosphorylation was associated with enhanced th activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase ii (camkii) activation." SIGNOR-20912 CAMK2B protein Q13554 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000938 20841359 t gcesareni "Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival." SIGNOR-167962 CAMK2B protein Q13554 UNIPROT PLCB3 protein Q01970 UNIPROT unknown phosphorylation Ser537 PSLEPQKsLGDEGLN 11325525 t llicata "CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment" SIGNOR-250689 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 CAMK2G protein Q13555 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1071 SFLQRYSsDPTGALT 9606 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-250695 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 CAMK2G protein Q13555 UNIPROT RYR1 protein P21817 UNIPROT unknown phosphorylation Ser2843 KKKTRKIsQSAQTYD 8380342 t llicata "Phosphorylation of serine 2843 in ryanodine receptor-calcium release channel of skeletal muscle by cAMP-, cGMP- and CaM-dependent protein kinase." SIGNOR-250704 CAMK2G protein Q13555 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser568 PQATRQTsVSGPAPP 3118371 t llicata "Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II." SIGNOR-250707 CAMK2G protein Q13555 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser605 AGPTRQAsQAGPVPR 3118371 t llicata "Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II." SIGNOR-250708 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887;BTO:0001103 12058061 t lperfetto "Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs." SIGNOR-236575 CAMK4 protein Q16566 UNIPROT HNRNPL protein P14866 UNIPROT up-regulates phosphorylation Ser544 GKSERSSsGLLEWES 9606 22570490 t lperfetto "Here we show that the regulation of the stress axis-regulated exon of the slo1 potassium channel transcripts by membrane depolarization requires a highly conserved camkiv target serine (ser-513) of the heterogeneous ribonucleoprotein l. Ser-513 phosphorylation within the rna recognition motif 4 enhanced heterogeneous ribonucleoprotein l interaction with the camkiv-responsive rna element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the u2 auxiliary factor u2af65." SIGNOR-197367 CAMK4 protein Q16566 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates phosphorylation Ser91 RARPRKIsSPTGSKD 9606 BTO:0000887 21689744 t lperfetto "Here we show that calcium/calmodulin-dependent kinase iv (camk iv) specifically binds to the c terminus of phb2 and phosphorylates phb2 at serine 91. Camk iv effectively decreased phb2-mediated repression of mef2 activity through phosphorylation" SIGNOR-174437 CAMP protein P49913 UNIPROT FPR2 protein P25090 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11015447 t gcesareni "Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1." SIGNOR-82701 CAMTA1 protein Q9Y6Y1 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0005397 21385898 f irozzo "Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma." SIGNOR-259100 CAMTA1 protein Q9Y6Y1 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0005397 21385898 f irozzo "Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma." SIGNOR-259099 canagliflozin chemical CHEBI:73274 ChEBI SLC5A2 protein P31639 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190850 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 CAPN2 protein P17655 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-251612 carbamazepine chemical CHEBI:3387 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-258353 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 CASP12 protein Q6UXS9 UNIPROT CASP9 protein P55211 UNIPROT up-regulates cleavage 9606 BTO:0000222 12097332 t gcesareni "Caspase-12 specifically cleaves and activates procaspase-9 in cytosolic extracts. Results suggest that caspase-12 can activate caspase-9 without involvement of cytochromec." SIGNOR-90318 CASP1 protein P29466 UNIPROT "AIM2 inflammasome" complex SIGNOR-C222 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-256400 CASP3 protein P42574 UNIPROT ACIN1 protein Q9UKV3 UNIPROT up-regulates cleavage 9606 10490026 t amattioni "Induces apoptotic chromatin condensation after activation by casp3" SIGNOR-70800 CASP3 protein P42574 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni "Caspase-3 is responsible for apoptosis execution" SIGNOR-89244 CASP3 protein P42574 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni "Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation" SIGNOR-66860 CASP3 protein P42574 UNIPROT DFFA protein O00273 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000567 9108473 t lperfetto "DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3." SIGNOR-47416 CASP3 protein P42574 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni "Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation" SIGNOR-66866 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 CASP3 protein P42574 UNIPROT 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-180144 CASP8 protein Q14790 UNIPROT 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-171767 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000007 16964285 t amattioni "Casp8 induces apoptosis by directly activating casp3." SIGNOR-149420 CASP8 protein Q14790 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni "Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them." SIGNOR-59857 CASP8 protein Q14790 UNIPROT CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 18073771 t amattioni "Active caspase-8 then proteolytically processes and activates caspase-7" SIGNOR-159853 CASP8 protein Q14790 UNIPROT CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni "Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them." SIGNOR-58118 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni "Caspase-3 is responsible for apoptosis execution" SIGNOR-256474 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256455 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR BRCA1 protein P38398 UNIPROT "down-regulates quantity by destabilization" cleavage Asp1155 ETPDDLLdDGEIKED 9606 12149654 t miannu "We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable." SIGNOR-256432 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 t amattioni "Caspase-3 is required for the activation of caspases 6" SIGNOR-256467 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256465 "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 "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 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 CAV1 protein Q03135 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 16890161 t gcesareni "Overall, our data suggest that wnt-3a triggers the interaction of lrp6 with caveolin and promotes recruitment of axin to lrp6 phosphorylated by glycogen synthase kinase-3beta and that caveolin thereby inhibits the binding of beta-catenin to axin." SIGNOR-148665 CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR TP53 protein P04637 UNIPROT "down-regulates activity" binding 10090 BTO:0002882 26387755 t "Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8).Altogether, these results indicate that CM fusion protein binds to p53 and impairs acetylation and activation of p53." SIGNOR-255737 CBFB protein Q13951 UNIPROT "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "form complex" binding 9606 12495904 t irozzo "The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis" SIGNOR-255711 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 CBL protein P22681 UNIPROT MET protein P08581 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 19450681 t lperfetto "Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation" SIGNOR-185680 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT "up-regulates activity" acetylation 9606 9865691 t lperfetto "The closely related CBP and p300 proteins are also important coactivators for Smad activity. CBP and p300 act as coactivators of several transcription factors by bringing the sequence-specific activators within proximity of the general transcription machinery and by modifying the chromatin structure through histone acetylation.In response to TGF-b, Smad3 associates with CBP/p300 and TGF-b-induced C-terminal phosphorylation of Smad3 promotes this association. This association with CBP/p300 is likely to be essential for transcriptional activity of Smad3." SIGNOR-227553 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT "up-regulates activity" acetylation Lys19 VKRLLGWkKGEQNGQ 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 tgfb-dependent manner. the p300-dependent acetylation of smad3 was attenuated when lys19 was mutated, whereas mutation of lys20 had no effect, suggesting that lys19 is acetylated also in smad3." SIGNOR-236126 CBP/p300 complex SIGNOR-C6 SIGNOR THBD protein P07204 UNIPROT "up-regulates quantity by expression" "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-253908 CCKAR protein P32238 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-257236 CCKBR protein P32239 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-257238 CCL3 protein P10147 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-255115 CCND1 protein P24385 UNIPROT CDK6/CCND1 complex SIGNOR-C143 SIGNOR "form complex" binding 9606 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-250680 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 CD19 protein P15391 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 10090 BTO:0000776 25673924 f lperfetto "CD19 is a crucial regulator of B cell activation." SIGNOR-242888 CD19 protein P15391 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" 9606 10706702 f lperfetto "CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor." SIGNOR-249609 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 CD3E protein P07766 UNIPROT 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 CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε 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 αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ" SIGNOR-255294 CD74 protein P04233 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 BTO:0000007;BTO:0000876 19665027 t miannu "Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling." SIGNOR-187461 CD79A protein P11912 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 12324477 f gcesareni "Bcr ligation activated mitochondrial apoptotic pathways including down-regulation of bcl-x(l)." SIGNOR-93481 CD79B protein P40259 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0000776 12324477 f gcesareni "Bcr ligation resulted in p53 activation including its phosphorylation at ser15" SIGNOR-93526 CDC14A protein Q9UNH5 UNIPROT IREB2 protein P48200 UNIPROT "up-regulates activity" dephosphorylation Ser157 LQKAGKLsPVKVQPK 9606 18574241 t "IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis." SIGNOR-248829 CDC14A protein Q9UNH5 UNIPROT KMT5A protein Q9NQR1 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t "The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis." SIGNOR-248835 CDC14A protein Q9UNH5 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT unknown dephosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 t "Here, we demonstrate that SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1, and dephosphorylated by the phosphatases CDC14A and CDC14B. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation|Additionally, we found that SIRT2, like other Cdk1 targets, can be dephosphorylated by the phosphatases CDC14A and CDC14B. In contrast to a published report (8), we did not observe any degradation of SIRT2 by the 26 S proteasome in response to CDC14B overexpression|However, we cannot exclude the possibility that phosphorylation of serine 368 might affect the activity of SIRT2 on other unidentified acetylated substrates." SIGNOR-248834 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t "Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, 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.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3." SIGNOR-248336 CDC14B protein O60729 UNIPROT SKP2 protein Q13309 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser64 SNLGHPEsPPRKRLK 9606 18239684 t "The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1)." SIGNOR-248333 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 CDC25B protein P30305 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation 9606 SIGNOR-C17 7880537 t gcesareni "Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex" SIGNOR-34541 CDC25B protein P30305 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates dephosphorylation 9606 7880537 t lperfetto "Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex" SIGNOR-217511 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 19574738 t gcesareni "Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c" SIGNOR-186617 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 19574738 t gcesareni "Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c" SIGNOR-186621 CDC42 protein P60953 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 21902831 f lperfetto "Precisely how this complex results in p38 activation is not known, but complex recruitment of the gtpase cdc42 is required for p38 phosphorylation." SIGNOR-176501 CDC42 protein P60953 UNIPROT NFATC1 protein O95644 UNIPROT "up-regulates activity" 9606 BTO:0000661 18976935 f lperfetto "Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner." SIGNOR-253370 CDC7 protein O00311 UNIPROT RAD18 protein Q9NS91 UNIPROT unknown phosphorylation Ser434 IQEVLSSsESDSCNS 9606 21098111 t llicata "Although the cdc7/rad18 interaction and phosphorylation at s434 are induced by dna damage, s434 was also observed to be phosphorylated basally" SIGNOR-170049 CDCA7L protein Q96GN5 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-253768 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 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 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-176797 CDK13 protein Q14004 UNIPROT CDK13/CCNK 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-176844 CDK1 protein P06493 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Thr34 FLEGCACtPERMAEA 9606 11861764 t gcesareni "Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo" SIGNOR-115129 CDK1 protein P06493 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation 9606 18521620 t gcesareni "Our data additionally identify the cdk1 site s252 as critical for the recruitment of plk1 to hbora. collectively, our findings lead us to propose that hbora contributes to integrate the functions of three major mitotic kinases, cdk1, plk1, and aurora a." SIGNOR-178799 CDK1 protein P06493 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Thr609 SAAQLAStPFHKLPV 9606 BTO:0000567 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 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 CDK1 protein P06493 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation Thr376 QVAPRAGtPGFRAPE 9606 10846177 t gcesareni "Hucdc7 and ask proteins can also be phosphorylated by cdks in vitro. Among four possible cdk phosphorylation sites of hucdc7, replacement of thr-376, corresponding to the activating threonine of cdk, with alanine (t376a mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue." SIGNOR-78311 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 CDK1 protein P06493 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-173677 CDK1 protein P06493 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-200400 CDK1 protein P06493 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates phosphorylation Ser1126 IAPSTNSsPVLKTKP 9606 11747808 t lperfetto "Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro" SIGNOR-113126 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 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 CDK1 protein P06493 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Thr412 DTEIANStPNPKPAA 9606 16378098 t gcesareni "Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase." SIGNOR-143387 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 CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 BTO:0000671 16103124 t gcesareni "Moreover, app stabilized tip60 through cdk-dependent phosphorylation" SIGNOR-139649 CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser90 LPGSRPGsPEREVPA 9606 BTO:0000671 16103124 t lperfetto "Moreover, app stabilized tip60 through cdk-dependent phosphorylation" SIGNOR-139653 CDK1 protein P06493 UNIPROT LIG1 protein P18858 UNIPROT "up-regulates activity" phosphorylation Ser76 EEEDEALsPAKGQKP 9606 BTO:0000567 12851383 t lperfetto "We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner." SIGNOR-103242 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser22 QASSTPLsPTRITRL 9606 18815303 t gcesareni "Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm" SIGNOR-181310 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser390 EEERLRLsPSPTSQR 9606 18815303 t gcesareni "Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm" SIGNOR-181314 CDK1 protein P06493 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser96 SFSVKDPsPLYDMLR 9606 15735705 t lperfetto "Cdc2p34 phosphorylates mdmx on ser 96 in vitro. Mutation within this site (mdmx(s96a)) impairs, whereas phosphomimic substitution (mdmx(s96d)) increases the cytoplasmic localization of mdmx, suggesting that cdk2/cdc2p34 phosphorylation is required for export of mdmx from the nucleus" SIGNOR-134388 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 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 SIGNOR-C17 12058066 t gcesareni "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-89601 CDK1 protein P06493 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-161801 CDK1 protein P06493 UNIPROT PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 SIGNOR-C17 15541388 t llicata "Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles." SIGNOR-130439 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 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 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Thr292 PQLQAHStPHPDDFA 9606 BTO:0000567 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 CDK1 protein P06493 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser23 GAGGYTQsPGGFGSP 9606 1318195 t llicata "Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell" SIGNOR-16971 CDK1 protein P06493 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser29 QSPGGFGsPAPSQAE 9606 1318195 t llicata "Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell" SIGNOR-16975 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 t "The effect has been demonstrated using Q01196-8." gcesareni "Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction." SIGNOR-138920 CDK1 protein P06493 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser439 AGSPFQSsPLSLGSR 9606 SIGNOR-C17 16880739 t llicata "Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis." SIGNOR-148354 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 BTO:0000093 11078726 t gcesareni "Stoichiometric phosphorylation of human p53 at ser315 stimulates p53-dependent transcription." SIGNOR-84256 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 SIGNOR-C17 20808790 t gcesareni "The mitochondrial kinase activity of cyclin b1/cdk1 was found to specifically phosphorylate p53 at ser-315 residue, leading to enhanced mitochondrial atp production and reduced mitochondrial apoptosis." SIGNOR-167779 CDK1 protein P06493 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 t gcesareni "We show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of beta-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2)" SIGNOR-139465 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Ser54 RVKALPLsPRKRLGD 9606 SIGNOR-C83 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-67544 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 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 CDK2 protein P24941 UNIPROT CROCC protein Q5TZA2 UNIPROT down-regulates phosphorylation Ser1460 APRPVPGsPARDAPA 9606 22610972 t llicata "Finally, phosphorylation of tax1bp2 at serine-763 by cyclin-dependent kinase (cdk)2 abolished the tax1bp2-mediated p38 activation and tumor-suppressive activity, indicating that tax1bp2 can adapt cdk2 signaling to the p38/p53/p21 pathway." SIGNOR-197593 CDK2 protein P24941 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 t lperfetto "Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1." SIGNOR-150028 CDK2 protein P24941 UNIPROT FOXO4 protein P98177 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-183655 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-252891 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Ser54 ELQPMPTsPGVDLQS 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-100885 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 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 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/cdk4" SIGNOR-62365 CDK2 protein P24941 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C16 21902831 t gcesareni "Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation." SIGNOR-176509 CDK2 protein P24941 UNIPROT NFYA protein P23511 UNIPROT "up-regulates activity" phosphorylation Ser326 FSPKEKDsPHMQDPN BTO:0000007 12857729 t llicata "Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa)" SIGNOR-250743 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1270 SDLPVPRtPGSGAGE 9606 10995387 t llicata "Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter." SIGNOR-82137 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1350 ISRTTSAtPLKDNTQ 9606 10995387 t llicata "Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter." SIGNOR-82141 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 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 22334659 t gcesareni "Phosphorylation at thr-116 and thr-226 of orc2 occurs by cyclin-dependent kinase during the s phase and is maintained until the m phase. Phosphorylation of orc2 at thr-116 and thr-226 dissociated the orc2-5 from chromatin." SIGNOR-196048 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 SIGNOR-C83 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-116476 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 t miannu "Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome" SIGNOR-74708 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates phosphorylation Ser1112 LLEDGSEsPAKRICP 9606 BTO:0001938 12006580 t gcesareni "When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity" SIGNOR-87492 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1068 HKNETMLsPREKIFY 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-104667 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1080 IFYYFSNsPSKRLRE 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-104671 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser413 VRYIKENsPCVTPVS 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-104675 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser639 DEICIAGsPLTPRRV 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-104679 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 CDK2 protein P24941 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser44 LENDFFNsPPRKTVR 9606 SIGNOR-C16 15004009 t miannu "Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia" SIGNOR-123231 Silmitasertib chemical CID:24748573 PUBCHEM CSNK2A2 protein P19784 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0005475 21159648 t Federica "In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2." SIGNOR-261130 SIRT1 protein Q96EB6 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-256662 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 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 22945643 t lperfetto "Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation." SIGNOR-198934 sitagliptin chemical CHEBI:40237 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000131 20927248 t Luana "Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor" SIGNOR-257883 "Sitagliptin phosphate monohydrate" chemical CID:11591741 PUBCHEM DPP4 protein P27487 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206923 CHEK2 protein O96017 UNIPROT PML protein P29590 UNIPROT unknown phosphorylation Ser117 ESLQRRLsVYRQIVD 9606 12402044 t llicata "Hcds1/chk2 phosphorylates pml at ser 117 in vitro. hcds1/chk2 phosphorylates pml in vivo." SIGNOR-94872 clemastine chemical CHEBI:3738 ChEBI P2RX7 protein Q99572 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 21262970 t Luana "Clemastine potentiates the human P2X7 receptor by sensitizing it to lower ATP concentrations." SIGNOR-257893 CHUK protein O15111 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t gcesareni "Cascade of distinct histone modifications during collagenase gene activation." SIGNOR-98365 CNTFR protein P26992 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 10582086 f gcesareni "Clc/clf activates stat1 and stat3." SIGNOR-72774 crizotinib chemical CHEBI:64310 ChEBI ALK protein Q9UM73 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191133 SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR "form complex" 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-235188 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 t gcesareni "CK2 hyperactivates AKT by phosphorylation at Ser129" SIGNOR-252595 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002861 18682241 t flangone "We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity." SIGNOR-242052 CTF1 protein Q16619 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9030543 t gcesareni "In the cos-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for ct-1 signaling" SIGNOR-46509 CTSB protein P07858 UNIPROT S protein P0DTC2 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000195 32142651 t miannu "SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines." SIGNOR-260738 CTSL protein P07711 UNIPROT S protein P0DTC2 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000195 32142651 t miannu "SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines." SIGNOR-260737 Dinaciclib chemical CID:46926350 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191322 DNM2 protein P50570 UNIPROT MYO1C protein O00159 UNIPROT up-regulates binding 9606 17257598 t miannu "Dynamin bind directly to the sh3 domain of myo1e / an intriguing possibility is that binding of dynamin and synaptojanin to myo1e tail may activate motor activity since it has been demonstrated that myo1e atpase activity is autoinhibited by its sh3 domain" SIGNOR-152910 DNM2 protein P50570 UNIPROT VAV1 protein P15498 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000584 23537630 t "Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability." SIGNOR-259080 DNMBP protein Q6XZF7 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-260547 DNMT3B protein Q9UBC3 UNIPROT HOXB13 protein Q92826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 22808286 f miannu "EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex." SIGNOR-254145 SOX17 protein Q9H6I2 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-72006 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" ubiquitination 7227 22162134 t lperfetto "The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch" SIGNOR-219269 DTNB protein O60941 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-255990 DTX1 protein Q86Y01 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates binding 9606 11564735 t gcesareni "Through its binding to p300, dtx1 inhibited transcriptional activation by the neural-specific helix-loop-helix-type transcription factor mash1" SIGNOR-110626 DTX1 protein Q86Y01 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 11564735 t gcesareni "We found that a significant fraction of dtx1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300." SIGNOR-110629 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 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" ubiquitination 10090 BTO:0000165 11226752 t gcesareni "Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis" SIGNOR-236870 DTX1 protein Q86Y01 UNIPROT TCF3 protein P15923 UNIPROT down-regulates 9606 BTO:0000776 9528794 f gcesareni "Our experiments indicate that deltex expression alone is suffcient to inhibit e47." SIGNOR-56141 DTX4 protein Q9Y2E6 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates ubiquitination 9606 BTO:0000938 10531053 t gcesareni "Nlrp4 negatively regulates type i interferon signaling by targeting the kinase tbk1 for degradation via the ubiquitin ligase dtx4" SIGNOR-71565 DUSP10 protein Q9Y6W6 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 10391943 t gcesareni "Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk" SIGNOR-68986 EFEMP2 protein O95967 UNIPROT ELN protein P15502 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-252136 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 DUSP4 protein Q13115 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 9020184 t lperfetto "Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2" SIGNOR-27756 DUSP9 protein Q99956 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 21908610 t gcesareni "In addition, although mutation of ser-58 to either alanine or glutamic acid does not affect the intrinsic catalytic activity of dusp9/mkp-4, phospho-mimetic (ser-58 to glu) substitution inhibits both the interaction of dusp9/mkp-4 with erk2 and p38? In vivo and its ability to dephosphorylate and inactivate these map kinases." SIGNOR-176586 DUSP9 protein Q99956 UNIPROT MAPK3 protein P27361 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-176589 dutasteride chemical CHEBI:521033 ChEBI ESR2 protein Q92731 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-191445 DUX4 protein Q9UBX2 UNIPROT HEY1 protein Q9Y5J3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24278031 f miannu "HEY1, a repressor of myogenesis, is activated by DUX4 through a MaLR promoter." SIGNOR-253840 DVL1P1 protein P54792 UNIPROT CCDC88C protein Q9P219 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Daple binds to dvl and functions as a negative regulator of the wnt signalling pathway." SIGNOR-199448 DVL1P1 protein P54792 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells." SIGNOR-199451 DVL1P1 protein P54792 UNIPROT PRKCA protein P17252 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Our findings suggest a molecular interaction between pka, hdpr1, and dvl and a possible contribution of this interaction to tumorigenesis." SIGNOR-199454 DVL1P1 protein P54792 UNIPROT PRKCB protein P05771 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Taken together, these results suggest that site-specific dvl2 phosphorylation is required for dvl2 association with pkc_. This interaction is likely to be one of the mechanisms essential for wnt3a-dependent neurite outgrowth." SIGNOR-199457 DVL1 protein O14640 UNIPROT APC protein P25054 UNIPROT "down-regulates activity" binding 9606 10330181 t amattioni "Dvl-1 inhibits Axin-promoted GSK-3_-dependent phosphorylation of _-catenin and APC, leading to beta-catenin stabilization." SIGNOR-167951 DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 15735151 f amattioni "Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1." SIGNOR-134285 DVL1 protein O14640 UNIPROT DAAM1 protein Q9Y4D1 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-185271 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 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-252905 DYRK1A protein Q13627 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 24119401 t lperfetto "Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells." SIGNOR-202838 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT "up-regulates activity" phosphorylation Ser529 SNSGRARsDPTHQHR 9606 BTO:0001938 17229891 t llicata "In the present study, we show that DYRK1A autophosphorylates, via an intramolecular mechanism, on Ser-520, in the PEST domain of the protein. | Instead, we demonstrate that this phosphorylation allows the binding of 14-3-3beta, which in turn stimulates the catalytic activity of DYRK1A." SIGNOR-251090 DYRK1A protein Q13627 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation 9606 12138125 t "Dyrk1 acts synergistically with Shh to induce transcription of a Gli-promoter-driven luciferase reporter gene and of endogenous alkaline phosphatase." gcesareni "Dyrk1 phosphorylates gli1 on more than one domain." SIGNOR-90809 DYRK1A protein Q13627 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser641 YRYPRPAsVPPSPSL 9534 BTO:0000298 14593110 t miannu "DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity." SIGNOR-260632 DYRK1B protein Q9Y463 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 t lperfetto "Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation" SIGNOR-235805 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr271 CQLGQRIyQYIQSRF 9606 10910078 t lperfetto "Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site" SIGNOR-79806 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr273 LGQRIYQyIQSRFYR 9606 10910078 t lperfetto "Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site" SIGNOR-79810 DYRK1B protein Q9Y463 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser641 YRYPRPAsVPPSPSL 9534 BTO:0000298 14593110 t miannu "DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity." SIGNOR-260633 DYRK1B protein Q9Y463 UNIPROT HNF1A protein P20823 UNIPROT up-regulates phosphorylation Ser249 IQRGVSPsQAQGLGS 9606 BTO:0000887;BTO:0001103 11980910 t lperfetto "Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk" SIGNOR-86728 E2F1 protein Q01094 UNIPROT CDC25A protein P30304 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 11154267 f 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-245468 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 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 E2F1 protein Q01094 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 8649818 f lperfetto "We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB." SIGNOR-245471 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 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 E2F1 protein Q01094 UNIPROT SERPINB5 protein P36952 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001938 20197383 f lperfetto "Importantly, we show that E2F1-mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization." SIGNOR-254135 ECM stimulus SIGNOR-ST20 SIGNOR "A2/b1 integrin" complex SIGNOR-C160 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-259043 ECSIT protein Q9BQ95 UNIPROT MAVS protein Q7Z434 UNIPROT "up-regulates activity" binding 9606 "BTO:0000567; BTO:0002181" 22588174 t Giorgia "ECSIT interacts with IPS-1|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation" SIGNOR-260371 EDA protein Q92838 UNIPROT EDA2R protein Q9HAV5 UNIPROT up-regulates binding 9606 BTO:0001253 12084975 t gcesareni "Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed." SIGNOR-90040 EDA protein Q92838 UNIPROT EDAR protein Q9UNE0 UNIPROT up-regulates binding 9606 BTO:0001253 18304980 t gcesareni "Ultimately, in mammals, eda-a1 and eda-a2 trimers each bind a different receptor, edar and xedar, respectively, through their trimerized tnf domain." SIGNOR-161109 EDN1 protein P05305 UNIPROT EDNRA protein P25101 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-145759 EDNRA protein P25101 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-257378 EDNRB protein P24530 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-257379 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 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" SIGNOR-56901 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni "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-52005 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 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-56904 EFNA3 protein P52797 UNIPROT EPHA7 protein Q15375 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" SIGNOR-52384 EFNA5 protein P52803 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Members of the epha subfamily of receptor tyrosine kinases and their ephrin-a ligands have been implicated in the guidance of retinal axons along the anterior-posterior axis of the chick optic tectum." SIGNOR-52467 EGF protein P01133 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 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-251785 EGF protein P01133 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 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 EGFR protein P00533 UNIPROT CALM1 protein P62158 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 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-24778 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1110 GSVQNPVyHNQPLNP 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-236483 EGFR protein P00533 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 t 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-106500 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr307 MRHVSISyDIPPTPG -1 10734310 t lperfetto "Gab1 is also phosphorylated in response to epidermal growth factor (egf) but is unable to induce tubule formation. nine tyrosines are phosphorylated by both receptors. Three of them (y307, y373, y407) bind phospholipase c-gamma (plc-gamma)." SIGNOR-233233 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr373 ASDTDSSyCIPTAGM 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-236408 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 EGFR protein P00533 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000375 15284024 f "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-252088 EGFR protein P00533 UNIPROT KRT14 protein P02533 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 11875647 f "Regulation of expression" miannu "UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK." SIGNOR-251901 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr771 IGTAEPDyGALYEGR 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-20984 EGFR protein P00533 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 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-167646 EGFR protein P00533 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 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 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 EGR1 protein P18146 UNIPROT COL4A2 protein P08572 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21931594 f Regulation miannu "Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)" SIGNOR-251918 EGR1 protein P18146 UNIPROT COL7A1 protein Q02388 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21931594 f Regulation miannu "Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)" SIGNOR-251920 EGR1 protein P18146 UNIPROT SF1 protein Q15637 UNIPROT "up-regulates activity" binding 10090 BTO:0004467 19106114 t miannu "GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity." SIGNOR-254914 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT "down-regulates activity" phosphorylation 9606 24714526 t miannu "HRI is an intracellular heme sensor that coordinates heme and globin synthesis in erythropoiesis by inhibiting protein synthesis of globins and heme biosynthetic enzymes during heme deficiency. HRI is a heme-regulated kinase that phosphorylates the α-subunit of eIF2 in heme deficiency, impairing another round of translational initiation and thereby inhibiting translation." SIGNOR-251817 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser83 NKEKKAVsPLLLTTT 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-85769 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr255 DLPDMKEtKYTVDKR 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-85773 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 EIF2AK4 protein Q9P2K8 UNIPROT EIF2A protein Q9BY44 UNIPROT "down-regulates activity" phosphorylation Ser265 YIATNGEsAVVQLPK 9606 BTO:0000567 25329545 t gcesareni "One of the key cellular responses to stress is the attenuation of mRNA translation and protein synthesis via the phosphorylation of eIF2 (eukaryotic translation initiation factor 2). This is mediated by four eIF2 kinases" SIGNOR-246157 EIF4A2 protein Q14240 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-108512 EIF4B protein P23588 UNIPROT EIF4A1 protein P60842 UNIPROT "up-regulates activity" binding -1 11418588 t "Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability" SIGNOR-261293 "EIF4E2/GIGYF1 complex" complex SIGNOR-C256 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 30917308 f lperfetto "4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression" SIGNOR-261012 ELF3 protein P78545 UNIPROT SPRR1B protein P22528 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 12682075 f "Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3" SIGNOR-254281 ELF3 protein P78545 UNIPROT SPRR2A protein P35326 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 10773884 f "Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter." SIGNOR-254292 EML4-ALK "fusion protein" SIGNOR-FP8 SIGNOR SMYD2 protein Q9NRG4 UNIPROT "up-regulates activity" methylation 9606 BTO:0001911 28370702 t irozzo "In the present study, we have shown that SMYD2‐mediated methylation of lysine 1610 on the EML4‐ALK fusion protein is likely to be critically important for autophosphorylation of some tyrosine residues and the oncogenic activity of the fused proteins." SIGNOR-259175 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 entinostat chemical CHEBI:132082 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-257902 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191478 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191481 enzalutamide chemical CHEBI:68534 ChEBI AR protein P10275 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194325 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 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 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 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 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys70 GKAVRGAkGHHHPHP 9606 15831498 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-135473 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT "up-regulates activity" phosphorylation Tyr596 KLPGLRTyVDPHTYE 9606 BTO:0000007 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 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT "up-regulates activity" phosphorylation Tyr602 TYVDPHTyEDPTQAV 9606 BTO:0000007 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-251116 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 EPN1 protein Q9Y6I3 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "up-regulates quantity by stabilization" binding 24789820 t lperfetto "Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth" SIGNOR-260716 EPN1 protein Q9Y6I3 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19054389 t gcesareni "Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr." SIGNOR-182562 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding 10090 BTO:0002882 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 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 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1222 PAFDNLYyWDQDPPE 9606 BTO:0000150 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 ERBB2 protein P04626 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000150 BTO:0000975;BTO:0000763 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 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 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 ERBB4 protein Q15303 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146879 ERBB4 protein Q15303 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146882 ERG protein P11308 UNIPROT ADAMTS1 protein Q9UHI8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 19396168 f miannu "ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression." SIGNOR-253910 ERG protein P11308 UNIPROT CXCL8 protein P10145 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001949 19359602 f miannu "ERG can inhibit the activity of the IL-8 promoter in a dose dependent manner." SIGNOR-253912 ERG protein P11308 UNIPROT VWF protein P04275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 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-253914 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto "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-α 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-244494 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation 9606 23616010 t lperfetto "Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1." SIGNOR-233520 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto "The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation" SIGNOR-252081 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-252085 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 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-251523 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 24890514 f apalma "The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation" SIGNOR-255573 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t lperfetto "Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity" SIGNOR-244688 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser296 SPSALSSsPNNLSPT 9606 16407412 t lperfetto "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-244681 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 t lperfetto "In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1" SIGNOR-249574 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 18267068 t lperfetto "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-249572 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 t lperfetto "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-249573 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX9 protein P48436 UNIPROT up-regulates "transcriptional regulation" 9606 20457810 f lperfetto "Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression." SIGNOR-244750 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" phosphorylation 9606 23616010 t lperfetto "Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1." SIGNOR-233523 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni "Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation." SIGNOR-118542 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f "Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival" SIGNOR-254948 ERN1 protein O75460 UNIPROT OS9 protein Q13438 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000007 18417469 f miannu "Here we characterize the function in ER quality control of two proteins derived from alternative splicing of the OS-9 gene. OS-9.1 and OS-9.2 are ubiquitously expressed in human tissues and are amplified in tumors. They are transcriptionally induced upon activation of the Ire1/Xbp1 ER-stress pathway." SIGNOR-261063 ERO1A protein Q96HE7 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-261049 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 ESR1 protein P03372 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000150 16169518 t gcesareni "Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k." SIGNOR-252675 ESR2 protein Q92731 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-253939 estriol smallmolecule CHEBI:27974 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-258585 etorphine chemical CHEBI:4912 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-258804 ETS2 protein P15036 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0001957 11175361 t miannu "we demonstrated that Ets2 is capable of binding to and transactivating the OPN promoter using gel shift and transient transfection assays" SIGNOR-259872 ETV2 protein O00321 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0001086 24583263 f irozzo "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-256009 ETV2 protein O00321 UNIPROT FLI1 protein Q01543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24727028 f miannu "We have identified a novel positive feed-forward regulatory loop in which etv2 activates expression of genes involved in vasculogenesis, including fli1." SIGNOR-203272 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 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 EZH2 protein Q15910 UNIPROT DACT3 protein Q96B18 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004094 22144423 f miannu "For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci." SIGNOR-254142 F2 protein P00734 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-41090 F2RL1 protein P55085 UNIPROT AREG protein P15514 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-254855 F2RL1 protein P55085 UNIPROT CD44 protein P16070 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-254843 F2RL1 protein P55085 UNIPROT CORO1C protein Q9ULV4 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-254838 F2RL1 protein P55085 UNIPROT GNAS protein Q5JWF2 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-256752 F2RL2 protein O00254 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-257360 F2RL3 protein Q96RI0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22318735 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-196012 F2RL3 protein Q96RI0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 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-196015 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 F2R protein P25116 UNIPROT CD44 protein P16070 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-254851 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22972936 t milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-199010 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates 9606 BTO:0000007 22972936 t milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-192042 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 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 F2R protein P25116 UNIPROT LATS1 protein O95835 UNIPROT down-regulates 9606 BTO:0000007 22972936 f "Here we report that stimulation of protease-activated receptors (PARs) activates YAP/TAZ by decreasing phosphorylation and increasing nuclear localization." milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-192045 FARP2 protein O94887 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19276662 f "Regulation of expression" miannu "FIR induced the expression of IAP1, IAP2, XIAP Survivin, MnSOD, TNFalpha, pAKT and IL-1alpha" SIGNOR-251761 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 14965271 t lperfetto "Fas (CD95) is activated by its natural ligand FasL" SIGNOR-216292 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 BTO:0000671 9228058 t lperfetto "The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl)" SIGNOR-49688 FASN protein P49327 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0001130 18838960 f lperfetto "Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer" SIGNOR-242878 FASN protein P49327 UNIPROT Lipogenesis phenotype SIGNOR-PH30 SIGNOR up-regulates 9606 20373869 f lperfetto "Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis" SIGNOR-242874 FBN1 protein P35555 UNIPROT MMP1 protein P03956 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16442122 f "Regulation of expression" miannu "In this study we show that a fibrillin-1 fragment containing a EGFEPG sequence that conforms to a putative GxxPG elastin-binding protein (EBP) consensus sequence upregulates the expression and production of matrix metalloproteinase (MMP)-1 by up to ninefold in a cell culture system. Mutations in the gene for fibrillin-1 cause Marfan syndrome (MFS), a common hereditary disorder of connective tissue" SIGNOR-251887 FBN1 protein P35555 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" 9606 17242066 f Regulation miannu "Fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling." SIGNOR-251889 FBXO11 protein Q86XK2 UNIPROT BCL6 protein P41182 UNIPROT down-regulates binding 9606 BTO:0000785 22113614 t miannu "Fbxo11 targets bcl6 for degradation" SIGNOR-177652 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 9784611 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-60751 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys21 EGPRDGLkKERLLDD 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-26573 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 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 FCER1A protein P12319 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-254959 FCER1G/FCER1G complex SIGNOR-C199 SIGNOR 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-254962 fentanyl chemical CHEBI:119915 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-258938 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr713 REEADGVyAASGGLR 9606 BTO:0002181 8663427 t llicata "Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713." SIGNOR-42655 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr811 RPSFSTIyQELQSIR 9606 BTO:0002181 8663427 t llicata "Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713." SIGNOR-42659 FFAR2 protein O15552 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-257342 FFAR3 protein O14843 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-256821 FGA protein P02671 UNIPROT ITGAX protein P20702 UNIPROT up-regulates binding 9606 BTO:0000130 7679388 t gcesareni "To map the binding sites for four distinct ligands for mac-l: ic3b, fibrinogen, icam-1. __the i domain on the ot chain of mac-1 is an important recognition site for all four ligands." SIGNOR-31320 FGA protein P02671 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-253372 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 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 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 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 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 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 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr410 GVVDSGVyAVPPPAE 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-98569 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 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr730 SNCTNELyMMMRDCW 10116 BTO:0003293 19224897 t lperfetto "Furthermore, under conditions in which wild-type or mutant FGFR1 are overexpressed, Y463, Y583, Y585, and Y730 are dispensable for tyrosine phosphorylation of Shc, the mitogen-activated protein kinase (MAPK) response, and stimulation of FGFR1-mediated cell proliferation and differentiation" SIGNOR-236191 FGFR1 protein P11362 UNIPROT FRS2 protein Q8WU20 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0002809 9182757 t fspada "In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway." SIGNOR-236944 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 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 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr648 DVHNLDYyKKTTNGR 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3." SIGNOR-106734 FGFR3 protein P22607 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0000527 22891331 t llicata "Fgfrs phosphorylate pten at tyrosine 240" SIGNOR-191797 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 FGR protein P09769 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 12387730 t gcesareni "Phosphorylated on tyrosine residues upon activation. Phosphorylation at tyr-925 is important for interaction with grb2 and depends on the complex formation between fak and the src-kinase fgr." SIGNOR-94405 fingolimod chemical CHEBI:63115 ChEBI S1PR1 protein P21453 UNIPROT down-regulates "chemical inhibition" 9606 22225501 t gcesareni "Sphingosine-1-phosphate (s1p(1)) receptor agonists such as fingolimod (fty-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis." SIGNOR-195343 FIP1L1 protein Q6UN15 UNIPROT FIP1L1/CPSF1 complex SIGNOR-C53 SIGNOR "form complex" 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-121649 FKBP8 protein Q14318 UNIPROT MTOR protein P42345 UNIPROT down-regulates binding 9606 17991864 t gcesareni "Fkbp38 binds to mtor and inhibits its activity in a manner similar to that of the fkbp12-rapamycin complex." SIGNOR-159013 FLI1 protein Q01543 UNIPROT IL10 protein P22301 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 20879862 f "In terms of cytokine expression, increased FLI-1 levels specifically enhanced IL-10 expression" SIGNOR-254516 FLI1 protein Q01543 UNIPROT KLF1 protein Q13351 UNIPROT "down-regulates activity" binding 10090 BTO:0004475 12556498 t irozzo "FLI-1 represses the transcriptional activity of EKLF.Our data indicate that the ETS domain of FLI-1 is absolutely required to inhibit EKLF activity. Since the FLI-1 ETS domain interacts with the DNA binding domain of EKLF, one possibility could be that FLI-1 inhibits the binding of EKLF to its DNA targets" SIGNOR-256044 FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 BTO:0001271 12681969 t gcesareni "Flt3 is activated by binding of its natural flt3-ligand (flt3-l)," SIGNOR-99750 FLT3 protein P36888 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16146838 t lperfetto "Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1." SIGNOR-250563 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0001545 30552988 f miannu "Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC." SIGNOR-260132 FLT3 protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 BTO:0004760 15574429 f "Furthermore, a small but reproducible growth/survival advantage was observed in both TF-1 and TF-1/ITD cells when SHP-1 expression was knocked down by RNAi. Taken together, these data provide the first evidence that suppression of SHP-1 by FLT3/ITD signaling may be another mechanism contributing to the transformation by FLT3/ITD mutations" SIGNOR-259950 Fluocinonide chemical CHEBI:5109 ChEBI SMO protein Q99835 UNIPROT "up-regulates activity" binding 10090 BTO:0004278 20439738 t gcesareni "we identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling." SIGNOR-248218 fluoxetine chemical CHEBI:5118 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 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 fluoxymesterone chemical CHEBI:5120 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-259264 flutamide chemical CHEBI:5132 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001321 18571420 t Luana "Among the compounds obtained, N-[4-[(benzyl)(4-nitrophenyl)amino]-1-methylpyrrole-2-carbonyl]pyrrolidine (22) is as potent an AR antagonist as the typical anilide-type AR antagonists hydroxyflutamide and bicalutamide. " SIGNOR-257807 fosinoprilat chemical CHEBI:116962 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-258613 FOXA1 protein P55317 UNIPROT NFIX protein Q14938 UNIPROT up-regulates binding 9606 BTO:0001129 24801505 t miannu "Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex." SIGNOR-205082 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f "Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice." SIGNOR-254973 FOXO1 protein Q12778 UNIPROT SMURF1 protein Q9HCE7 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000165 15125842 t "The IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors;" SIGNOR-256258 FOXO3 protein O43524 UNIPROT NOTCH3 protein Q9UM47 UNIPROT "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-244079 FOXO3 protein O43524 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates quantity" "transcriptional regulation" BTO:0000007 22848740 t "SGK-1 Negatively Regulates LKB1 Expression via FOXO3 Transcription Factor" SIGNOR-255758 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 FOXO proteinfamily SIGNOR-PF27 SIGNOR CITED2 protein Q99967 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 18158893 f gcesareni "Foxo3a induces expression of cited2" SIGNOR-252933 FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-253016 FOXO proteinfamily SIGNOR-PF27 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-252938 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 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 PMC3619734 f areggio "Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1induction." SIGNOR-254990 FRAT1 protein Q92837 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 9635432 t lperfetto "The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway" SIGNOR-227994 FRAT1 protein Q92837 UNIPROT GSK3B protein P49841 UNIPROT up-regulates binding 9606 SIGNOR-C110 9635432 t gcesareni "The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway" SIGNOR-58219 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT "down-regulates activity" binding 10090 BTO:0005787 24627466 t lperfetto "Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-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-251715 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT "down-regulates activity" binding 9606 22037168 t gcesareni "Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality" SIGNOR-235134 furtrethonium chemical CHEBI:134764 ChEBI CHRM2 protein P08172 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-258643 FYN protein P06241 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Tyr453 ASHVDNEySQPPRNS -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-251151 FYN protein P06241 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Tyr15 EKIGEGTyGTVFKAK 9606 BTO:0000007 14757045 t "Constitutively active Fyn phosphorylated Tyr15 of Cdk5. Fyn Facilitates Kinase Activity of Cdk5 Via Tyr15 Phosphorylation" SIGNOR-251156 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 8162590 t gcesareni "The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase." SIGNOR-36557 FYN protein P06241 UNIPROT FYB1 protein O15117 UNIPROT "up-regulates activity" phosphorylation Tyr595 IEDDQEVyDDVAEQD 9606 BTO:0000661 10570256 t " two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription." SIGNOR-251163 FYN protein P06241 UNIPROT FYB1 protein O15117 UNIPROT "up-regulates activity" phosphorylation Tyr651 LDMGDEVyDDVDTSD 9606 BTO:0000661 10570256 t " two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription." SIGNOR-251164 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates phosphorylation Tyr1325 RLLEGNFyGSLFSVP 9606 19834457 t gcesareni "The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation site. Tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum. Tyr 1325 was most prominently phosphorylated by fyn in vitro." SIGNOR-188527 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 FYN protein P06241 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-249340 FYN protein P06241 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 11005864 t lperfetto "Study of t cells from a fyn-deficient tcr transgenic mouse also showed that fyn was required for tyrosine phosphorylation and activation of vav induced by both antagonist and agonist peptides." SIGNOR-82287 FZD1 protein Q9UP38 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-80595 FZD1 protein Q9UP38 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 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-253512 FZD2 protein Q14332 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-258965 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 FZD7 protein O75084 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism." SIGNOR-198831 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 FZD8 protein Q9H461 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000971 21078818 t amattioni "Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane 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-169638 FZD9 protein O00144 UNIPROT SPRY4 protein Q9C004 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002058 15705594 f miannu "In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity." SIGNOR-253035 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0002181 23279204 f SARA "G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs" SIGNOR-260984 GAB2 protein Q9UQC2 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica "The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival" SIGNOR-204966 GABARAPL1 protein Q9H0R8 UNIPROT SQSTM1 protein Q13501 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17580304 t lperfetto "P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha" SIGNOR-156304 GABARAP protein O95166 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 11146101 t lperfetto "N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions" SIGNOR-219391 GABARAP protein O95166 UNIPROT TBC1D25 protein Q3MII6 UNIPROT up-regulates binding 9606 21383079 t gcesareni "In this study, we report evidence demonstrating that oatl1, a putative rab guanosine triphosphatase-activating protein (gap), is a novel binding partner of atg8 homologues in mammalian cells. Oatl1 is recruited to isolation membranes and autophagosomes through direct interaction with atg8 homologues and is involved in the fusion between autophagosomes and lysosomes through its gap activity." SIGNOR-172536 GALR1 protein P47211 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-256966 GALR2 protein O43603 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-257296 GDF2 protein Q9UK05 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-183535 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 16362042 t gcesareni "Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. 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-143109 GNAI1 protein P63096 UNIPROT HCK protein P08631 UNIPROT "up-regulates activity" binding -1 11007482 t "Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases." SIGNOR-256528 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 GATA1 protein P15976 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR "up-regulates activity" 10090 BTO:0000843 12032775 f "Studies involving point mutants of GATA-1 have shown that a direct physical interaction between GATA-1 and FOG-1 is essential for normal human erythroid and megakaryocyte maturation in vivo." SIGNOR-259961 GATA1 protein P15976 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-254162 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 GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0001086 24583263 f irozzo "We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression." SIGNOR-256007 GATA3 protein P23771 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 f fspada "Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage." SIGNOR-78830 GATA6 protein Q92908 UNIPROT SEMA3C protein Q99985 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 19666519 f 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-253150 GATOR1 complex SIGNOR-C192 SIGNOR RRAGA protein Q7L523 UNIPROT "down-regulates activity" "gtpase-activating protein" -1 23723238 t "GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer." SIGNOR-253562 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 GDF5 protein P43026 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004291 16716349 f Regulation miannu "GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription." SIGNOR-251871 GDF5 protein P43026 UNIPROT Ossification phenotype SIGNOR-PH74 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-252419 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 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 GDP smallmolecule CHEBI:17552 ChEBI GNAI1 protein P63096 UNIPROT down-regulates "chemical inhibition" 9606 12040175 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-88226 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 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-150549 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192623 GFI1B protein Q5VTD9 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "Here, we analyzed the MEF2C 5'-region, thus identifying potential regulatory binding sites for GFI1B, basic helix-loop-helix proteins, STAT5, and HOXA9/HOXA10. Chromatin immunoprecipitation and overexpression analyses demonstrated direct activation by GFI1B and LYL1 and inhibition by STAT5." SIGNOR-254206 GFI1 protein Q99684 UNIPROT BAX protein Q07812 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 17213822 f miannu "Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo." SIGNOR-254203 GFI1 protein Q99684 UNIPROT CYP27B1 protein O15528 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 15947108 f miannu "Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells." SIGNOR-254205 GGCX protein P38435 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10116 BTO:0004850 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-261231 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 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 GH1 protein P01241 UNIPROT PRLR protein P16471 UNIPROT up-regulates binding 9606 BTO:0000887 7984244 t gcesareni "Hprl does not bind to the hgh receptor, but hgh binds to both the hghr and hprlr, and mutagenesis studies have shown that the receptor-binding sites on hgh overlap." SIGNOR-35575 GIGYF1 protein O75420 UNIPROT "EIF4E2/GIGYF1 complex" complex SIGNOR-C256 SIGNOR "form complex" binding 9606 30917308 t lperfetto "4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression" SIGNOR-261011 GIGYF2 protein Q6Y7W6 UNIPROT "EIF4E2/GIGYF2 complex" complex SIGNOR-C257 SIGNOR "form complex" binding 9606 BTO:0000568 22751931 t SARA "A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated." SIGNOR-261009 GLI1 protein P08151 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 3563490 f gcesareni "The gli gene is a member of a select group of cellular genes that are genetically altered in primary human tumors." SIGNOR-235196 GLI2 protein P10070 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-209635 GMIP protein Q9P107 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-260507 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 GNAI1 protein P63096 UNIPROT TNFAIP8 protein O95379 UNIPROT "up-regulates activity" binding 9606 20607800 t "TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation" SIGNOR-256491 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 GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT "down-regulates activity" binding 9606 19703466 t "Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)" SIGNOR-256499 GNAS protein P63092 UNIPROT HCK protein P08631 UNIPROT "up-regulates activity" binding -1 11007482 t "Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases." SIGNOR-256529 GNAS protein P63092 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR "down-regulates activity" binding -1 10224115 f "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-256524 GNAS protein P63092 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 t gcesareni "Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7." SIGNOR-252678 GNG12 protein Q9UBI6 UNIPROT PIK3CA protein P42336 UNIPROT 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-141795 GNRH1 protein P01148 UNIPROT EGR1 protein P18146 UNIPROT "up-regulates activity" binding 10090 BTO:0004467 19106114 t miannu "EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity." SIGNOR-254918 GNRH1 protein P01148 UNIPROT EGR1 protein P18146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004467 19106114 f miannu "GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity." SIGNOR-254917 GOLGA2 protein Q08379 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 16489344 t Giulio "Previous studies have implicated the GM130–GRASP65 complex in diverse Golgi functions. Therefore, GM130–GRASP65 interactions are required for Golgi ribbon formation.|A surprising clue came from the observation that GM130 was required for stability of GRASP65." SIGNOR-260601 GOLPH3 protein Q9H4A6 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 BTO:0000018;BTO:0005011 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 GOLPH3 protein Q9H4A6 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR "up-regulates activity" 9606 BTO:0000018;BTO:0005011 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-253556 GPI protein P06744 UNIPROT AMFR protein Q9UKV5 UNIPROT up-regulates binding 9606 12527360 t gcesareni "Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r)" SIGNOR-97270 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 GPR132 protein Q9UNW8 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-257444 GPR174 protein Q9BXC1 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-256900 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 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 GRB2 protein P62993 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica "The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival" SIGNOR-204969 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 GRIP1 protein Q9Y3R0 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-83883 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT "up-regulates activity" phosphorylation Ser334 PLGDDEAsATVSKTE -1 8617805 t "That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated." SIGNOR-251189 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT "up-regulates activity" phosphorylation Ser338 DEASATVsKTETSQV -1 8617805 t "That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated." SIGNOR-251190 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Ser332 TEDSTQTsDTATNST -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-249680 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 GRK2 protein P25098 UNIPROT PDE6G protein P18545 UNIPROT "up-regulates activity" phosphorylation Thr62 PGMEGLGtDITVICP 9606 BTO:0000007 11502744 t "Rod PDEγ is predominantly phosphorylated by GRK2 at the Thr-62. GRK2 is required for the stimulatory effect of rod PDEγ on both the EGF- and thrombin-dependent activation of p42/p44 MAPK" SIGNOR-251459 GRK2 protein P25098 UNIPROT RPLP2 protein P05387 UNIPROT up-regulates phosphorylation Ser102 KDEKKEEsEESDDDM 9606 12379128 t gcesareni "The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity." SIGNOR-94254 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 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t "Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization." SIGNOR-251193 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser396 GHQGTVPsDNIDSQG -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-251195 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 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-251205 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser375 GTLRTSIsVERQIHK 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-251206 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 g-secretase complex SIGNOR-C98 SIGNOR NOTCH4 protein Q99466 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-209729 g-secretase complex SIGNOR-C98 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR "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-254328 GSK1059615 chemical CHEBI:71955 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252667 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192774 GSK3A protein P49840 UNIPROT GSK3A protein P49840 UNIPROT up-regulates phosphorylation Tyr279 RGEPNVSyICSRYYR 9606 BTO:0000527 18701488 t gcesareni "Gsk3a is activated by phosphorylation at tyr-279." SIGNOR-180035 GSK3A protein P49840 UNIPROT GYS1 protein P13807 UNIPROT down-regulates phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 t gcesareni "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-118927 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 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 1846781 t lperfetto "Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity." SIGNOR-21776 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 UNIPROT up-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-159429 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 16293724 t lperfetto "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-227889 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto "GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation" SIGNOR-227874 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Thr481 HVQRVLRtPGRQSPG 9606 BTO:0000007 10581160 t "Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP" SIGNOR-251222 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 BTO:0000586 SIGNOR-C110 SIGNOR-C110 9734785 t lperfetto "Interaction with beta-catenin and GSK-3beta was required for the Axin-mediated beta-catenin reduction." SIGNOR-60046 GSK3B protein P49841 UNIPROT CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 t lperfetto "We have previously shown that both basal and camp-induced degradation of cyclin d3 in reh cells is dependent on thr-283 phosphorylation by glycogen synthase kinase-3beta (gsk-3beta)." SIGNOR-142880 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 14536078 t gcesareni "Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380" SIGNOR-118559 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 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr514 PATPKYAtPAPSAKS 9606 BTO:0000938 16611631 t lperfetto "Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5" SIGNOR-145999 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 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-141799 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "down-regulates activity" phosphorylation Thr509 PVFDLTTtPKGGTPA 10116 BTO:0000938 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 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "down-regulates activity" phosphorylation Thr514 TTTPKGGtPAGSARG 10116 BTO:0000938 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 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 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 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-139316 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 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser641 YRYPRPAsVPPSPSL 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-251239 GSK3B protein P49841 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 21658600 t gcesareni "We demonstrate that gsk-3 phosphorylates serine 86 of the p53-acetyltransferase tip60. A tip60(s86a) mutant was less active to induce p53 k120 acetylation, histone 4 acetylation, and expression of puma" SIGNOR-174049 INTS10 protein Q9NVR2 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261473 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT up-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-159473 GSK3B protein P49841 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-159438 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT up-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-159435 GSK3B protein P49841 UNIPROT 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-249347 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr529 TPGSRSRtPSLPTPP 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-249348 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 GSK690693 chemical CHEBI:90677 ChEBI AKT2 protein P31751 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193003 GSK3B protein P49841 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 15276472 t lperfetto "Gsk3 was previously shown to directly phosphorylate the n-terminal regulatory domain of nfatc1, thus antagonizing the action of calcineurin and inhibiting nuclear shuttling of nfat." SIGNOR-179784 GSK3B protein P49841 UNIPROT NFE2L1 protein Q14494 UNIPROT down-regulates phosphorylation Ser379 SQDFLLFsPEVESLP 9606 BTO:0000938 23623971 t lperfetto "Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (nrf1) and inhibits pro-survival function of nrf1" SIGNOR-193450 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 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 GSK3B protein P49841 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 18045539 t gcesareni "Phosphorylation at the gsk3 sites represses the transcriptional activity of smad1 by enhancing proteasomal degradation of psmad1cter" SIGNOR-159484 GSK3B protein P49841 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr66 NVNTKCItIPRSLDG 9606 18172167 t lpetrilli "Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation." SIGNOR-160318 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser96 TSLSDEDsGKGSQPP 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-164637 GSK3B protein P49841 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates phosphorylation Ser556 AQKSEGKsLPSSPSS 9606 BTO:0000938 16174773 t lperfetto "Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1" SIGNOR-140609 GSK3B protein P49841 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000971 11483158 t "Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity." SIGNOR-251258 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 GTF2H1 protein P32780 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser403 PEEFISLsPPHEALD -1 10428966 t "TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase." SIGNOR-251259 GTF2H2 protein Q13888 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" phosphorylation S118 LHPPPQLSPF 9606 BTO:0001538 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 Guanfacine chemical CHEBI:5558 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-258918 GUCA2A protein Q02747 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 BTO:0000672 10845107 t gcesareni "Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney" SIGNOR-78096 GUCA2B protein Q16661 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 BTO:0000672 10845107 t gcesareni "Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney." SIGNOR-78120 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 GUCY1A1 protein Q02108 UNIPROT GUCY1A3-B3 complex SIGNOR-C140 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-243983 GUCY1A2 protein P33402 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-243971 GXYLT2 protein A0PJZ3 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 22117070 t "Xylosylation in ER membrane." gcesareni "Recently, we have shown (28) that two members of the human glycosyltransferase 8 family (gt8) (29), gxylt1 and gxylt2 (glucoside-xylosyltransferase 1/2), are able to transfer the first alfa1,3-linked xylose to o-glucosylated mammalian notch egf repeats." SIGNOR-254314 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 GZMA protein P12544 UNIPROT SET protein Q01105 UNIPROT down-regulates cleavage 9606 11555662 t miannu "Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity." SIGNOR-110462 GZMB protein P10144 UNIPROT IGF2R protein P11717 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000776 11081635 t gcesareni "The serine proteinase granzyme b is crucial for the rapid induction of target cell apoptosis by cytotoxic t cells. We now present evidence that this receptor is the cation-independent mannose 6-phosphate/insulin-like growth factor receptor (ci-mpr). Inhibition of the granzyme b ci-mpr interaction prevented granzyme b cell surface binding, uptake, and the induction of apoptosis." SIGNOR-84314 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 HABP4 protein Q5JVS0 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates activity" binding 10116 15862299 t llicata "MEF2C DNA-binding activity is inhibited through its interaction with the regulatory protein Ki-1/57." SIGNOR-238283 haloperidol chemical CHEBI:5613 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-258522 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 HBB protein P68871 UNIPROT ADAMTS13 protein Q76LX8 UNIPROT "down-regulates activity" 9606 15367436 f "Regulation of binding" miannu "Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher." SIGNOR-251748 HBB protein P68871 UNIPROT AHSP protein Q9NZD4 UNIPROT "down-regulates activity" 9606 2545495 f Regulation miannu "EDRF is rapidly inactivated by hemoglobin and superoxide." SIGNOR-251750 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Y875 GLITTLHYPAPKRNK 9606 BTO:0004760 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 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR up-regulates phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 BTO:0001271 9407116 t lperfetto "The src family kinase hck interacts with bcr-abl by a kinase-independent mechanism and phosphorylates the grb2-binding site of bcr" SIGNOR-53964 HCK protein P08631 UNIPROT BCR protein P11274 UNIPROT "up-regulates activity" phosphorylation Tyr177 ADAEKPFyVNVEFHH 9534 BTO:0000298 9407116 t "Hck (and Lyn) kinase might cooperate in phosphorylating a binding site for Grb2, Tyr177, in Bcr." SIGNOR-251261 HCK protein P08631 UNIPROT CBL protein P22681 UNIPROT unknown phosphorylation 10090 BTO:0000944 10092522 t "Hck is one member of the Src-family PTKs that is able to phosphorylate Cbl. Upon enzymatic activation of Hck either by pharmacological agents or genetic mutation, Cbl becomes tyrosine phosphorylated." SIGNOR-251262 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 HCK protein P08631 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-249363 HCK protein P08631 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC -1 12244095 t "Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. Direct Phosphorylation of STAT3 on Tyr-705 by Src Family Kinases" SIGNOR-251267 HCRTR1 protein O43613 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-257012 HCRTR2 protein O43614 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-257124 HDAC1 protein Q13547 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 BTO:0000887 11684023 t gcesareni "Interaction of myod with hdac1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression." SIGNOR-111243 HDAC1 protein Q13547 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 17183360 t lperfetto "Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1." SIGNOR-217409 HDAC1 protein Q13547 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 17183360 t gcesareni "Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1." SIGNOR-151425 HDAC1 protein Q13547 UNIPROT RELN protein P78509 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-254577 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 HDAC4 protein P56524 UNIPROT HOXB13 protein Q92826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001130 19013255 f miannu "Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers." SIGNOR-254232 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates activity" deacetylation 9606 BTO:0000007 16613856 t lperfetto "HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation" SIGNOR-227547 Hemoglobin complex SIGNOR-C209 SIGNOR hb:hp complex SIGNOR-C149 SIGNOR "form complex" binding 9606 11854029 t mianuu "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-255284 hexestrol chemical CHEBI:31669 ChEBI AKR1C1 protein Q04828 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193230 hexestrol chemical CHEBI:31669 ChEBI AKR1C2 protein P52895 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193300 HEXIM1 protein O94992 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "down-regulates activity" binding 9606 BTO:0001545 18371977 t miannu "Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. The mislocalization of HEXIM1 and the increased P-TEFb-dependent transcription caused by NPMc+ suggests that the misregulated activity of PTEFb may contribute to the tumorigenesis of NPMc+ AML." SIGNOR-260135 HIC1 protein Q14526 UNIPROT ACKR3 protein P25106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 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 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 HIC1 protein Q14526 UNIPROT EFNA1 protein P20827 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 20154726 f miannu "we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers." SIGNOR-254240 HIF1A protein Q16665 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-254768 HIF1A protein Q16665 UNIPROT EPO protein P01588 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 8663540 t lperfetto "Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene." SIGNOR-253695 HIF1A protein Q16665 UNIPROT EPO protein P01588 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0000972 8756616 t "We demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells" SIGNOR-256593 HIF1A protein Q16665 UNIPROT FAM162A protein Q96A26 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001061 15082785 t Giulio "In this work, we report the identification of an HIF-1 alpha-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1 alpha through a hypoxia-responsive element on the HGTD-P promoter region." SIGNOR-260292 HIPK1 protein Q86Z02 UNIPROT PAGE4 protein O60829 UNIPROT "up-regulates activity" phosphorylation T51 PGQEREGTPPIEERK 9606 BTO:0001129 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 HIPK2 protein Q9H2X6 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 21715331 t lperfetto "Homeodomain-interacting protein kinase-2 stabilizes p27(kip1) by its phosphorylation at serine 10 and contributes to cell motility" SIGNOR-174617 HIPK2 protein Q9H2X6 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser271 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 HK2 protein P52789 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR "down-regulates activity" 10090 BTO:0000452 16892090 f "HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host" SIGNOR-259979 HK2 protein P52789 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR "up-regulates activity" 9606 18350175 f "The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase." SIGNOR-259980 HLA-G protein P17693 UNIPROT KIR2DL4 protein Q99706 UNIPROT up-regulates binding 9606 10190900 t gcesareni "Recombinant soluble kir2dl4 binds to cells expressing hla-g but not to cells expressing other hla class i molecules." SIGNOR-66132 HMGB1 protein P09429 UNIPROT HOXB3 protein P14651 UNIPROT "up-regulates activity" binding -1 8890171 t miannu "We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein." SIGNOR-219902 HMGB1 protein P09429 UNIPROT HOXD10 protein P28358 UNIPROT "up-regulates activity" binding -1 8890171 t 2 miannu "We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein." SIGNOR-240556 HMOX1 protein P09601 UNIPROT BAD protein Q92934 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000356 26722274 f irozzo "The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells." SIGNOR-256304 HMOX1 protein P09601 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates activity" 9606 10490932 t Regulation miannu "Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme" SIGNOR-251813 HNF1A protein P20823 UNIPROT UGT1A9 protein O60656 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-253973 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 HNF1B protein P35680 UNIPROT ALB protein P02768 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1673926 f Regulation miannu "VHNF1 transactivated the albumin promoter in transfection experiments" SIGNOR-251930 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 HNF4A protein P41235 UNIPROT LDLR protein P01130 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-254454 HNRNPA2B1 protein P22626 UNIPROT CDK5R1 protein Q15078 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000938 24792867 f miannu "Hnrnpa2/b1 protein directly interacts with the r1 and r2 regions ofcdk5r13_-utr and displays a negative regulatory activity on its expression" SIGNOR-205023 HOXA10 protein P31260 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-254212 HOXA10 protein P31260 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-254215 HOXC11 protein O43248 UNIPROT HNF1A protein P20823 UNIPROT up-regulates 9606 BTO:0000567;BTO:0000195 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 HOXC13 protein P31276 UNIPROT FOXN1 protein O15353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001253 21191399 f miannu "Hoxc13-dependent activation of foxn1 is part of a regulatory cascade controlling the expression of terminal differentiation markers." SIGNOR-170850 HOXD9 protein P28356 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding 9606 10523646 t miannu "We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9" SIGNOR-220721 HPS1 protein Q92902 UNIPROT BLOC-3 complex SIGNOR-C253 SIGNOR "form complex" binding 9606 20048159 t lperfetto "Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer." SIGNOR-260691 HPS3 protein Q969F9 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR "form complex" binding 9606 15030569 t lperfetto "Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6" SIGNOR-260688 HPS5 protein Q9UPZ3 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR "form complex" binding 9606 15030569 t lperfetto "Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS7" SIGNOR-260689 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 8052307 t gcesareni "In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. 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-35878 HRAS protein P01112 UNIPROT PIK3CB protein P42338 UNIPROT "up-regulates activity" binding 9606 21779497 t lperfetto "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." SIGNOR-175189 HRAS protein P01112 UNIPROT PIK3CD protein O00329 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-175192 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 HRH2 protein P25021 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-257375 HSF2 protein Q03933 UNIPROT HSPA6 protein P17066  UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12813038 f miannu "These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells." SIGNOR-254478 HSF4 protein Q9ULV5 UNIPROT DNASE2B protein Q8WZ79 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23507146 f miannu "We found that HSF4 promoted the expression and DNase activity of DLAD by directly binding to the DLAD promoter." SIGNOR-254479 HSP90AA1 protein P07900 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 15861399 t miannu "The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes." SIGNOR-251536 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 HSPA1B protein P0DMV9 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-252417 HSPA2 protein P54652 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 12391142 t gcesareni "Coimmunoprecipitation analysis revealed a physical interaction between endogenous hsp72 and ask1 in nih 3t3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ask1 and ask1-dependent apoptosis." SIGNOR-94565 HSPA5 protein P11021 UNIPROT ATF6 protein P18850 UNIPROT "down-regulates activity" binding 9606 31226023 t miannu "Similar to PERK and IRE1, ATF6 is activated by ER stress-induced dissociation from GRP78" SIGNOR-260179 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 HSPA5 protein P11021 UNIPROT ERN1 protein O75460 UNIPROT "down-regulates activity" binding 9606 31226023 t miannu "Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain" SIGNOR-260176 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 HSPB1 protein P04792 UNIPROT CASP3 protein P42574 UNIPROT down-regulates 9606 10544189 f gcesareni "Hsp27 overexpression delays poly(adp-ribose)polymerase cleavage and procaspase-3 activation." SIGNOR-71869 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 HSPG2 protein P98160 UNIPROT PTPRS protein Q13332 UNIPROT up-regulates binding 9606 11865065 t gcesareni "We demonstrate here that cptpsigma is a heparin-binding protein and that its basal lamina ligands include the heparan sulfate proteoglycans (hspgs) agrin and collagen xviii." SIGNOR-115246 HTR1A protein P08908 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-256972 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 HTR2A protein P28223 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-257227 HTR2B protein P41595 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-257022 HTR4 protein Q13639 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-257416 HTR6 protein P50406 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-257395 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 hydroxyurea chemical CHEBI:44423 ChEBI RRM2 protein P31350 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001061 14583450 t miannu "In PC3 cells, hydroxyurea inhibited hRRM2 and resulted in increased sensitivity to UV irradiation." SIGNOR-259355 "ibritumomab tiuxetan" antibody DB00078 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0002846 27497027 t miannu "Zevalin® (ibritumomab tiuxetan) is a radioactive drug product, which is the combination of a β-emitting isotope, 90Y, linked to the anti-CD20 monoclonal antibody (mAb), rituximab. It has demonstrated therapeutic efficacy with durable responses and allows delivery of ionizing radiation directly to the tumor site, while minimizing toxicity to normal tissue. Ibritumomab tiuxetan is indicated for treatment of patients with relapsed or refractory low-grade, follicular NHL" SIGNOR-259893 ibrutinib chemical CHEBI:76612 ChEBI BTK protein Q06187 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189641 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 IC-87114 chemical CHEBI:90686 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252662 ID1 protein P41134 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-241128 ID1 protein P41134 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-241125 IDE protein P14735 UNIPROT INS protein P01308 UNIPROT "down-regulates quantity by destabilization" cleavage -1 29596046 t SARA "IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds" SIGNOR-260986 IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0001690 26178471 t lperfetto "Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)" SIGNOR-253135 IDH1 protein O75874 UNIPROT "isocitric acid" smallmolecule CHEBI:30887 ChEBI "down-regulates quantity" 26178471 t lperfetto "Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)" SIGNOR-253137 IFNAR complex SIGNOR-C243 SIGNOR CCL7 protein P80098 UNIPROT "up-regulates quantity" "transcriptional activation" 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-260852 IFNAR complex SIGNOR-C243 SIGNOR JAK1 protein P23458 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-260147 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 10986460 t fspada "Molecular interactions among cytokines and cytokine receptors form the basis of many cell-signaling pathways relevant to immune function. Interferon-g (ifng) signals through a multimeric receptor complex consistingof two different but structurally related transmembrane chains: the high-affinityreceptor-binding subunit (ifn-gra) and a species-specific accessory factor (af-1 or ifn-grb)." SIGNOR-81804 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15864272 t gcesareni "The only type ii ifn, ifn-, 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-135955 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 IFNL1 protein Q8IU54 UNIPROT IFNLR1 protein Q8IU57 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-96174 IGF1 protein P05019 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0000951 17200203 f "Regulation of expression" miannu "Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts" SIGNOR-251862 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 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 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr980 YASVNPEyFSAADVY -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 kinase. We 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-246256 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 IGF1R protein P08069 UNIPROT PIK3R1 protein P27986 UNIPROT 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-179386 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "up-regulates activity" phosphorylation Ser436 TNGSIGHsPLSLSAQ 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-204728 IKBKB protein O14920 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-204736 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser695 MSQPSTAsNSLPEPA 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-251281 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser697 QPSTASNsLPEPAKK 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-251282 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser274 RSKSQSSsNCSNPIS -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-251291 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser307 TRRSRTEsITATSPA -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-251292 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 10469655 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-217400 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000150;BTO:0000782 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-217427 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser398 VDLHISNsHPLSLTS -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-178375 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser402 ISNSHPLsLTSDQYK -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-178379 IKBKG protein Q9Y6K9 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser536 SGDEDFSsIADMDFS 9606 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-129947 IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser25 AERGLGPsPAGDGPS 10090 BTO:0002572 23332762 t lperfetto "Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation." SIGNOR-209776 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 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 IL10 protein P22301 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t milica "Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling." SIGNOR-68007 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 IL11 protein P20809 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 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 IL12A protein P29459 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni "Like il-12, il-23 binds to the il-12r subunit il-12rbeta1." SIGNOR-87677 IL12A protein P29459 UNIPROT IL12RB2 protein Q99665 UNIPROT up-regulates binding 9606 11086056 t gcesareni "Il-12r beta 2 plays an essential role in mediating the biological functions of il-12 in mice." SIGNOR-84361 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 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT "up-regulates quantity by expression" "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-192477 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 IL17A protein Q16552 UNIPROT KLF3 protein P57682 UNIPROT "up-regulates quantity by expression" "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-192610 IL1B protein P01584 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-253316 IL1B protein P01584 UNIPROT ENPP1 protein P22413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000249 7479785 f miannu "Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes. IL-1 beta may be an important regulator of mineralization in chondrocytes by inhibiting TGF beta-induced PPi production and PC-1 expression." SIGNOR-252199 IL1R1 protein P14778 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 f lperfetto "The Il-1 family of ligands and receptors is primarily associated with acute and chronic inflammation." SIGNOR-171876 IL1R1 protein P14778 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" 9606 BTO:0000007 14625308 f lperfetto "Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1." SIGNOR-119208 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 IL22 protein Q9GZX6 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 17208301 t gcesareni "See table 2" SIGNOR-151880 IL22 protein Q9GZX6 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 12941475 t fspada "In addition, il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4." SIGNOR-86340 IL22RA1 protein Q8N6P7 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-124489 IL22RA1 protein Q8N6P7 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 12087100 t gcesareni "Il-22 activates jak1 and tyk2" SIGNOR-90165 IL22RA2 protein Q969J5 UNIPROT IL22 protein Q9GZX6 UNIPROT up-regulates binding 9606 BTO:0000763;BTO:0000149 11390453 t gcesareni "Il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4." SIGNOR-86113 IL31 protein Q6EBC2 UNIPROT OSMR protein Q99650 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 BTO:0001253 15184896 t gcesareni "Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor." SIGNOR-125347 IL31RA protein Q8NI17 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782 18926762 t gcesareni "Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex." SIGNOR-161342 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "IL-4R Is a 140-kd protein that binds il-4 with high affinity" SIGNOR-100762 IL4R protein P24394 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR "up-regulates activity" 10090 23582327 f "Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes" SIGNOR-256482 IL4R protein P24394 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 20824124 t "Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5" SIGNOR-254298 IL5 protein P05113 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 21106848 f "It has been reported that IL-5 family members and selected chemotactic factors can activate the PI3K-Akt pathway in human blood eosinophils" SIGNOR-254351 IL6 protein P05231 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates 10090 23531613 f "AMPK phosphorylation was increased nearly fourfold (Fig. 2C) with the high dose of IL-6" SIGNOR-255338 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT "up-regulates activity" phosphorylation Ser661 NVPDPSKsHIAQWSP -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-238625 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 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 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 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 9736715 t acerquone "Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation." SIGNOR-252597 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 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;VIRAL ABL" gcesareni SIGNOR-193372 IMPDH2 protein P12268 UNIPROT GTP smallmolecule CHEBI:15996 ChEBI "up-regulates quantity" "small molecule catalysis" -1 10930578 t lperfetto "IMPDH catalyzes the rate‐limiting step of de novo guanosine‐triphosphate (GTP) biosynthesis." SIGNOR-261263 INCENP protein Q9NQS7 UNIPROT AURKA protein O14965 UNIPROT "up-regulates activity" binding 7227 16824953 t lperfetto "INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop" SIGNOR-252048 INHBA protein P08476 UNIPROT ACVR2B protein Q13705 UNIPROT "up-regulates activity" binding 9606 8622651 t gcesareni "Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB." SIGNOR-235142 INPP5D protein Q92835 UNIPROT "phosphatidylinositol bisphosphate" smallmolecule CHEBI:37328 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 23650141 t gcesareni "PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain-containing inositol 5-phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5-position" SIGNOR-252427 INS protein P01308 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" 10116 BTO:0000671 15069075 f lperfetto "The mechanism by which the phosphorylation of ser307 or ser318 inhibits irs-1 tyrosine phosphorylation is not known. Prolonged insulin-stimulation inhibits irs-1 binding to the phosphorylated npey motif in the juxta-membrane region of the irbeta -subunit." SIGNOR-236625 INS protein P01308 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" 9606 17360977 f lperfetto "Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223" SIGNOR-236737 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT "up-regulates activity" 9606 BTO:0001487 21966368 f Regulation miannu "Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms" SIGNOR-251858 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT "up-regulates activity" phosphorylation Tyr700 EGEEDTEyMTPSSRP 10090 BTO:0000944 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 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1190 DIYETDYyRKGGKGL -1 2449432 t lperfetto "We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151;" SIGNOR-106518 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr465 GEEELSNyICMGGKG 10116 BTO:0000443 7651388 t lperfetto "All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10)." SIGNOR-236713 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 BTO:0000443 12220227 t lperfetto "Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions." SIGNOR-236725 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Tyr66 LHQEDNDyINASLIK -1 11506178 t lperfetto "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" SIGNOR-249370 INSR protein P06213 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 BTO:0000975 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 INSR protein P06213 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr427 ELFDDPSyVNVQNLD 11075717 t "Insulin predominantly phosphorylates the Shc Tyr-317 residue. Phosphorylated Shc binds to Grb2 which forms a complex with Sos guanine nucleotide exchange factor for p21ras. " SIGNOR-251325 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Thr66 CERSGQRtASVLWPW 9534 BTO:0001538 12138165 t "T66E mutations interfered with the ability of IRAK to autophosphorylate. Thr-66 mutations abolished the capacity of IRAK to dimerize." SIGNOR-251327 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 12874243 t gcesareni "Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity." SIGNOR-103983 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 t "In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4." SIGNOR-251328 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 t "In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4." SIGNOR-251329 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 IRF3 protein Q14653 UNIPROT ABCC2 protein Q92887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15185298 f miannu "Expression of recombinant human IRF3 increased MRP2 promoter activity. " SIGNOR-254533 IRF3 protein Q14653 UNIPROT IFNB1 protein P01574 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 16699525 t lperfetto "Similarly, exogenous expression of wild-type Pin1 suppressed TLR3-mediated, IRF3-dependent activation of the IFN-beta promoter and reduced IFN-beta secretion in culture supernatants" SIGNOR-252257 IRF3 protein Q14653 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto "The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response." SIGNOR-216316 IRF4 protein Q15306 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 BTO:0000801 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-249561 IRF8 protein Q02556 UNIPROT CYBB protein P04839 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001412 11483597 f 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-222710 IRF8 protein Q02556 UNIPROT NCF2 protein P19878 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001412 11483597 f 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-222789 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 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 Isoetharine chemical CHEBI:6005 ChEBI DRD3 protein P35462 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-258433 ITCH protein Q96J02 UNIPROT CFLAR protein O15519 UNIPROT "down-regulates quantity" ubiquitination 10090 BTO:0000759 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 ITCH protein Q96J02 UNIPROT TNFAIP3 protein P21580 UNIPROT "up-regulates activity" binding 9606 BTO:0000782;BTO:0001271 18246070 t lperfetto "Here we demonstrate that the regulatory molecule tax1bp1 recruited the e3 ligase itch to a20 via two 'ppxy' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling a20-mediated recruitment and inactivation of rip1. (abstract)" SIGNOR-160621 ITGB1BP1 protein O14713 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-257647 ITGA6 protein P23229 UNIPROT "A6/b1 integrin" complex SIGNOR-C164 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-253179 ITGA7 protein Q13683 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-241508 ITGAL protein P20701 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 t apalma "This leads to further neutrophil-endothelial cell interactions through the binding of LFA-1 to its endothelial counterreceptor ICAM-1 during the slow rolling phase" SIGNOR-255040 ITGAM protein P11215 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000751 12393465 f apalma "CD11b, another marker for differentiation, was also less expressed in patients with t(8;21) in comparison to patients without t(8;21)" SIGNOR-255662 ITGAM protein P11215 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 BTO:0000130 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 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 ITGB1BP1 protein O14713 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-257638 ITGB1BP1 protein O14713 UNIPROT ITGB2 protein P05107 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-257649 ITGB1BP1 protein O14713 UNIPROT ITGB3 protein P05106 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-257656 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 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 ITGB4 protein P16144 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-257720 ITGB5 protein P18084 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 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-253208 ITGB8 protein P26012 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates 9606 BTO:0000142 11970960 f lperfetto "Integrin _v_8-mediated tgf_ activation is also required to regulate neurovascular homeostasis in the adult brain" SIGNOR-117386 ITK protein Q08881 UNIPROT BMX protein P51813 UNIPROT "up-regulates activity" phosphorylation Tyr216 SSTSLAQyDSNSKKI -1 12573241 t "Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. 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." SIGNOR-251331 ITPR1 protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 24646566 t miannu "The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell." SIGNOR-256238 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 ITSN1 protein Q15811 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "up-regulates quantity by stabilization" binding 24789820 t lperfetto "Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth" SIGNOR-260714 ITSN1 protein Q15811 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000567 30540523 t lperfetto "Significantly, here we identify the long isoform of ITSN-1, which has Cdc42 GEF activity| We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A)." SIGNOR-260612 JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates phosphorylation Tyr457 KAPTSFGyDKPHVLV 9606 7615558 t lperfetto "Interferon gamma activation of stat1alpha requires both jak1 and jak2 as well as tyrosine phosphorylation of the alpha chain of the ifngamma receptor." SIGNOR-29866 JAK1 protein P23458 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "up-regulates activity" phosphorylation 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-249492 JAK1 protein P23458 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 9305869 t "Janus kinase-dependent activation of insulin receptor substrate 1" SIGNOR-251343 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 t lperfetto "The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions" SIGNOR-236373 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 21576360 t "When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita" SIGNOR-256247 JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" phosphorylation 9606 9852261 t gcesareni "Stat6 activation is mediated through jak1 and jak2 tyrosine kinases" SIGNOR-62582 JAK2 protein O60674 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1069 EDSFLQRySSDPTGA 9534 BTO:0004055 9363897 t "Tyrosine at residue 1,068 of the EGFR is proposed to be one of the principal phosphorylation sites and Grb2-binding sites stimulated by growth hormone via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression, independently of the intrinsic tyrosine kinase activity of EGFR. " SIGNOR-251347 JAK2 protein O60674 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Tyr641 KNEFISEyCGEIISQ 9606 BTO:0000785 24469040 t lperfetto "Oncogenic y641 mutations in ezh2 prevent jak2/beta-trcp-mediated degradationbeta-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs beta-trcp-mediated ezh2 degradation." SIGNOR-202711 JAK2 protein O60674 UNIPROT ITGAL protein P20701 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000876 25624455 t miannu "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." SIGNOR-254739 JAK2 protein O60674 UNIPROT ITGB2 protein P05107 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000876 25624455 t miannu "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." SIGNOR-254738 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Ser523 GVSDVPTsPTLQRPT 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-176054 JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0002882 12370803 f irozzo "In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells. " SIGNOR-255811 JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" binding 10090 BTO:0002882 12370803 t irozzo "In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells. " SIGNOR-255810 JAK2 protein O60674 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR "up-regulates activity" phosphorylation 9606 15526160 t mainnu "Downstream of JAKs are the signal transducers and activators of transcription (STATs), which are phosphorylated by JAKs." SIGNOR-254999 JAK2 protein O60674 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation 9606 9575217 t gcesareni "Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein" SIGNOR-56894 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" phosphorylation 9606 9852261 t gcesareni "Stat6 activation is mediated through jak1 and jak2 tyrosine kinases." SIGNOR-62585 JAKMIP1 protein Q96N16 UNIPROT GABBR1 protein Q9UBS5 UNIPROT "up-regulates quantity" 9534 BTO:0004055 14718537 f SARA "Reduction in the Marlin-1 protein levels interferes with the translation, assembly, or stability of GABAB receptors during the maturation of cortical neurons." SIGNOR-260988 JAKMIP1 protein Q96N16 UNIPROT TUBB protein P07437 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000661 15277531 t SARA "In Jamip1, the N-terminal region mediates the association with microtubules, when highly expressed, N-ter drastically affects the organization of microtubules that appear to be bundled, stabilized against the depolymerizing effect of nocodazole, and enriched in acetylated tubulin." SIGNOR-260987 JARID2 protein Q92833 UNIPROT GATA4 protein P43694 UNIPROT "down-regulates activity" binding 10116 BTO:0003324 15542826 t miannu "JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4." SIGNOR-224697 JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 24315690 t miannu "In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity" SIGNOR-253340 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr227 PAPPEGAtPTSPVGH 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto "Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451)." SIGNOR-252954 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto "Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451)." SIGNOR-252955 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding 9606 1904542 t irozzo "The proteins encoded by the proto-oncogenes c-fos and c-jun (Fos and Jun, respectively) form a heterodimeric complex that regulates transcription by interacting with the DNA-regulatory element known as the activator protein 1 (AP-1) binding site." SIGNOR-256363 JUN protein P05412 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-256367 JUN protein P05412 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto "Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors." SIGNOR-233467 JUN protein P05412 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000452 18641051 f lperfetto "Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death." SIGNOR-253148 JUN protein P05412 UNIPROT SMAD3/JUN complex SIGNOR-C86 SIGNOR "form complex" binding 9606 9732876 t gcesareni "These results show a ligand-dependent association of smad3 with c-jun" SIGNOR-59867 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000567 17868033 t "Simone Vumbaca" "Apicidin inhibited rhHDACs 2 and 3 in the nanomolar range." SIGNOR-261128 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 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM 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-257976 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0001271;BTO:0000876 11742995 t lperfetto "The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription" SIGNOR-217201 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 11965546 t lperfetto "Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation." SIGNOR-217204 KDM2B protein Q8NHM5 UNIPROT 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-252244 KDM2B protein Q8NHM5 UNIPROT "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR "up-regulates activity" binding 10090 BTO:0000011 25533466 t 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-252247 KDM2B protein Q8NHM5 UNIPROT PPARG protein P37231 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-252246 KDM6A protein O15550 UNIPROT FLI1 protein Q01543 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0004178 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-260034 KDM6A protein O15550 UNIPROT HOXA10 protein P31260 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000007 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-260020 KDM6B protein O15054 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 BTO:0000801 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 KDM6B protein O15054 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 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-249564 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1054 FGLARDIyKDPDYVR 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-157081 KHSRP protein Q92945 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 10090 BTO:0000165 16364914 t lperfetto "Importantly, KSRP knockdown in C2C12 GM cells (Figure 2D) stabilized endogenous my- ogenin and p21 transcripts (Figure 2E). Furthermore, stable knockdown of KSRP, using shRNA, induced the accumulation of p21 mRNA in C2C12 GM while it did not affect the expression of late myogenic markers (MHC and muscle-creatine kinase [MCK])" SIGNOR-235859 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "AE/b7 integrin" complex SIGNOR-C186 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-259010 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "AL/b2 integrin" complex SIGNOR-C169 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-259024 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "AM/b2 integrin" complex SIGNOR-C170 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-259025 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "Av/b2 integrin" complex SIGNOR-C176 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-259027 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" binding 9606 BTO:0000830 17259966 t mainnu "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 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT up-regulates binding 9606 1698556 t gcesareni "We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor." SIGNOR-21193 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr703 DHAEAALyKNLLHSK 9606 10377264 t miannu "Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr" SIGNOR-68643 KLF10 protein Q13118 UNIPROT TGFBI protein Q15582 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 18359287 t lperfetto "Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia." SIGNOR-253212 KLF11 protein O14901 UNIPROT HBE1 protein P02100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 10207080 f Regulation miannu "Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression." SIGNOR-251829 KLF2 protein Q9Y5W3 UNIPROT THBD protein P07204 UNIPROT "up-regulates quantity by expression" "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-254543 KLF3 protein P57682 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18391014 f fspada "We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice." SIGNOR-161370 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 KMT2A protein Q03164 UNIPROT KMT2A/WDR5 complex SIGNOR-C57 SIGNOR "form complex" binding 9606 15960975 t miannu "The mll1-wdr5 complex is enzymatically active" SIGNOR-138248 KPNA1 protein P52294 UNIPROT KPNB1 protein Q14974 UNIPROT "up-regulates activity" binding 9534 17596301 t lperfetto "Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization." SIGNOR-260273 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 KPNA3 protein O00505 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR 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-254321 KPNA4 protein O00629 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-165314 KRAS protein P01116 UNIPROT PIK3CD protein O00329 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-175210 KRAS protein P01116 UNIPROT PIK3CG protein P48736 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." SIGNOR-175213 KRAS protein P01116 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9727023 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." SIGNOR-59819 LAMA3 protein Q16787 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR "form complex" binding 9211848 t lperfetto "Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2." SIGNOR-253235 LAMA5 protein O15230 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR "form complex" binding 11821406 t lperfetto "The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia." SIGNOR-255317 Laminin-10 complex SIGNOR-C182 SIGNOR Laminin-10 complex SIGNOR-C182 SIGNOR "up-regulates activity" binding 10090 BTO:0001086 18757303 t 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-253277 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 LAMTOR4 protein Q0VGL1 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR "form complex" binding 9606 20381137 t lperfetto "Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat 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-164778 LAMTOR5 protein O43504 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR "form complex" binding 9606 20381137 t lperfetto "Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat 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-164781 LARP4B protein Q92615 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 BTO:0005238 20573744 f miannu "Our data suggest LARP4B to act as a general stimulatory factor of translation, associated in poly(A)-mRNA-bound mRNP complexes. Under physiological conditions, LARP4B co-sedimented with polysomes in cellular extracts, suggesting a role in translation. In agreement with this notion, overexpression of LARP4B stimulated protein synthesis, whereas knockdown of the factor by RNA interference impaired translation of a large number of cellular mRNAs." SIGNOR-260942 LARP4B protein Q92615 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0005238 20573744 f miannu "Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules." SIGNOR-260939 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 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 LATS1 protein O95835 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t "Together,the YAP/TAZ-TEAD complex promotes proliferative and survival programs." milica "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-197643 LCK protein P06239 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr735 LKGPTCQyRAAQSGP 9606 BTO:0000661 11741929 t lperfetto "Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling." SIGNOR-112935 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT "up-regulates activity" phosphorylation Tyr210 SMAIHEVyQELIQDV -1 12923183 t "In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck" SIGNOR-251372 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 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr423 NSLNEEWyVSYITRP -1 8702662 t "Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro" SIGNOR-251381 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 LCK protein P06239 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 BTO:0000782 17998336 f gcesareni "The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1." SIGNOR-159164 LCK protein P06239 UNIPROT PRKCQ protein Q04759 UNIPROT unknown phosphorylation Tyr90 SETTVELySLAERCR 9606 BTO:0000782 10652356 t llicata "Tyrosine 90 (tyr-90) in the regulatory domain of pkctheta was identified as the major phosphorylation site by lck." SIGNOR-74574 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 11948419 t gcesareni "Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo." SIGNOR-116499 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 phosphorylation:Tyr319 TSVYESPySDPEELK 10318843 t lperfetto "Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation" SIGNOR-67443 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 phosphorylation:Tyr319 TSVYESPySDPEELK 8798643 t lperfetto "Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation" SIGNOR-43659 LEF1 protein Q9UJU2 UNIPROT NCAM1 protein P13591 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 BTO:0003952 11696550 f miannu "Consistent with our observation that expression of exogenous LEF-1 causes transactivation of the N-CAM promoter, a recent study demonstrated that noggin-dependent induction of LEF-1 coincidentally increased N-CAM expression (50). Ectopic noggin added to skin cultures up-regulates LEF-1 expression and stimulates hair induction. Based on promoter assays and EMSAs, our results further support the notion that N-CAM is a direct target of LEF-1." SIGNOR-254549 lenalidomide chemical CHEBI:63791 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-259284 letrozole chemical CHEBI:6413 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193651 "leukotriene D4(1-)" smallmolecule CHEBI:63166 ChEBI CYSLTR1 protein Q9Y271 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-257475 "leuprolide acetate" chemical CHEBI:63597 ChEBI GNRHR protein P30968 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001033 22416801 t miannu "Clinical data have shown that the GnRH antagonist, degarelix, is associated with more rapid PSA suppression and improved PSA PFS compared with the GnRH agonist, leuprolide." SIGNOR-259163 LFNG protein Q8NES3 UNIPROT DLL3 protein Q9NYJ7 UNIPROT up-regulates binding 9606 10934472 t gcesareni "We find that mammalian lunatic fringe (lfng) inhibits jagged1-mediated signalling and potentiates delta1-mediated signalling through notch1." SIGNOR-80524 LHB protein P01229 UNIPROT LHCGR protein P22888 UNIPROT up-regulates binding 9606 10446903 t gcesareni "Hcg is a heterodimeric glycoprotein hormone, consisting of a common? -subunit and a hormone-specific ?-Subunit (2). It binds to the lh receptor (lhr)." SIGNOR-70028 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 t gcesareni "Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44)." SIGNOR-48111 linifanib chemical CHEBI:91435 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193660 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB2 protein P07550 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-257457 LMX1B protein O60663 UNIPROT "LMX1B/SFPQ/PSPC1 complex" complex SIGNOR-C106 SIGNOR "form complex" binding 10090 BTO:0000669 23308148 t miannu "LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo." SIGNOR-223966 LNX1 protein Q8TBB1 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 11782429 t esanto "Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation." SIGNOR-112201 lofepramine chemical CHEBI:47782 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 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-258882 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 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 20331961 t milica "The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits)." SIGNOR-164679 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 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t 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-236985 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 20331961 t milica "The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits)." SIGNOR-230761 LPAR2 protein Q9HBW0 UNIPROT GNA13 protein Q14344 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-135837 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 LPAR3 protein Q9UBY5 UNIPROT GNA12 protein Q03113 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-135843 LPAR3 protein Q9UBY5 UNIPROT GNA12 protein Q03113 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-198544 LPAR3 protein Q9UBY5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 11093753 t gcesareni "Lpa3 can couple to gi/o" SIGNOR-84562 LPAR3 protein Q9UBY5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000938 12531543 t gcesareni "Lpa3couples to gq" SIGNOR-97400 LPAR5 protein Q9H1C0 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-257205 LPAR6 protein P43657 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-256725 LRIG1 protein Q96JA1 UNIPROT ERBB3 protein P21860 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-139951 LRIG1 protein Q96JA1 UNIPROT ERBB4 protein Q15303 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-202146 LRIG1 protein Q96JA1 UNIPROT LRIG3 protein Q6UXM1 UNIPROT down-regulates 9606 23723069 f miannu "Lrig1 destabilizes lrig3, limiting lrig3's positive effects on receptors and identifying lrig3 as a new target of lrig1." SIGNOR-202177 LRIG3 protein Q6UXM1 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates 9606 23723069 f miannu "Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors." SIGNOR-202180 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR 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-205115 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 LRRK2 protein Q5S007 UNIPROT MSN protein P26038 UNIPROT up-regulates phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0000142 17447891 t lperfetto "This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process." SIGNOR-154498 LRRK2 protein Q5S007 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-260267 LRRK2 protein Q5S007 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Ser75 LSMINTMsKIRGQEK 9606 22998870 t gcesareni "We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75." SIGNOR-192072 LSM-1231 chemical CHEBI:91471 ChEBI NTRK3 protein Q16288 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-258240 LSM-1988 chemical CHEBI:92015 ChEBI PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189394 LSM-20934 chemical CHEBI:109533 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-258726 LTA protein P01374 UNIPROT LTBR protein P36941 UNIPROT up-regulates binding 9606 BTO:0000782 BTO:0000975 7995952 t gcesareni "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-35708 MAML1 protein Q92585 UNIPROT CCNT1 protein O60563 UNIPROT up-regulates relocalization 9606 15546612 t 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-130712 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 lurasidone chemical CHEBI:70735 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 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-257838 lurasidone chemical CHEBI:70735 ChEBI Drd2 protein P61169 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 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-259462 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193775 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates phosphorylation Tyr500 TSLGSQSyEDMRGIL 9606 BTO:0000776 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 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 LYN protein P07948 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-249383 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 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR4 protein Q99677 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-257531 "lysophosphatidylserine 14:0(1-)" chemical CHEBI:72402 ChEBI GPR34 protein Q9UPC5 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-257505 MAF protein O75444 UNIPROT ETS1 protein P14921 UNIPROT down-regulates binding 9606 9566892 t miannu "Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity." SIGNOR-56808 MAF protein O75444 UNIPROT MYB protein P10242 UNIPROT down-regulates binding 9606 9566892 t miannu "Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity." SIGNOR-56811 MAML1 protein Q92585 UNIPROT H3C1 protein P68431 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." SIGNOR-153038 MAML1 protein Q92585 UNIPROT H4C1 protein P62805 UNIPROT down-regulates acetylation 9606 17300219 t gcesareni "We speculated that maml1, in addition to recruiting p300, might directly interact with histones to facilitate histone acetylation. We had observed acetylation of the histones h3 and h4." SIGNOR-153041 MAP1LC3B protein Q9GZQ8 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates binding 9606 22170151 t gcesareni "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-191549 MAP1LC3B protein Q9GZQ8 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-219403 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000443 12270934 t lperfetto "Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis." SIGNOR-235940 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 11971971 t lperfetto "Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity." SIGNOR-235937 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 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 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." SIGNOR-40349 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr182 TDDEMTGyVATRWYR 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." SIGNOR-40353 MAP2K3 protein P46734 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" phosphorylation 9534 BTO:0000298 7839144 t Luana "Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase." SIGNOR-260723 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni "MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53" SIGNOR-244982 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni "MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53" SIGNOR-249654 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 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT "up-regulates activity" phosphorylation Thr180 RHADAEMtGYVVTRW -1 9218798 t "SKK3 mediates the activation of SAPK4. Phosphorylation and activation of SAPK4 and SAPK2a by purified SKK3." SIGNOR-251424 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 11242034 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily." SIGNOR-105698 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 8663074 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily." SIGNOR-42390 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 10480932 t lperfetto "We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta." SIGNOR-70607 MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9534 BTO:0000298 9430721 t Luana "The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms" SIGNOR-260721 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Tyr185 TSFMMTPyVVTRYYR 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-51203 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT "up-regulates activity" phosphorylation Ser407 STEQTLAsDTDSSLD -1 11062067 t "MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. 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-251416 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 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 11062067 t lperfetto "In the present study, we found that mkk7 phosphorylates sapk2a/p38 exclusively at tyr-182, albeit at a low rate. Therefore one possibility is that the interaction of mkk7 and/or sapk1/jnk with another cellular protein alters the conformation of one of these enzymes in such a way as to facilitate phosphorylation of tyr-185 by mkk7 in vivo." SIGNOR-83748 MAP3K10 protein Q02779 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-234599 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser341 KALASIYsPDHSSNN 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161523 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser352 SSNNFSSsPSTPVGS 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161527 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser359 SPSTPVGsPQGLAGT 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161531 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser379 AGAPGALsPSYDGGL 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161540 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Thr355 NFSSSPStPVGSPQG 9606 BTO:0000938 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161544 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT "up-regulates activity" phosphorylation Ser180 DQGSLCTsFVGTLQY 9606 BTO:0000007;BTO:0000567 SIGNOR-C14 9520446 t lperfetto "NIK preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa." SIGNOR-55946 MAP3K14 protein Q99558 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C14 9520446 t gcesareni "Activation of the transcription factor nf-kappab by inflammatory cytokines involves the successive action of nf-kappab-inducing kinase (nik) and two ikappab kinases, ikk-alpha and ikk-beta. Here we show that nik preferentially phosphorylates ikk-alpha over ikk-beta" SIGNOR-55949 MAP3K14 protein Q99558 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 9520446 t lperfetto "Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176.Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa." SIGNOR-217433 MAP3K14 protein Q99558 UNIPROT MAP3K14 protein Q99558 UNIPROT "up-regulates activity" phosphorylation 9606 20651737 t lperfetto "As nik levels increase, nik presumably becomes activated by autophosphorylation (p)." SIGNOR-167063 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser866 TAEVKEDsAYGSQSV 9606 BTO:0000007 11239468 t lperfetto "NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870" SIGNOR-105553 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser870 KEDSAYGsQSVEQEA 9606 BTO:0000007 11239468 t lperfetto "NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870" SIGNOR-105557 MAP3K14 protein Q99558 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 9020361 f amattioni "Nik stimulates nf-kappab activity" SIGNOR-46212 MAP3K1 protein Q13233 UNIPROT CRTC1 protein Q6UUV9 UNIPROT up-regulates phosphorylation 9606 18784253 t miannu "We report on the activation oftorc1through mekk1-mediated phosphorylation." SIGNOR-180816 MAP3K1 protein Q13233 UNIPROT FADD protein Q13158 UNIPROT down-regulates phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 BTO:0001130 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 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 t lperfetto "Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity." SIGNOR-235587 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 10090 BTO:0000944 8131746 t lperfetto "Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity." SIGNOR-235564 MAP3K2 protein Q9Y2U5 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11343802 t lperfetto "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-244888 MAP3K3 protein Q99759 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation Ser218 ISGYLVDsVAKTMDA 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-48625 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 MAP3K3 protein Q99759 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation 9606 12912994 t gcesareni "Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5." SIGNOR-104637 MAP3K3 protein Q99759 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates 9606 BTO:0000007 10347227 f gcesareni "However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2." SIGNOR-68020 MAP3K3 protein Q99759 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates phosphorylation Ser526 MSGTGMRsVTGTPYW 9606 BTO:0000007 16407301 t lperfetto "Phosphorylation of serine 526 is required for mekk3 activity, and association with 14-3-3 blocks dephosphorylationautophosphorylation of mekk3 at ser526" SIGNOR-143647 MAP3K3 protein Q99759 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 12809556 t gcesareni "Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation" SIGNOR-102294 MAP3K3 protein Q99759 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 16126726 t gcesareni "Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation" SIGNOR-138945 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K3 protein P46734 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-50891 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 9841871 t lperfetto "When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro." SIGNOR-62369 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 9841871 t lperfetto "When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro." SIGNOR-62372 MAP3K4 protein Q9Y6R4 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 21152872 f lperfetto "We found that mekk1/mekk4 as opposed to ask1, are responsible for trail-induced c-jun nh2-terminal kinase (jnk) or p38 activation," SIGNOR-170534 MAP3K5 protein Q99683 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Ser98 GGRRPGTsPALLQGT 9606 17325029 t lperfetto "P21cip1 is phosphorylated in vitro by both ask1 and jnk1 at s98. /phosphorylation of p21cip1 at s98, which in vivo appears to be regulated by ask1, may therefore mediate negative feedback in the ask1 signaling pathway." SIGNOR-153440 MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation 9534 BTO:0004055 8974401 t lperfetto "ASK1 activated SEK1 and MKK3 up to 7.0- and 11.8-fold, respectively" SIGNOR-226672 MAP3K5 protein Q99683 UNIPROT MAP3K6 protein O95382 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 17210579 t Manara "C-terminal region of ASK1 binds to ASK2 and inhibits the degradation of ASK2" SIGNOR-260831 MAP3K5 protein Q99683 UNIPROT ZNF622 protein Q969S3 UNIPROT up-regulates phosphorylation Thr318 KGKSFYStEAVQAHM 9606 21771788 t gcesareni "Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis." SIGNOR-175117 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" phosphorylation T838 GINPCTETFT 9606 BTO:0000007 17210579 t Manara "These results suggested that ASK2 activates ASK1 by direct phosphorylation of Thr838 of ASK1." SIGNOR-260773 MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation 9606 11460167 t lperfetto "The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination" SIGNOR-109497 MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 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-236145 MAP3K7 protein O43318 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT "up-regulates activity" 9606 BTO:0000007 9890973 f lperfetto "These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway." SIGNOR-63979 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 8131746 t gcesareni "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf" SIGNOR-36449 MAP4K1 protein Q92918 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni "Hpk1 binds and phosphorylates mekk1 directly," SIGNOR-43996 MAP4K5 protein Q9Y4K4 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000776 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 MAP4K5 protein Q9Y4K4 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000776 16914735 t lperfetto "Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3_ and enhance the in vivo phosphorylation of gsk3_ on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3_ at serine 9 and decreases the accumulation of cytosolic _-catenin." SIGNOR-148908 MAPK10 protein P53779 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 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 MAPK10 protein P53779 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-134537 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 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 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 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-59447 MAPK11 protein Q15759 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 17254968 t gcesareni "We show that prak activates p53 by direct phosphorylation." SIGNOR-152843 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 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr522 SSPGSPGtPGSRSRT -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-250087 MAPK13 protein O15264 UNIPROT CDC25B protein P30305 UNIPROT down-regulates 9606 11333986 f gcesareni "P38 map k can also induce a g2/m checkpoint through the phosphorylation and the phosphatase cdc25b." SIGNOR-85999 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 10581258 t gcesareni "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-72691 MAPK14 protein Q16539 UNIPROT CASP3 protein P42574 UNIPROT down-regulates phosphorylation Ser150 FRGDRCRsLTGKPKL 9606 BTO:0000130 14970175 t gcesareni "Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response." SIGNOR-122099 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 MAPK14 protein Q16539 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8702807 f gcesareni "This result suggests that the p38mapk cascade could be involved in the negative regulation of cyclin d1 transcription and thus antagonize the mitogen-dependent stimulation of cyclin d1 transcription mediated, at least in part, by the p42/p44mapk cascade." SIGNOR-43096 MAPK14 protein Q16539 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates phosphorylation 9606 16138080 t gcesareni "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-140085 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 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 MAPK14 protein Q16539 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr367 NNSSRPStPTINVLE 10090 BTO:0000165 28067271 t "Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372" SIGNOR-255663 MAPK14 protein Q16539 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 20626350 t gcesareni "Fgfr1 translocation requires p38 mapk activation which phosphorylates the c-term tail of fgfr1 on ser777" SIGNOR-166598 MAPK14 protein Q16539 UNIPROT JUNB protein P17275 UNIPROT up-regulates phosphorylation Ser79 QGSDTGAsLKLASSE 9606 15308641 t lperfetto "These results clearly demonstrate that phosphorylation by p38 kinase is essential for the regulation of dmp1 transcription by junb and p300. phosphorylation of junb at ser-79 was found to be essential for its interaction with p300." SIGNOR-127545 MAPK14 protein Q16539 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-67535 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 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 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates activity" phosphorylation Ser387 LSLPSTQsLNIKSEP 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-62788 MAPK14 protein Q16539 UNIPROT PIP4K2B protein P78356 UNIPROT down-regulates phosphorylation Ser326 SYGTPPDsPGNLLSF 9606 16949365 t gcesareni "Inhibition of pip4kbeta activity occurs through the direct phosphorylation of pip4kbeta at ser326 by the p38 stress-activated protein kinase." SIGNOR-149359 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 MAPK14 protein Q16539 UNIPROT PPARG protein P37231 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-210090 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000567 9687510 t lperfetto "Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38,." SIGNOR-59454 MAPK14 protein Q16539 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation 9606 17003045 t gcesareni "We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3." SIGNOR-149890 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0001946 14512875 t lperfetto "P38 mapk mediates fibrogenic signal through smad3 phosphorylation in rat myofibroblasts. the phosphorylation promoted hetero-complex formation and nuclear translocation of smad3 and smad4." SIGNOR-236136 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0001939 15520018 t miannu "Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways." SIGNOR-250112 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser392 FKTEGPDsD 10747897 t miannu "We demonstrate that anisomycin- and tumor necrosis factor--induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase" SIGNOR-250114 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 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 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 MAPK15 protein Q8TD08 UNIPROT MAPK15 protein Q8TD08 UNIPROT up-regulates phosphorylation Thr175 GPEDQAVtEYVATRW 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.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation" SIGNOR-142969 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 15456867 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-129585 MAPK1 protein P28482 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 t 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-137171 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 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 15210796 t gcesareni "Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-126254 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 18245089 t gcesareni "Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. ... Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-160613 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser323 HCSAEAGsPAMAVLD 9606 16286470 t lperfetto "The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain" SIGNOR-141601 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 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr45 PGGTLFStTPGGTRI 9606 11777913 t gcesareni "Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. 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. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126." SIGNOR-113563 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 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000150 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-178137 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 BTO:0000007 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-252958 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 BTO:0000007 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-252959 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 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 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT up-regulates phosphorylation 9606 18045539 t fspada "In vitro phosphorylations were performed in two stages, and it was found that gsk3b caused the incorporation of [g-32p]atp by smad1 linker protein, but only after prephosphorylation by erk/mapk" SIGNOR-159487 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Thr72 PLLPPSAtGPDATVG 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-96414 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr334 QSTKVPQtPLHTSRV 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-44347 MAPK1 protein P28482 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 21666810 t fstefani "Like mk2, mk5 could be phosphorylated and activated by p38mapk and erk2 in vitro, but not by sapk?/Jnk3" SIGNOR-174076 MAPK1 protein P28482 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 t gcesareni "Activated following phosphorylation at thr-182 by p38-alpha/mapk14, p38-beta/mapk11, erk2/mapk1, erk3/mapk6, and erk4/mapk4." SIGNOR-58127 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 10737616 t lperfetto "Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease." SIGNOR-249418 MAPK1 protein P28482 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-22420 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 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 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 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 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT "up-regulates activity" phosphorylation Thr215 ATGSVPStPIAHRGP 9606 BTO:0000007 12556484 t lperfetto "Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did" SIGNOR-249422 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Ser126 SVYYKPSsPPTPTTP 9606 BTO:0000938 BTO:0000142 17681692 t llicata "We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter." SIGNOR-157167 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Thr132 SSPPTPTtPGFQVQH 9606 BTO:0000938 BTO:0000142 17681692 t llicata "We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter." SIGNOR-157171 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 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 BTO:0000801 16973330 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-149570 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT up-regulates phosphorylation 9606 10828059 t "The effect has been demonstrated using Q08499-4" llicata "The short pde4d1 isoenzyme is activated by erk2 phosphorylation this signifies that erk2 phosphorylated pde4d1 at a single site, ser491, that is cognate to the single erk2 phosphorylation site (ser579) found in pde4d3." SIGNOR-77559 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 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-120096 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 21035469 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-169150 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 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-120164 MAPK1 protein P28482 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-120168 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser296 SPSALSSsPNNLSPT 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-249442 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t llicata "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-136075 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "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-219312 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 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 7545671 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-28800 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 BTO:0000150 19085255 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase." SIGNOR-182808 MAPK1 protein P28482 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-134658 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser8 MESEMLQsPLLGLGE 9606 SIGNOR-C3 21071439 t llicata "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-169518 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates phosphorylation Ser276 VHPATPIsPGRASGM 9606 BTO:0000887 17015473 t "The effect has been demonstrated using Q01196-8" gcesareni "Mutation of the four phosphorylation sites necessary for transcriptional regulation (serine 276, serine 293, serine 303, and threonine 300) mimics the effects of the proteasome inhibitor, increasing the levels of ubiquitinated, matrix-bound aml1c. Thus, phosphorylation of aml1c on specific serine/threonine residues controls both transcriptional activity and rate of degradation." SIGNOR-149983 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161686 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161702 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 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. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1." SIGNOR-116162 MAPK1 protein P28482 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. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1." SIGNOR-116166 MAPK1 protein P28482 UNIPROT THRB protein P10828 UNIPROT down-regulates phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 t 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-102216 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 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-88716 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 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 t llicata "Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo" SIGNOR-135696 MAPK1 protein P28482 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000007;BTO:0000150 21502402 t gcesareni "We identified the serine 68 (s68) as a major phosphorylation site of twist1 by mass spectrometry and with specific antibodies. This s68 is phosphorylated by p38, jnk and erk1/2 in vitro, and its phosphorylation levels positively correlate with twist1 protein levels in hek293 and breast cancer cells." SIGNOR-173401 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 MAPK1 protein P28482 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-112809 MAPK3 protein P27361 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000567 18211802 t gcesareni "Activates rhoa and as a result regulates actin assembly." SIGNOR-160420 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 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-67634 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 15456867 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-129589 MAPK3 protein P27361 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 t gcesareni "Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells." SIGNOR-188172 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 19933846 t gcesareni "Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity." SIGNOR-161819 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0000887;BTO:0001260 11983427 t amattioni "The actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759. This phosphorylation leads to markedly diminished actin affinity." SIGNOR-86741 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 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-169682 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 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-165212 MAPK3 protein P27361 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-156860 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser344 QDDDAPLsPMLYSSS 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-252962 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser425 TKGSGLGsPTSSFNS 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-252963 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 MAPK3 protein P27361 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser674 QSPKRPRsPGSNSKV 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-74308 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 BTO:0000783 15001544 t lperfetto "Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation." SIGNOR-123177 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" phosphorylation Thr202 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-249471 MAPK3 protein P27361 UNIPROT 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-182628 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 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121994 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 19143636 t lperfetto "Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor." SIGNOR-209859 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 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-217556 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 21757713 t lperfetto "The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation." SIGNOR-217544 MAPK3 protein P27361 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD 9606 BTO:0000938 17440046 t gcesareni "Furthermore, we show that this gnrh-stimulated phosphorylation of the unliganded gr is mediated by a combination of the mapks jnk, p38, and erk as well as pkc in l t2 cells, because individual kinase inhibitors or combinations thereof inhibit this phosphorylation in intact cells." SIGNOR-154409 MAPK3 protein P27361 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-188143 MAPK3 protein P27361 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-120196 MAPK3 protein P27361 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 23024368 t gcesareni "Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5." SIGNOR-192101 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 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 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 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000938 8387505 t 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-38999 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 12832467 t lperfetto "Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3." SIGNOR-102648 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 t gcesareni "Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3." SIGNOR-184583 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 t gcesareni "In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758." SIGNOR-131379 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 15568999 t gcesareni "In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758." SIGNOR-131383 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 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser441 SPRRFIGsPRTPVSP 10116 15774499 t lperfetto "Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats" SIGNOR-111515 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 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 MAPK8IP1 protein Q9UQF2 UNIPROT MAP4K2 protein Q12851 UNIPROT down-regulates binding 9606 BTO:0000007 10702297 t gcesareni "DLK mutants were used to demonstrate that a DLK leucine zipper-leucine zipper interaction is necessary for DLK dimerization and to show that DLK dimerization mediated by the leucine zipper domain is prerequisite for DLK activity and subsequent activation of stress-activated protein kinase (SAPK)." SIGNOR-75385 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 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-91746 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 MAPK3 protein P27361 UNIPROT SP3 protein Q02447 UNIPROT up-regulates phosphorylation Ser73 CSKIGPPsPGDDEEE 9606 17685427 t 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-157276 MAPK3 protein P27361 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni "Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation." SIGNOR-118550 MAPK3 protein P27361 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Ser780 DSLDSRLsPPAGLFT 9606 BTO:0000975 10194762 t gcesareni "Serine 780 is the only substrate in full-length stat5a for active erk" SIGNOR-66247 MAPK3 protein P27361 UNIPROT STMN1 protein P16949 UNIPROT "down-regulates activity" phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000007 9731215 t 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-249482 MAPK3 protein P27361 UNIPROT STMN1 protein P16949 UNIPROT "down-regulates activity" phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0000007 9731215 t 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-249483 MAPK3 protein P27361 UNIPROT SULT4A1 protein Q9BR01 UNIPROT down-regulates phosphorylation Thr11 SEAETPStPGEFESK 9606 BTO:0000938 BTO:0000142 20920535 t gcesareni "The phosphorylation of sult4a1 allows interaction with pin1, which then promotes degradation of the sulfotransferase." SIGNOR-168248 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12050114 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk" SIGNOR-88728 MAPK3 protein P27361 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-88732 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 BTO:0000782 12151396 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk" SIGNOR-91059 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk" SIGNOR-88736 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 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 18486448 t gcesareni "The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus" SIGNOR-178655 MAPK8 protein P45983 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 12917434 t lperfetto "Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1" SIGNOR-117852 MAPK8 protein P45983 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 24610780 t lperfetto "Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1" SIGNOR-204679 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7737130 t gcesareni "Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro." SIGNOR-32421 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation 9606 10567572 t amattioni "Jnk was capable of phosphorylating bcl-2. Phosphorylation of bcl-2 inactivates the molecule" SIGNOR-72364 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Ser87 AAAGPALsPVPPVVH 9606 10567572 t gcesareni "Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy." SIGNOR-48038 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Ser87 AAAGPALsPVPPVVH 9606 18570871 t gcesareni "Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy." SIGNOR-179092 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 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 8846788 t gcesareni "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-44356 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 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 18728222 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-180532 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto "The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity." SIGNOR-235766 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu "JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain." SIGNOR-250122 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 MAPK8 protein P45983 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 t gcesareni "These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation." SIGNOR-145297 MAPK8 protein P45983 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-187." SIGNOR-124016 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 MAPK8 protein P45983 UNIPROT STAT6 protein P42226 UNIPROT down-regulates phosphorylation Ser707 IPPYQGLsPEESVNV 9606 21123173 t llicata "Deactivation of stat6 through serine 707 phosphorylation by jnk." SIGNOR-170153 MAPK8 protein P45983 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 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 phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax" SIGNOR-124020 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 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-163262 MAPK9 protein P45984 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-163266 MAPK9 protein P45984 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser29 ATKAARKsAPSTGGV 9606 15994958 t gcesareni "Phosphorylation of histone h3 at serine 10 is indispensable for neoplastic cell transformation. When h3 wt was overexpressed, egf induction of c-fos and c-jun promoter activity was significantly increased compared with control cells but not in the h3 mutant s10a or s28a cells." SIGNOR-138463 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632" SIGNOR-118881 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Map kinases and mtor mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632" SIGNOR-118873 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni "Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632" SIGNOR-118877 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser165 RESSLSPsPASSISS 9606 BTO:0000782 9374467 t lperfetto "Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation" SIGNOR-53368 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates relocalization 9606 BTO:0000782 14517246 t gcesareni "Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin." SIGNOR-103360 MAPK9 protein P45984 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-178934 MAPK9 protein P45984 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t gcesareni "Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188" SIGNOR-124031 MAPKAPK2 protein P49137 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser272 CSLERQLsLEQEVQQ -1 11844797 t miannu "Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO." SIGNOR-250143 MAPKAPK2 protein P49137 UNIPROT ARPC5 protein O15511 UNIPROT unknown phosphorylation Ser77 AVKDRAGsIVLKVLI -1 12829704 t miannu "MAPKAPK2 also phosphorylated p16-Arc in intact Arp2/3 complexes precipitated from neutrophil lysates. Mutation of serine-77 to alanine on the A isoform prevented phosphorylation by MAPKAPK2." SIGNOR-250144 MAPKAPK2 protein P49137 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser166 SSRRRAIsETEENSD 9606 15688025 t gcesareni "Hdm2 phosphorylation by mapkap kinase 2 enhances hdm2 activity and promote the degradation of p53." SIGNOR-133560 MAPKAPK2 protein P49137 UNIPROT PARN protein O95453 UNIPROT down-regulates phosphorylation Ser557 NHYYRNNsFTAPSTV 9606 20932473 t lperfetto "Mk2 phosphorylates parn, blocking gadd45_ mrna degradation. Parn can serve as a direct substrate for mk2, and demonstrating that ser-557 is the dominant mk2 phosphorylation site." SIGNOR-168377 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser66 TSLVEGRsCGWVPPP -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-250154 MAPT protein P10636 UNIPROT "Neurofibrillary tangle formation" phenotype SIGNOR-PH58 SIGNOR up-regulates 9606 BTO:0000590 11578751 f lperfetto "Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly" SIGNOR-251642 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser641 KVTSKCGsLGNIHHK 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process" SIGNOR-171054 MARK2 protein Q7KZI7 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 22072711 t "The effect has been demonstrated using Q92974-2" gcesareni "We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation" SIGNOR-177096 masitinib chemical CHEBI:63450 ChEBI PDGFRB protein P09619 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-258246 MAST1 protein Q9Y2H9 UNIPROT PTEN protein P60484 UNIPROT down-regulates phosphorylation 9606 15951562 t gcesareni "Mast1 was found to associate to pten." SIGNOR-138003 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 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 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 MAX protein P61244 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 8425218 t esanto "In vivo transactivation assays suggest that myc-max and mad-max complexes have opposing functions in transcription and that max plays a central role in this network of transcription factors" SIGNOR-39137 MC1R protein Q01726 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-256956 MC3R protein P41968 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-257230 MC3R protein P41968 UNIPROT GNAS protein P84996 UNIPROT "up-regulates activity" 9606 22215617 t lperfetto "We hypothesize that XLαs may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus." SIGNOR-253068 MC3R protein P41968 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-257142 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 10935507 t lperfetto "Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53." SIGNOR-80528 MC4R protein P32245 UNIPROT GNAS protein P84996 UNIPROT "up-regulates activity" 9606 22215617 t lperfetto "We hypothesize that XLαs may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus." SIGNOR-253067 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000093 22337874 t lperfetto "The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2." SIGNOR-196116 MDM2 protein Q00987 UNIPROT TP73 protein O15350 UNIPROT "down-regulates activity" binding 9606 17700533 t miannu "Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis." SIGNOR-255470 MC5R protein P33032 UNIPROT GNAS protein Q5JWF2 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-256798 MCHR1 protein Q99705 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-257235 MCHR2 protein Q969V1 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-257268 MCM10 protein Q7L590 UNIPROT RECQL4 protein O94761 UNIPROT down-regulates binding 9606 19696745 t miannu "Mcm10 inhibits recq4 helicase activity." SIGNOR-187701 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 MECP2 protein P51608 UNIPROT ALOX5 protein P09917 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001412 19781662 f "Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene." SIGNOR-254062 MEF2A protein Q02078 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 BTO:0001103 19725819 f areggio "In response to increases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin" SIGNOR-255957 MEF2A protein Q02078 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 9418854 t lperfetto "Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis." SIGNOR-54086 MEF2C protein Q06413 UNIPROT CDKL5 protein O76039 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20513142 f "Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5." SIGNOR-254031 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 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 11971971 t lperfetto "Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity." SIGNOR-244788 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR 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-258991 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 t lperfetto "Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis." SIGNOR-244798 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 MELK protein Q14680 UNIPROT CDC25B protein P30305 UNIPROT "down-regulates activity" phosphorylation Ser219 HALAEWAsRREAFAQ 9606 BTO:0001938 12400006 t "In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323[Ä] Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase" SIGNOR-255655 MELK protein Q14680 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser169 VLRNITNsQAPDGRR 9606 15908796 t lperfetto "We demonstrate that cdc25b is phosphorylated in vitro by peg3 on serine 169this phosphorylated form of cdc25b accumulates during mitosis, and is localized to the centrosomes" SIGNOR-137378 Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR 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-249584 MEN1 protein O00255 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000567 15640349 f irozzo "Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions." SIGNOR-255889 Merimepodib chemical CID:153241 PUBCHEM IMPDH2 protein P12268 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001931 11288107 t Federica "These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation." SIGNOR-261106 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr749 FGLSKKIySGDYYRQ 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-42914 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr753 KKIYSGDyYRQGRIA 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-42918 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 metformin chemical CHEBI:6801 ChEBI G6PC protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17909097 f gcesareni "In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp." SIGNOR-158056 metformin chemical CHEBI:6801 ChEBI NDUFS1 protein P28331 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001109 24843020 t Federica "In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration" SIGNOR-261080 metformin chemical CHEBI:6801 ChEBI NR0B2 protein Q15466 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17909097 f gcesareni "In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp." SIGNOR-158059 methylnaltrexone chemical CHEBI:136007 ChEBI OPRM1 protein P35372 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-258148 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 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-147187 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 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-147191 MFF protein Q9GZY8 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 21149567 t gcesareni "Mff functions as an essential factor in mitochondrial recruitment of Drp1." SIGNOR-245957 MGLL protein Q99685 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 "BTO:0005721; BTO:0000972" 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 MIB1 protein Q86YT6 UNIPROT DLL1 protein O00548 UNIPROT "up-regulates activity" ubiquitination 9606 16140393 t lperfetto "Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity." SIGNOR-209750 MIB1 protein Q86YT6 UNIPROT DLL3 protein Q9NYJ7 UNIPROT "up-regulates activity" ubiquitination 9606 16140393 t lperfetto "Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity." SIGNOR-209672 MIB1 protein Q86YT6 UNIPROT DLL4 protein Q9NR61 UNIPROT "up-regulates activity" ubiquitination 9606 16140393 t lperfetto "Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity." SIGNOR-209626 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT "up-regulates activity" binding 9606 BTO:0000452 12782713 t gcesareni "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-252060 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000876 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 MIF protein P14174 UNIPROT CXCR2 protein P25025 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-252061 miR-155 mirna MI0000681 miRBase JARID2 protein Q92833 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004620 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 MITF protein O75030 UNIPROT DCT protein P40126 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000847 22371403 f miannu "MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription." SIGNOR-254592 MITF protein O75030 UNIPROT PMEL protein P40967 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-254589 MK-2461 chemical CID:44137946 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194367 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 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 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 9606 BTO:0005014 27856324 t irozzo "Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4." SIGNOR-255882 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000725 21389315 f irozzo "Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair." SIGNOR-255872 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001412 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-260128 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR "AEP complex" complex SIGNOR-C117 SIGNOR "up-regulates activity" binding 9606 BTO:0005261 19956800 t irozzo "Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription." SIGNOR-255878 "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 "MLL Fusion" "fusion protein" SIGNOR-FP14 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0001412 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-260129 "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "MLL1 complex" complex SIGNOR-C89 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-204819 MLNR protein O43193 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-257016 MMP2 protein P08253 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage Leu40 QAENGPHLLVEAEQA -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-256333 MMP9 protein P14780 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-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation." SIGNOR-74461 MN1 protein Q10571 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004850 17494859 f irozzo "MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment." SIGNOR-256016 MN1 protein Q10571 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0004850 17494859 f irozzo "MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment." SIGNOR-256015 motesanib chemical CHEBI:51098 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194560 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 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-258252 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194563 motesanib chemical CHEBI:51098 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194566 motesanib chemical CHEBI:51098 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194569 motesanib chemical CHEBI:51098 ChEBI RET protein P07949 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194572 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 MRAP protein Q8TCY5 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-252360 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 MRGPRX2 protein Q96LB1 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-257434 MSH2 protein P43246 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-257594 MSH2 protein P43246 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR "form complex" binding 9606 15064730 t miannu "The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors." SIGNOR-123702 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 MSH6 protein P52701 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR "form complex" binding 9606 15064730 t miannu "The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors." SIGNOR-123708 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 MSX1 protein P28360 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001103 15192231 f gcesareni "We found that msx1 and h1b bind to a key regulatory element of myod, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin." SIGNOR-125765 MTCH1 protein Q9NZJ7 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002181 12377771 f SARA "PSAP is an important regulator of apoptosis" SIGNOR-260994 MTCH2 protein Q9Y6C9 UNIPROT BID protein P55957 UNIPROT up-regulates binding 9606 21295084 t gcesareni "Mtch2/mimp and its role in bid recruitment may synergise with cl-induced mitosome formation to facilitate momp." SIGNOR-171773 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 MTCP1 protein P56278 UNIPROT AKT1 protein P31749 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-81671 MTMR3 protein Q13615 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" 9606 BTO:0000007 26787466 t lperfetto "The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity." SIGNOR-245108 mTORC1 complex SIGNOR-C3 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 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 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 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 12747827 t lperfetto "Our data demonstrate that the TOS motif functions as a docking site for the mTOR/raptor complex, which is required for multisite phosphorylation of 4E-BP1, eIF4E release from 4E-BP1, and cell growth." SIGNOR-236678 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 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-236690 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 10942774 t lperfetto "Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies." SIGNOR-236702 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 20516213 t lperfetto "The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly." SIGNOR-217153 mTORC1 complex SIGNOR-C3 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000944 18372248 t lperfetto "We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competition. We also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1." SIGNOR-235518 mTORC1 complex SIGNOR-C3 SIGNOR TFEB protein P19484 UNIPROT "down-regulates activity" phosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000567 SIGNOR-C3 22692423 t gcesareni "Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB." SIGNOR-248274 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 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto "The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1" SIGNOR-252600 mTORC2 complex SIGNOR-C2 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu "MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity" SIGNOR-256171 mTORC2 complex SIGNOR-C2 SIGNOR SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 BTO:0000567 BTO:0000671 18925875 t lperfetto "Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422)" SIGNOR-217016 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 MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "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-134185 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 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-219257 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 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-219266 MTOR protein P42345 UNIPROT ISCU protein Q9H1K1 UNIPROT up-regulates phosphorylation Ser14 FRLRRAAsALLLRSP 9606 SIGNOR-C3 23508953 t llicata "Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein." SIGNOR-201595 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser60 PHVLEALsPPQTSGL 9606 SIGNOR-C3 20516213 t fstefani "The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly." SIGNOR-165791 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 20233713 t gcesareni "The identification of maf1 as an mtor-regulated phosphoprotein implicates mtor in the broader regulatory mechanisms governing pol iii activity in cancer cells." SIGNOR-164348 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 BTO:0000007 SIGNOR-C3 10579915 t lperfetto "S6 kinases are under the control of the PI3K relative, mammalian Target Of Rapamycin (mTOR), which may serve an additional function as a checkpoint for amino acid availability." SIGNOR-72682 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 9823 BTO:0004712 23486913 t lperfetto "Collectively, 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" SIGNOR-201538 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 t miannu "In vitro phosphorylation and activation of p70β by mTOR and PDK1. replacement of Ser383 to Gly (S383G) reduced but still retained nearly half of the kinase activity of the wild-type." SIGNOR-250293 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 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 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 MTSS1 protein O43312 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 16280553 t lperfetto "Mim-b binds and activates rac via its irsp53/mim domain" SIGNOR-141573 MYCN protein P04198 UNIPROT ABCC1 protein P33527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000793;BTO:0002104 7923112 f miannu "Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene." SIGNOR-254617 MYCN protein P04198 UNIPROT CTSD protein P07339 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000931 18566016 f miannu "In primary neuroblastomas, high CTSD messenger RNA (mRNA) levels were associated with amplified MYCN, a strong predictive marker of adverse outcome. Chromatin immunoprecipitation and luciferase promoter assays revealed that MYCN protein binds to the CTSD promoter and activates its transcription, suggesting a direct link between deregulated MYCN and CTSD mRNA expression." SIGNOR-254618 MYC protein P01106 UNIPROT FUT3 protein P21217 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000182;BTO:0000391 22547830 f miannu "We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2." SIGNOR-254612 MYC protein P01106 UNIPROT HLA-A protein P30443 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-254603 MYC protein P01106 UNIPROT ST3GAL1 protein Q11201 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000182;BTO:0000391 22547830 f "We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2." SIGNOR-253961 MYC protein P01106 UNIPROT ST3GAL3 protein Q11203 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000182;BTO:0000391 22547830 f "We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2." SIGNOR-253962 MYC protein P01106 UNIPROT ST3GAL4 protein Q11206 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000182;BTO:0000391 22547830 f "We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2." SIGNOR-253959 MYF5 protein P13349 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 f miannu "The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers." SIGNOR-37409 MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 f miannu "The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers." SIGNOR-37455 MYOCD protein Q8IZQ8 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-254620 MYOCD protein Q8IZQ8 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 BTO:0000887;BTO:0001260 21673106 f "miR-143 and miR-145 target KLF4" gcesareni "These results further confirm that bmp4 requires mrtf-a, whereas tgf-_ requires myocd for the induction of pri-mir-143/145 and down-regulation of klf4." SIGNOR-174319 MYOCD protein Q8IZQ8 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni "A coactivator of srf, myocd, interacts with srf and activates vsmc expression of contractile genes." SIGNOR-174322 MYOD1 protein P15172 UNIPROT CCND3 protein P30281 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 10373569 t gcesareni "Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator." SIGNOR-238526 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 7791789 f lperfetto "The upregulation of p21 occurred at the levels of mrna and protein," SIGNOR-235831 MYOD1 protein P15172 UNIPROT RB1 protein P06400 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 10373569 t gcesareni "Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator." SIGNOR-238532 MYOD1 protein P15172 UNIPROT SMARCA4 protein P51532 UNIPROT up-regulates binding 9606 BTO:0001103 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 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR IGFBP5 protein P24593 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-136601 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 17194702 f 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-151688 MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 BTO:0001103 23612709 f "Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin" SIGNOR-255466 MYOG protein P15173 UNIPROT FBXO32 protein Q969P5 UNIPROT "down-regulates activity" binding 9534 BTO:0004055 19631210 t llicata "Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin." SIGNOR-237854 MYOG protein P15173 UNIPROT ITGA7 protein Q13683 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222;BTO:0001760 8798472 t lperfetto "Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development." SIGNOR-241521 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 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-258111 N-[2-(4-bromocinnamylamino)ethyl]isoquinoline-5-sulfonamide chemical CHEBI:47495 ChEBI PRKACA protein P17612 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0001676 2156866 t "Simone Vumbaca" "Kinetic analysis indicated that H-89 inhibits protein kinase A, in competitive fashion against ATP." SIGNOR-261087 N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide chemical CHEBI:91401 ChEBI IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192880 N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide chemical CHEBI:91401 ChEBI INSR protein P06213 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192883 N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide chemical CHEBI:47322 ChEBI CSNK1E protein P49674 UNIPROT down-regulates "chemical inhibition" 9606 11524435 t amattioni "Cki-7, an inhibitor of ck1epsilon" SIGNOR-110053 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB3 protein P13945 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-257855 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 N-[(2S)-1-[[(2S)-1-[[3-[4-(Aminomethyl)piperidine-1-carbonyl]phenyl]methylamino]-3-methyl-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]-1,2-oxazole-5-carboxamide chemical CID:49843508 PUBCHEM F2RL1 protein P55085 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000182 20873792 t "Simone Vumbaca" "Agonist GB110 (19, EC50 0.28 μM) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca2+ release in HT29 human colorectal carcinoma cells." SIGNOR-261125 "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 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-257971 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 17891169 t fspada "Hydroxamate derivatives are the most powerful category of hdaci, active on class i and ii hdac,especially on hdac1 and hdac2. In the study reported here, we described the anti-leukaemic properties of itf2357, a recently synthesized, orally active hydroxamate derivative." SIGNOR-157857 "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 N-(4-methoxyphenyl)sulfonyl-N-[2-[2-(1-oxido-4-pyridin-1-iumyl)ethenyl]phenyl]acetamide chemical CHEBI:91440 ChEBI PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193309 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 AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191274 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 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 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 "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207084 NAE complex SIGNOR-C131 SIGNOR CUL1 protein Q13616 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-243151 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 nalbuphine chemical CHEBI:7454 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-258658 naloxone chemical CHEBI:7459 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-258661 Naltrindole chemical CHEBI:81528 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-258818 NAMPT protein P43490 UNIPROT CLOCK/ARNTL 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 NANOG protein Q9H9S0 UNIPROT SOX17 protein Q9H6I2 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-253168 naproxen chemical CHEBI:7476 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-258603 NBR1 protein Q14596 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-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) 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." SIGNOR-184270 NBR1 protein Q14596 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni "Nbr1 and p62 interact and form oligomers." SIGNOR-184273 NCOA1 protein Q15788 UNIPROT CYP7A1 protein P22680 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255063 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 NCOA4 protein Q13772 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10347167 t miannu "Identification of ara70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. / ppargamma and ara70 interact in the absence of the ppargamma ligand 15-deoxy-delta12,14-prostaglandin j2, although the addition of exogenous ligand enhances this interaction." SIGNOR-67687 NCOR2 protein Q9Y618 UNIPROT BCL6 protein P41182 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10898795 t miannu "The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT." SIGNOR-252240 NDFIP1 protein Q9BT67 UNIPROT NEDD4 protein P46934 UNIPROT "up-regulates activity" relocalization 9606 BTO:0002181 26363003 t SARA "Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2." SIGNOR-260997 NDFIP2 protein Q9NV92 UNIPROT NEDD4 protein P46934 UNIPROT "down-regulates activity" relocalization 9606 BTO:0002181 26363003 t SARA "Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2." SIGNOR-260995 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 NEDD4L protein Q96PU5 UNIPROT SCNN1A protein P37088 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 15586017 t "Regulation of localization" miannu "The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane." SIGNOR-251948 NEFL protein P07196 UNIPROT "Neurofilament L/M" complex SIGNOR-C207 SIGNOR "form complex" binding 9606 BTO:0000938 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 NEFM protein P07197 UNIPROT "Neurofilament bundle assembly" phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 BTO:0000938 8376466 f miannu "Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons." SIGNOR-252391 NEFM protein P07197 UNIPROT "Neurofilament L/M" complex SIGNOR-C207 SIGNOR "form complex" binding 9606 BTO:0000938 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 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT "up-regulates activity" phosphorylation Ser422 AEAFLGFsYAPPTDS -1 12023960 t miannu "The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6." SIGNOR-250297 Neuregulin proteinfamily SIGNOR-PF37 SIGNOR "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "up-regulates activity" binding 9606 18415007 t miannu "The neuregulin family consists of four genes, NRG1-4 which can each encode products containing a domain related to the epidermal growth factor family of ligands. they may be released by regulated proteolysis to act as soluble proteins which can interact and activate members of the EGF receptor family of receptor tyrosine kinases" SIGNOR-256161 "Neurofibrillary tangle formation" phenotype SIGNOR-PH58 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000590 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 NF1 protein P21359 UNIPROT ADCY10 protein Q96PN6 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-203921 NF1 protein P21359 UNIPROT ADCY2 protein Q08462 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-203983 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" 9606 BTO:0002373 19777070 t "NF1 negatively regulates Ras as an exchangefactor converting Ras-GTP to Ras-GDP by its GTPase-activating (Ras-GAP) domain." SIGNOR-256067 NFATC1 protein O95644 UNIPROT IL4 protein P05112 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 8668213 t lperfetto "Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response." SIGNOR-254498 NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates "transcriptional regulation" 9606 23612709 f "Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin" SIGNOR-255460 NFATC3 protein Q12968 UNIPROT TFF1 protein P04155 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16219765 f miannu "Overexpression of NFAT3 enhanced both ERalpha and ERbeta transcriptional activities in a ligand-independent manner and up-regulated downstream estrogen-responsive genes including pS2 and cathepsin D. Reduction of endogenous NFAT3 with NFAT3 small interfering RNA or overexpression of NFAT3 deletion mutants that lack the ER-binding sites reduced the NFAT3 coactivation of ERalpha and ERbeta." SIGNOR-254639 NFE2L2 protein Q16236 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22493435 f miannu "BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2" SIGNOR-254653 NFE2L2 protein Q16236 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22493435 f miannu "BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2" SIGNOR-254652 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000018 14565864 f miannu "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-253907 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 NFIL3 protein Q16649 UNIPROT NFIL3 protein Q16649 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-224248 NFIL3 protein Q16649 UNIPROT SOSTDC1 protein Q6X4U4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 25338303 f lperfetto "E4BP4 is a repressor of epigenetically regulated SOSTDC1 expression in breast cancer cells." SIGNOR-242767 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" binding 9606 BTO:0000567 9914500 t lperfetto "In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon." SIGNOR-64092 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD86 protein P42081 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19164127 f miannu "We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40." SIGNOR-254782 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 22021368 f apalma "Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB." SIGNOR-256654 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CITED1 protein Q99966 UNIPROT up-regulates binding 9606 9660950 t lperfetto "The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276." SIGNOR-216331 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 f gcesareni "The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types." SIGNOR-245043 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 22021368 f apalma "In normal hematopoiesis, AML1 suppresses NF-κB signaling and thus may contribute to inhibition of excessive proliferation of hematopoietic cells." SIGNOR-255692 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR PTGS2 protein P35354 UNIPROT "up-regulates quantity by expression" 9606 17705188 f lperfetto "Inflammatory stimuli can activate IkappaB kinase (IKK) signalsome and subsequently the nuclear factor kappa B (NF-kappaB), which influences gene expression of cyclooxygenase-2 (Cox-2) along with other transcription factors." SIGNOR-260262 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR S100A6 protein P06703 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 12859951 f miannu "NF-kappaB transcription factor contributes to the activation of S100A6 gene expression in response to TNFalpha in HepG2 cells." SIGNOR-254803 NFYA protein P23511 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-254434 NFYA protein P23511 UNIPROT NFY complex SIGNOR-C1 SIGNOR "form complex" binding 9606 BTO:0000801;BTO:0000876 9885213 t lperfetto "Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding." SIGNOR-63013 NFYA protein P23511 UNIPROT PHGDH protein O43175 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18378410 f miannu "Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y." SIGNOR-255209 NFYC protein Q13952 UNIPROT PHGDH protein O43175 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18378410 f miannu "Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y." SIGNOR-255211 NFYC protein Q13952 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-254822 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 14699954 t amattioni "Neurotrophin binding to p75ntrhas also been shown to induce apoptosis" SIGNOR-120555 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257931 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257981 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 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 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-257983 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 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194640 nintedanib chemical CHEBI:85164 ChEBI FGFR3 protein P22607 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-257798 nintedanib chemical CHEBI:85164 ChEBI FGFR4 protein P22455 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-257803 nintedanib chemical CHEBI:85164 ChEBI FLT1 protein P17948 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-257800 NKD1 protein Q969G9 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 BTO:0000671 15064403 t gcesareni "Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation" SIGNOR-123695 NKX2-5 protein P52952 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9060 BTO:0001106 21261500 f "Taken together, our results indicate that the expression of MEF2C in T-ALL cells is principally deregulated via activating leukemic transcription factors GFI1B or NKX2-5 and by escaping inhibitory developmental STAT5 signaling." SIGNOR-253656 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation Thr155 SHAVHPLtPLITYSD 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-97812 NLK protein Q9UBE8 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-253525 NLRX1 protein Q86UT6 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" relocalization 9606 BTO:0002181 18219313 f lperfetto "NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time." SIGNOR-260399 NLRX1 protein Q86UT6 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates activity" binding 9606 28956771 t Giorgia "Moreover, poly(rC) binding protein 2 (PCBP2) interacts with NLRX1 to participate in the NLRX1-induced degradation of MAVS and the inhibition of antiviral responses during HCV infection." SIGNOR-260359 NLRX1 protein Q86UT6 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" relocalization 9606 BTO:0002181 18219313 f Giorgia "NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time." SIGNOR-260358 NMBR protein P28336 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-257248 NME1 protein P15531 UNIPROT NETO2 protein Q8NC67 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-255166 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser120 GRNIIHGsDSVESAE -1 8810265 t miannu "For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown." SIGNOR-250300 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser122 NIIHGSDsVESAEKE -1 8810265 t miannu "For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown." SIGNOR-250301 NMS protein Q5H8A3 UNIPROT NMUR2 protein Q9GZQ4 UNIPROT up-regulates binding 9606 BTO:0000142 15635449 t gcesareni "Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus." SIGNOR-133131 NMUR1 protein Q9HB89 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-256751 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 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 NOTCH1 protein P46531 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782;BTO:0001271;BTO:0000785 16847353 f gcesareni "We identified c-myc as a direct target of notch1" SIGNOR-147944 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding BTO:0001103 22045613 t svumbaca "NICD is translocated to the nucleus where it binds recombining binding protein-Jj (RBP-Jj)" SIGNOR-255364 N protein P59595 UNIPROT JNK proteinfamily SIGNOR-PF15 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-261131 nutlin-3A chemical CID:11433190 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194874 Odanacatib chemical CID:10152654 PUBCHEM CTSK protein P43235 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195007 olaparib chemical CHEBI:83766 ChEBI PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195016 orantinib chemical CHEBI:91088 ChEBI PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207441 PAK2 protein Q13177 UNIPROT PRL protein P01236 UNIPROT up-regulates phosphorylation Ser207 LHCLRRDsHKIDNYL 9606 19555049 t gcesareni "Phosphorylated form of prolactin has a higher affinity for heparin." SIGNOR-186211 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI CSF1R protein P07333 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-199527 PCBP2 protein Q15366 UNIPROT MAVS protein Q7Z434 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0002181 19881509 t Giorgia "PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4." SIGNOR-260360 PCSK6 protein P29122 UNIPROT VWF protein P04275 UNIPROT "up-regulates activity" cleavage BTO:0001538 8218226 t Giorgia "Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine" SIGNOR-260367 PDIA6 protein Q15084 UNIPROT ERN1 protein O75460 UNIPROT "down-regulates activity" 10090 BTO:0000944 24508390 t "A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine148 in the luminal domain of the sensor," SIGNOR-256536 PIK-294 chemical CID:24905149 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206202 PIK3C3 protein Q8NEB9 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 10090 BTO:0000142 19270693 t lperfetto "The beclin 1-vps34 interaction regulates autophagy." SIGNOR-184521 PIK3R3 protein Q92569 UNIPROT PI3K complex SIGNOR-C156 SIGNOR 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-252723 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 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser191 EDQAEEIsDELMEFS 9606 14968113 t lperfetto "Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation" SIGNOR-122090 PML protein P29590 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001271 15093545 f gcesareni "The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor" SIGNOR-124320 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 t gcesareni "Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity." SIGNOR-162146 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 13760840 t gcesareni SIGNOR-251700 PRKAA2 protein P54646 UNIPROT ACACB protein O00763 UNIPROT "down-regulates activity" phosphorylation Ser222 PTMRPSMsGLHLVKR 9606 BTO:0000887 14613924 t miannu "ACCβ(Ser221) is a known target for AMPK in human skeletal muscle" SIGNOR-250316 PRKACA protein P17612 UNIPROT CACNG2 protein Q9Y698 UNIPROT "down-regulates activity" phosphorylation Thr321 NTANRRTtPV 9534 BTO:0000298 11805122 t miannu "phosphorylation of stargazin at T321 by PKA inhibits its interaction with PSD-95." SIGNOR-250342 PRKACA protein P17612 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t miannu "Ser-42 can be phosphorylated by either protein kinase A or protein kinase C" SIGNOR-249999 PRKACA protein P17612 UNIPROT PDE3B protein Q13370 UNIPROT unknown phosphorylation Ser442 TPQLRRSsGTSGLLP -1 8163498 t miannu "Serine 427 is the target for cAMP-PK phosphorylation of the rat adipocyte cGI-PDE in vitro" SIGNOR-250023 PRKAR2A protein P13861 UNIPROT PRKAR2A protein P13861 UNIPROT "up-regulates activity" phosphorylation Ser99 SRFNRRVsVCAETYN -1 6293815 t miannu "RII subunit containing the 'autophosphorylation' site (Ser-95)" SIGNOR-250073 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 PRKCG protein P05129 UNIPROT EIF4E protein P06730 UNIPROT unknown phosphorylation Ser209 DTATKSGsTTKNRFV 10090 BTO:0000944 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 PRKCG protein P05129 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser368 QRPSSRAsSRASSRP 10116 BTO:0002931 10871288 t lperfetto "Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication." SIGNOR-249050 PRKCG protein P05129 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-97558 PRKCD protein Q05655 UNIPROT KRT8 protein P05787 UNIPROT "down-regulates quantity" phosphorylation S74 TVNQSLLSPLVLEVD 9606 BTO:0000018 15972820 t Manara "In this study, we demonstrate that shear stress, but not stretch, causes disassembly of keratin IF in lung alveolar epithelial cells (AEC) and that this disassembly is regulated by protein kinase C δ-mediated phosphorylation of keratin 8 (K8) Ser-73." SIGNOR-260887 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 PRKCD protein Q05655 UNIPROT LIMK2 protein P53671 UNIPROT down-regulates phosphorylation Ser283 EGTLRRRsLRRSNSI 9606 16820362 t "Translocation from Cytosol to Nucleus" gcesareni "Recently we have shown that limk2 shuttles between cytoplasm and nucleus in endothelial cells and that nuclear import is inhibited by protein kinase c-mediated phosphorylation of ser-283." SIGNOR-147716 PRKCD protein Q05655 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation 9606 17183360 t gcesareni "By contrast, after uv stimulation, rela directly induces the expression of pkcdelta, which in turn activates jnk." SIGNOR-151428 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -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-248924 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -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-248927 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 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 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 PRKCD protein Q05655 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Ser289 GQVLGRRsFEGRICA 9606 12097319 t llicata "The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation." SIGNOR-90279 PRKCD protein Q05655 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates phosphorylation Ser473 SGVKRSRsGEGEVSG 9606 18590578 t gcesareni "This work demonstrates that tif1beta is phosphorylated on ser473, the alteration of which is dynamically associated with cell cycle progression and functionally linked to transcriptional regulation. Phosphorylation of tif1beta/ser473 is mediated by the pkcdelta pathway and is closely linked to cell proliferation. Phosphorylation of tif1beta/ser473 coincides with the induction of cell cycle gene cyclin a2 at the s-phase. Promoter of cyclin a2 gene is occupied by tif1beta and such occupancy is inversely correlated with ser473 phosphorylation. Non-phosphorylated tif1beta/ser473 allowed greater tif1beta association with the regulatory regions and the consequent repression of these genes." SIGNOR-179250 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 PRKCD protein Q05655 UNIPROT YWHAZ protein P63104 UNIPROT "down-regulates activity" phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 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 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 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 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 PRKCE protein Q02156 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-163912 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 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-163916 PRKCE protein Q02156 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-129300 PRKCE protein Q02156 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-129308 PRKCQ protein Q04759 UNIPROT PRKCQ protein Q04759 UNIPROT "up-regulates activity" phosphorylation Thr219 SAINSREtMFHKERF 9606 BTO:0000661 16252004 t lperfetto "Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCtheta in T lymphocytes." SIGNOR-249298 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser518 LSASPRMsGFIYQGK 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-205234 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 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 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-249072 PRKCG protein P05129 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-249088 PRKCG protein P05129 UNIPROT GRK2 protein P25098 UNIPROT up-regulates phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000671 11042191 t acerquone "Phosphorylation of grk2 by protein kinase c abolishes its inhibition by calmodulinin vitro, grk2 was preferentially phosphorylated by pkc isoforms alpha, gamma, and delta" SIGNOR-83231 PRKCG protein P05129 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 11884598 t gcesareni "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-115726 PRKCG protein P05129 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249091 PRKCG protein P05129 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-37541 PRKCH protein P24723 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 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 PRKCH protein P24723 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto "Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka)." SIGNOR-188585 PRKCI protein P41743 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-251635 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 PRKCQ protein Q04759 UNIPROT FOSL1 protein P15407 UNIPROT "up-regulates activity" phosphorylation T217 LEPEALHTPTLMTTP 9606 BTO:0000093 27816489 t Manara "PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors." SIGNOR-260878 PRKCZ protein Q05513 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 8810272 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-43834 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 PRKCZ protein Q05513 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 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-249257 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 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-89280 PRKCZ protein Q05513 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-217370 PRKCZ protein Q05513 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Ser307 IRQIRQHsWFRKKHP 9606 BTO:0000887;BTO:0001103;BTO:0001260 19414597 t llicata "Here, we have identified s307 as a novel phosphorylation site in lkb1 and provide evidence that, in multiple cell types, phosphorylation of this site by protein kinase c ? (pkc-?) Induces nucleocytoplasmic transport of lkb1." SIGNOR-185640 PRKCZ protein Q05513 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0000567 18250273 t llicata "We conclude that pkc-zeta phosphorylates lkb1 at ser428, resulting in lkb1 nuclear export and hence ampk activation." SIGNOR-160681 PRKCZ protein Q05513 UNIPROT TRAF2 protein Q12933 UNIPROT unknown phosphorylation Ser55 QCGHRYCsFCLASIL 9606 BTO:0000785 19336568 t llicata "Here, we report that protein kinase czeta phosphorylates traf2 at ser(55), within the ring domain of the protein, after tnfalpha stimulation" SIGNOR-184941 PRKCZ protein Q05513 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser975 VRMKRPSsVKSLRSE -1 15081397 t lperfetto "PKCzeta phosphorylates KIBRA at serine 975 and 978" SIGNOR-249262 PRKCZ protein Q05513 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser978 KRPSSVKsLRSERLI -1 15081397 t lperfetto "PKCzeta phosphorylates KIBRA at serine 975 and 978" SIGNOR-249263 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 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser259 FPLRKTAsEPNLKVR 9534 BTO:0004055 15367659 t lperfetto "Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes." SIGNOR-249270 PRKD1 protein Q15139 UNIPROT KIDINS220 protein Q9ULH0 UNIPROT unknown phosphorylation Ser918 RTITRQMsFDLTKLL 10116 BTO:0001009 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 PRKD1 protein Q15139 UNIPROT PLCG1 protein P19174 UNIPROT "down-regulates activity" phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000661 1370476 t lperfetto "Thus, phosphorylation of PLC-gamma 1 by PKC or PKA at serine 1248 may modulate the interaction of PLC-gamma 1 with the protein tyrosine kinase or the protein tyrosine phosphatase; this altered interaction may, at least in part, be responsible for the decreased tyrosine phosphorylation of PLC-gamma 1 seen in PMA- and forskolin-treated Jurkat cells." SIGNOR-248846 PRKD1 protein Q15139 UNIPROT PPP1R14A protein Q96A00 UNIPROT unknown phosphorylation Thr38 QKRHARVtVKYDRRE -1 15003508 t lperfetto "For that purpose, PKCa, e, l, and f were incubated with CPI-17 in the presence of 50 lM [c- 32P]ATP and kinase buffer. The results indicated that all PKC isoforms were able to phosphorylate CPI-17 in vitro (Table 1). PKCa phosphorylated CPI-17 to a similar extent to PKCe and to a much greater extent than f and l." SIGNOR-249260 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser205 GVRRRRLsNVSLTGV 9606 10867018 t llicata "Activation of the serine/threonine kinase, protein kinase d (pkd/pkc mu) via a phorbol ester/pkc-dependent pathway involves phosphorylation events. the second autophosphorylation site (ser(203)) lies in that region of the regulatory domain" SIGNOR-78676 PRKD1 protein Q15139 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 BTO:0000150;BTO:0001130 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. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba." SIGNOR-168537 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT "up-regulates activity" phosphorylation Thr148 KETQPPEtVQNWIEL -1 BTO:0000567 24485452 t "In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents" SIGNOR-253558 PRKDC protein P78527 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation 9606 23620287 t gcesareni "Dna-dependentprotein_ kinase_ (dna-pk) that phosphorylate h2ax at dsbs" SIGNOR-192443 PRKDC protein P78527 UNIPROT HNRNPU protein Q00839 UNIPROT up-regulates phosphorylation Ser59 AMEPGNGsLDLGGDS 9606 19351595 t lperfetto "We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks" SIGNOR-185058 PRKDC protein P78527 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser232 LTQLPQQsQANLLQS 9606 9368058 t lperfetto "Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites" SIGNOR-53258 PRKDC protein P78527 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Thr226 LQAQNLLtQLPQQSQ 9606 9368058 t lperfetto "Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites" SIGNOR-53262 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT down-regulates phosphorylation Thr3950 GHAFGSAtQFLPVPE 9606 17189255 t gcesareni "Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster." SIGNOR-151453 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser11 SGFESYGsSSYGGAG -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248980 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser12 GFESYGSsSYGGAGG -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248981 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser700 FGEKRKNsILNPINS -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-248850 PRKG1 protein Q13976 UNIPROT GKAP1 protein Q5VSY0 UNIPROT unknown phosphorylation Ser106 SNPVQKDsREENWQE 9534 BTO:0000298 10671526 t lperfetto "Although both cGK-Ialpha and -Ibeta, but not cAMP-dependent protein kinase, phosphorylated GKAP42 in vitro, GKAP42 was a good substrate only for cGK-Ialpha in intact cells, suggesting that the association with kinase protein is required for the phosphorylation in vivo." SIGNOR-249037 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser412 GIPFRRPsTYGIPRL 9606 BTO:0000671 12082086 t lperfetto "G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells" SIGNOR-89849 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser784 GVPFRRPsTFGIPRL 9606 BTO:0000671 12082086 t lperfetto "G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells" SIGNOR-89853 PRKG1 protein Q13976 UNIPROT PRKG1 protein Q13976 UNIPROT up-regulates phosphorylation Ser65 TTRAQGIsAEPQTYR 9606 12080049 t miannu "Serines 64 and 79 are homologous residues that are juxtaposed to the autoinhibitory pseudosubstrate site in cgmp-dependent protein kinase type ialpha and type ibeta (pkg-ialpha and pkg-ibeta), respectively. Autophosphorylation of this residue is associated with activation of type i pkgs." SIGNOR-89839 PRKG1 protein Q13976 UNIPROT RGS2 protein P41220 UNIPROT "up-regulates activity" phosphorylation Ser46 KDWKTRLsYFLQNSS -1 14608379 t lperfetto "Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. " SIGNOR-249240 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 PRKG2 protein Q13237 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 "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-186943 PRKRA protein O75569 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR "form complex" binding 9606 23661684 t lperfetto "Immunoprecipitation and reconstitution experiments in various systems have shown that Dicer associates with proteins in the Argonaute (Ago) family of endonucleases and with specific double-stranded RNA-binding proteins (dsRBPs) (3–7). | In humans, these dsRBPs are protein activator of PKR (PACT) (5) and trans-activation response RNA-binding protein (TRBP) (3,4)." SIGNOR-255318 PRKX protein P51817 UNIPROT PKD1 protein P98161 UNIPROT up-regulates phosphorylation Ser4166 EPLPSRSsRGSKVSP 9606 BTO:0000671 17980165 t lperfetto "The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd." SIGNOR-158852 PRL protein P01236 UNIPROT KRT5 protein P13647 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251903 PRL protein P01236 UNIPROT LPL protein P06858 UNIPROT "down-regulates activity" 9606 BTO:0001487 12679477 f Regulation miannu "PRL inhibits lipoprotein lipase activity in human white adipose tissue" SIGNOR-251851 PRL protein P01236 UNIPROT PRLR protein P16471 UNIPROT up-regulates binding 9606 BTO:0000150 10585417 t gcesareni "Prolactin-dependent signaling occurs as the result of ligand-induced dimerization of the prolactin receptor (prlr)." SIGNOR-72810 PRLR protein P16471 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000975 17975019 f miannu "We also show that activation of RS represses the expression of the transcription factor Forkhead box O3 (FOXO3) and that of the enzyme galactose-1-phosphate uridyltransferase (Galt), two proteins known to be essential for normal follicular development." SIGNOR-254187 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg25 ECPTGGGrGRGMRSR 9606 24726729 t miannu "Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding" SIGNOR-204958 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg27 PTGGGRGrGMRSRGR 9606 24726729 t miannu "Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding" SIGNOR-204962 progesterone smallmolecule CHEBI:17026 ChEBI COMT protein P21964 UNIPROT down-regulates 17138778 f "Regulation of expression" miannu "Catechol-O-methyltransferase expression was down-regulated by progesterone or estrogen." SIGNOR-251960 "propionic acid" chemical CHEBI:30768 ChEBI FFAR3 protein O14843 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-257490 propranolol chemical CHEBI:8499 ChEBI ADRB2 protein P07550 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 10079020 t Luana "Similarly, the binding affinities of ICI 118–551, CGP 20712A, propranolol, bupranolol and CGP 12177 for human β1-, β2- and β3-adrenoceptors correlate with their affinities at human β1- (P=0.04), β2- (P=0.01)" SIGNOR-258334 "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 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI GNG12 protein Q9UBI6 UNIPROT up-regulates "chemical activation" 9606 16293724 t gcesareni "Although pge2 promotes nucleotide exchange on gas and subsequent dissociation of gtp-bound gas from gbg subunits." SIGNOR-141820 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI PTGER2 protein P43116 UNIPROT up-regulates "chemical activation" 9606 15299086 t gcesareni "Pge2 acts via four ep receptors termed ep1 to ep4." SIGNOR-127735 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI PTGER3 protein P43115 UNIPROT up-regulates "chemical activation" 9606 15299086 t gcesareni "Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4." SIGNOR-127738 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI PTGER4 protein P35408 UNIPROT up-regulates "chemical activation" 9606 15299086 t gcesareni "Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4." SIGNOR-127789 "prostaglandin F2alpha(1-)" smallmolecule CHEBI:57404 ChEBI PTGFR protein P43088 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-257573 PRR5 protein P85299 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-205621 PRRX1 protein P54821 UNIPROT MAFB protein Q9Y5Q3 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-221899 PSTPIP1 protein O43586 UNIPROT ABL1 protein P00519 UNIPROT down-regulates 9606 11163214 f lperfetto "Cytoskeletal protein pstpip1 directs the pest-type protein tyrosine phosphatase to the c-abl kinase to mediate abl dephosphorylationSeveral experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity" SIGNOR-105035 PSTPIP1 protein O43586 UNIPROT DNM2 protein P50570 UNIPROT down-regulates binding 9606 BTO:0000130 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 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 PTBP2 protein Q9UKA9 UNIPROT SRC protein P12931 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 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-261267 PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0001332 19903340 f lperfetto "PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression" SIGNOR-244439 PTEN protein P60484 UNIPROT DUSP1 protein P28562 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 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 PTEN protein P60484 UNIPROT PPM1A protein P35813 UNIPROT up-regulates binding 9606 18482992 t lpetrilli "Upon complex formation with pten, ppm1a is protected from degradation induced by the tgf-? Signaling. this study establishes a novel role for nuclear pten in the stabilization of ppm1a." SIGNOR-178643 PTEN protein P60484 UNIPROT PREX2 protein Q70Z35 UNIPROT "down-regulates activity" binding 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-259190 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 BTO:0000007 22413754 t miannu "Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites" SIGNOR-248544 PTGS2 protein P35354 UNIPROT "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 16540375 t "Arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES)" SIGNOR-255684 PTGER1 protein P34995 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-256954 PTGER3 protein P43115 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 BTO:0000938 12038972 t gcesareni "Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)" SIGNOR-88143 PTGER3 protein P43115 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 BTO:0000938 12038972 t gcesareni "Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)" SIGNOR-88192 PTGFR protein P43088 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-256953 PTH protein P01270 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005173 17656568 f miannu "Parathyroid hormone (PTH) functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We have already shown that PTH stimulates the expression of matrix metalloproteinase-13 (MMP-13), which is responsible for degrading components of extracellular matrix." SIGNOR-254234 PTH protein P01270 UNIPROT PTH1R protein Q03431 UNIPROT up-regulates binding 9606 18981475 t gcesareni "Here we show that binding of pth to its receptor pth1r induced association of lrp6, a coreceptor of wnt, with pth1r. The formation of the ternary complex containing pth, pth1r, and lrp6 promoted rapid phosphorylation of lrp6, which resulted in the recruitment of axin to lrp6, and stabilization of beta-catenin." SIGNOR-182039 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 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 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 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 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-166510 PTK6 protein Q13882 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr165 PSPATDLyQVPPGPG 9606 BTO:0001130 22084245 t lperfetto "Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro" SIGNOR-177238 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr435 ARPVKGAyREHPYGR 9606 BTO:0000567 16179349 t lperfetto "We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal." SIGNOR-249293 PTPA protein Q15257 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 t gcesareni "Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473)" SIGNOR-252607 PTPA protein Q15257 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 t gcesareni "Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473)" SIGNOR-170699 PTPN11 protein Q06124 UNIPROT CSF2RB protein P32927 UNIPROT up-regulates dephosphorylation 9606 phosphorylation:Tyr628 PPPGSLEyLCLPAGG 9162089 t gcesareni "Shp2 is thought to act as a positive mediator of growth factor signals.. Hp2 could act as an adaptor between the activated c and grb2, thus leading to activation of the ras/mitogen-activated protein kinase pathway, known to be activated by il-3" SIGNOR-48557 RUNX2 protein Q13950 UNIPROT TNFSF11 protein O14788 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-107242 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 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 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 BTO:0003892 11731619 t "PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site" SIGNOR-248658 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 BTO:0000149 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 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 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-132563 PTPN13 protein Q12923 UNIPROT NFKBIA protein P25963 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 BTO:0000007 11106428 t "Identification of IkappaBalpha as a substrate of Fas-associated phosphatase-1|A full-length FAP-1 protein preferentially dephosphorylates Tyr-42 of IkBa|Moreover, other studies have shown that tyrosine phosphorylation of IkBa on Tyr-42 (which occurs with Fas ligand binging) protected against inducible degradation both in vitro [30] and in vivo [38]" SIGNOR-248712 PTPN1 protein P18031 UNIPROT EPHA3 protein P29320 UNIPROT "down-regulates activity" dephosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 21135139 t "Nevertheless, the finding that phosphorylation of the activation loop tyrosine (EphA3-Y779), a recently identified PTP1B substrate (Mertins et al., 2008), is essential for ligand-induced endocytosis (Janes et al., 2009)" SIGNOR-248426 PTPN1 protein P18031 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-248418 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr487 SLSNIDFyAQVSDIT 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-248419 PTPN1 protein P18031 UNIPROT IGF1R protein P08069 UNIPROT "down-regulates activity" dephosphorylation 9606 11884589 t lperfetto "Ptp-1b can regulate igf-ir kinase activity and function and that loss of ptp-1b can enhance igf-i-mediated cell survival, growth, and motility in transformed cells." SIGNOR-115709 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 12857726 t gcesareni "Our results demonstrate that ptp1b plays an important role in the integrin-mediated dephosphorylation of lat in human platelets and is involved in the control of irreversible aggregation upon fcgammariia stimulation." SIGNOR-103599 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 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1009 LDTSSVLyTAVQPNE 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179064 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 18567737 t gcesareni "Interestingly, resveratrol increased the activity of protein tyrosine phosphatase ptp1b, which dephosphorylates pdgf-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on pdgfr with concomitant reduction in akt and erk1/2 kinase activity. these results for the first time provide evidence that the stilbene resveratrol targets ptp1b to inhibit pdgfr mitogenic signaling." SIGNOR-179068 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t "Overexpression of PTP1B increased Src specific activity in colon cancer cells by reducing phosphorylation at Y530 of Src." SIGNOR-248422 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 BTO:0000782 12857726 t gcesareni "The tyrosine kinase pp60c-src has also been identified as a good substrate of ptp1b leading to an activation of this kinase (27)." SIGNOR-103607 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 t "PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3." SIGNOR-248427 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 t gcesareni "Mechanism of protein tyrosine phosphatase 1b-mediated inhibition of leptin signalling. Ptp1b plays a critical role in the down-regulation of activated-stat3 by dephosphorylating tyr705, that is the phosphorylation site of activation of stat3." SIGNOR-135211 PTPN1 protein P18031 UNIPROT STAT5A protein P42229 UNIPROT "down-regulates activity" dephosphorylation Tyr694 LAKAVDGyVKPQIKQ 9534 BTO:0004055 10993888 t "A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b" SIGNOR-248428 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT down-regulates dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 BTO:0000007 16461343 t gcesareni "Native ptpn22 dephosphorylated lck at its activating tyrosine residues tyr-394." SIGNOR-144341 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 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 BTO:0000007 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 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1214 VCDPKFHyDNTAGIS 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-181546 PTPN2 protein P17706 UNIPROT SRC protein P12931 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 22080863 t gcesareni "We found that tcptp dephosphorylates and inactivates src family kinases to regulate t cell responses._" SIGNOR-177116 PTPN2 protein P17706 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 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-93998 PTPN2 protein P17706 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000567 12138178 t gcesareni "The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation." SIGNOR-90818 PTPN2 protein P17706 UNIPROT STAT6 protein P42226 UNIPROT "down-regulates activity" dephosphorylation 9606 17210636 t gcesareni "these results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors" SIGNOR-235192 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 11812650 t gcesareni "However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2." SIGNOR-114597 PTPN6 protein P29350 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782;BTO:0000785 11021818 t gcesareni "The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase." SIGNOR-82764 PTPN6 protein P29350 UNIPROT NTRK1 protein P04629 UNIPROT "down-regulates activity" dephosphorylation Tyr680 RDIYSTDyYRVGGRT 10116 BTO:0001009 "phosphorylation: tyr496" HIIENPQyFSDACVH 14662744 t "Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675." SIGNOR-248468 PTPN6 protein P29350 UNIPROT NTRK1 protein P04629 UNIPROT "down-regulates activity" dephosphorylation Tyr681 DIYSTDYyRVGGRTM 10116 BTO:0001009 "phosphorylation: tyr496" HIIENPQyFSDACVH 14662744 t "Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675." SIGNOR-248469 PTPN6 protein P29350 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates dephosphorylation Tyr402 CSIESDIyAEIPDET 9606 10521452 t gcesareni "Raftk binds constitutively to the protein tyrosine phosphatase shptp1.SHPTP1 Plays a negative role in pyk2/raftk signaling by dephosphorylating raftk on tyr-402, thereby inhibiting the interaction of the sh2 domain of c-src with raftk" SIGNOR-71414 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation 9606 11266449 t lperfetto "Overexpression of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation. We propose that shp-1 is an important downstream regulator of ros signaling." SIGNOR-105922 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2274 KNREGLNyMVLATEC 9606 11266449 t gcesareni "Phosphorylated ros strongly and directly associates with shp-1.Overexpression Of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation" SIGNOR-105919 PTPN6 protein P29350 UNIPROT SH3BP2 protein P78314 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 16649996 t gcesareni "Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling" SIGNOR-146508 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-146672 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-146676 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 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0000007 12754301 t llicata "The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop" SIGNOR-248449 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 PTPRF protein P10586 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 15896785 t "10226025:Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473." acerquone "Knock-down of lar by the l3 sirna probe markedly inhibited the insulin-stimulated increase in the phosphorylation of protein kinase b (pkb, also called akt) on serine 473 by >90%" SIGNOR-137246 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates dephosphorylation Tyr490 HCAAWHGyYSVAKAL 9606 17803936 t gcesareni "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." SIGNOR-157702 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates dephosphorylation Tyr491 CAAWHGYySVAKALC 9606 17803936 t amattioni "Lar tyrosine phosphatase dephosphorylates dapk at py491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of dapk" SIGNOR-157706 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000661 BTO:0000142;BTO:0000671 12496362 t lperfetto "Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule." SIGNOR-96768 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT up-regulates dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000661 BTO:0000142;BTO:0000671 12496362 t gcesareni "Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule." SIGNOR-96764 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 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-76005 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" dephosphorylation Tyr703 DHAEAALyKNLLHSK -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-254709 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" dephosphorylation Tyr730 DMKPGVSyVVPTKAD -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-254710 PTPRG protein P23470 UNIPROT LIMK1 protein P53667 UNIPROT "down-regulates activity" dephosphorylation Tyr507 KPDRKKRyTVVGNPY -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-254711 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18936167 t gcesareni "The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2." SIGNOR-181676 PTPRG protein P23470 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr716 RPPSAELySNALPVG -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-254715 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 PTPRG protein P23470 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" dephosphorylation Tyr701 DGPKGTGyIKTELIS -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-254727 PTPRJ protein Q12913 UNIPROT LAT protein O43561 UNIPROT "down-regulates activity" dephosphorylation 9606 11259588 t "Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation" SIGNOR-248696 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 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" dephosphorylation Tyr315 MPMDTSVyESPYSDP -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-254733 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" dephosphorylation Tyr319 TSVYESPySDPEELK -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-254734 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 PTPRH protein Q9HD43 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-76072 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 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 PTPRJ protein Q12913 UNIPROT FLT1 protein P17948 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni "Vegf acts by binding to two high affinity receptor tyrosine kinases: vegf receptor (vegfr)* 1 also called flt-1, and vegfr-2, also called flk-1/kdr 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-101272 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 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 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Tyr205 IMLNSKGyTKSIDIW 9606 19494114 t gcesareni "In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo." SIGNOR-161536 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12771128 t 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-101282 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000150;BTO:0000551 12475979 t gcesareni "Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase dep-1" SIGNOR-96347 PTPRK protein Q15262 UNIPROT EGFR protein P00533 UNIPROT unknown dephosphorylation Tyr1197 STAENAEyLRVAPQS 10029 BTO:0000246 16263724 t "RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro." SIGNOR-248723 PTPRR protein Q15256 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 11711538 t gcesareni "As shown, gst-ptp-sl dephosphorylated efficiently both erk2 and p38 wild typetogether, these results indicate that the defective association of the tyrosine phosphatase ptp-sl with erk2 d319n and p38 d316n mutations impairs the retention and inactivation in the cytosol of these map kinases by ptp-sl." SIGNOR-111762 PTPRR protein Q15256 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 11493009 t "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.|PTP-SL dephosphorylates the regulatory phosphotyrosine on the active loop of ERK1/2. Tyrosine dephosphorylation of ERK1/2 causes the inactivation of ERK1/2 and its retention in the cytoplasm" SIGNOR-248840 PYCARD protein Q9ULZ3 UNIPROT "NLRC4 inflammasome" complex SIGNOR-C223 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-256405 Pyridostigmine chemical CHEBI:8665 ChEBI ACHE protein P22303 UNIPROT "down-regulates activity" "chemical inhibition" -1 20627738 t Luana "The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors " SIGNOR-257879 quetiapine chemical CHEBI:8707 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000601 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 quetiapine chemical CHEBI:8707 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-258531 quinpirole chemical CHEBI:75401 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-258441 quinpirole chemical CHEBI:75401 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-258440 quizartinib smallmolecule CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206331 quizartinib smallmolecule CHEBI:90217 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-258271 R406 chemical CID:11984591 PUBCHEM SYK protein P43405 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206340 R547 chemical CID:6918852 PUBCHEM CCNB1 protein P14635 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206349 R547 chemical CID:6918852 PUBCHEM CCNE1 protein P24864 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206355 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206358 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206361 RAB14 protein P61106 UNIPROT RUFY1 protein Q96T51 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 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." SIGNOR-261279 RAB1A protein P62820 UNIPROT C9orf72 protein Q96LT7 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 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 RAB1A protein P62820 UNIPROT GOLGA2 protein Q08379 UNIPROT "up-regulates activity" relocalization 10116 BTO:0000951 11285137 t Giulio "Here, we demonstrate that the cis ‐Golgi tethering protein GM130, complexed with GRASP65 and other proteins, forms a novel Rab1 effector complex that interacts with activated Rab1‐GTP in a p115‐independent manner and is required for coat protein II vesicle targeting/fusion with the cis ‐Golgi" SIGNOR-261285 RAB1A protein P62820 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 27334615 t Giulio "Thus, these data show ULK1–Rab1a interaction in intact cells and reveal that this interaction is C9orf72 dependent." SIGNOR-261283 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 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 RABGEF1 protein Q9UJ41 UNIPROT RAB5A protein P20339 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 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-260707 RAC1 protein P63000 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 21712438 f gcesareni "Hypertonicity activates p38 via a rac1-osm-mekk3-mkk3-p38 pathway." SIGNOR-174602 RACK1 protein P63244 UNIPROT PPP2CA protein P67775 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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 RACK1 protein P63244 UNIPROT PTK7 protein Q13308 UNIPROT up-regulates binding 9606 21350015 t gcesareni "Here, we identify rack1 as a novel interaction partner of ptk7. Mechanistically, rack1 is necessary for the ptk7-mediated membrane localization of dishevelled (dsh). Rack1 facilitates the ptk7-dsh interaction by recruiting pkcdelta1, a known effector of dsh membrane translocation." SIGNOR-172322 (R)-adrenaline smallmolecule CHEBI:28918 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-258443 RAF1 protein P04049 UNIPROT STK4 protein Q13043 UNIPROT down-regulates binding 9606 BTO:0000782 BTO:0001253 22898666 t gcesareni "Raf1 binding to mst2 sarah domain interdicts mst2 homodimerization and autoactivation, and recruits protein phosphates 2a thereby promoting mst2 inactivation." SIGNOR-191843 "Raf265 derivative" chemical CID:23654923 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206394 RAG1 protein P15918 UNIPROT MTOR protein P42345 UNIPROT up-regulates relocalization 9606 22790199 t 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-198242 RANBP3 protein Q9H6Z4 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" relocalization 9606 19289081 t lperfetto "RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner." SIGNOR-217634 RANBP3 protein Q9H6Z4 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" relocalization 9606 20704570 t lperfetto "Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses" SIGNOR-217625 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" relocalization 9606 19289081 t lperfetto "RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner." SIGNOR-232116 RARA protein P10276 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 BTO:0000150 10607566 f gcesareni "We shown that retinoic acid (ra) decreases the activity of the beta-catenin-lef/tcf signaling pathway" SIGNOR-73274 RARA protein P10276 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11788593 f gcesareni "We show that retinoic acid receptor (rar)-selective ligands reduce egfr level and the magnitude and duration of egfr activation in egf-stimulated cells" SIGNOR-114087 RARA protein P10276 UNIPROT NR4A1 protein P22736 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782;BTO:0001271;BTO:0000661 10772826 f lperfetto "Retinoic acid and its receptors repress the expression and transactivation functions of nur77" SIGNOR-76980 RARA protein P10276 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-16433 RASGRF2 protein O14827 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-260574 RASGRF2 protein O14827 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-260573 RB1 protein P06400 UNIPROT ITGA10 protein O75578 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001957 24287699 f lperfetto "Integrin α10 expression is pRb-dependent in mouse osteoblasts|pRb-activated expression of integrin α10 mRNA is effectively translated into higher levels of integrin α10 protein as visualized by immunofluorescence" SIGNOR-253348 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 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HIF1A protein Q16665 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 19808903 t lperfetto "We report a Notch signal-induced pathway that leads to transcriptional activation of HIF1-alpha gene." SIGNOR-209720 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000785 16847353 t lperfetto "C-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma" SIGNOR-209593 RCAN1 protein P53805 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR "down-regulates activity" binding 9606 12554096 t "MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure" SIGNOR-252341 RCAN1 protein P53805 UNIPROT PPP3CA protein Q08209 UNIPROT "down-regulates activity" binding 9606 12554096 t "MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure" SIGNOR-252025 RCOR1 protein Q9UKL0 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR "form complex" binding 9606 20080105 t 1 miannu "Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex." SIGNOR-239220 regorafenib chemical CHEBI:68647 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206412 regorafenib chemical CHEBI:68647 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206415 regorafenib chemical CHEBI:68647 ChEBI MAPK11 protein Q15759 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-259211 regorafenib chemical CHEBI:68647 ChEBI RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206418 RELA protein Q04206 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 SIGNOR-C6 10207072 t gcesareni "Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo." SIGNOR-66953 RELA protein Q04206 UNIPROT EGR1 protein P18146 UNIPROT up-regulates binding 9606 SIGNOR-C13 10671503 t gcesareni "The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo" SIGNOR-75001 RELA protein Q04206 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates binding 9606 15988006 t gcesareni "P65 and histone deacetylases 4 cooperate to inhibit the ability of mef2 factors to induce the klf2 promoter" SIGNOR-138368 reserpine chemical CHEBI:28487 ChEBI SLC18A1 protein P54219 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000318 8643547 t miannu "Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2." SIGNOR-258492 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 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 RET protein P07949 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates binding 9606 8631863 t gcesareni "Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell" SIGNOR-41699 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1015 MMVKRRDyLDLAAST 9606 14981541 t llicata "Opn upregulation depended on the integrity of the ret/ptc kinase and tyrosines y1015 and y1062, two major ret/ptc autophosphorylation sites. ret signalling mainly depends on three key tyrosine residues: tyrosine 905, in the activation loop, whose phosphorylation stabilizes the active conformation of the catalytic domain , tyrosine 1015, a docking site for phospholipase citalic gamma and tyrosine 1062." SIGNOR-122915 RFXANK protein O14593 UNIPROT "RFX complex" complex SIGNOR-C104 SIGNOR "form complex" binding -1 10825209 t miannu "RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes" SIGNOR-221571 "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 RHOA protein P61586 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates binding 9606 11102529 t gcesareni "Our results demonstrate that direct stimulation of pld1 in vivo by rhoa" SIGNOR-84953 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 "Rigosertib sodium" chemical CID:23696523 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195028 RIN1 protein Q13671 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation 9606 BTO:0000149 15886098 t "CrkL forms a constitutive complex with Abl, thus explaining the strong preference of Bcr-Abl for CrkL." gcesareni "Rin1 binds to the abl sh3 and sh2 domains, and these inetractions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl" SIGNOR-136961 RIN1 protein Q13671 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 12783862 t gcesareni "The interaction between egfr and rin1 delineates a novel signal transduction pathway between egfr and its effectors, rin1, rab5a, and ras, which together coordinate and regulate both signaling and membrane trafficking." SIGNOR-101530 RIPK1 protein Q13546 UNIPROT Necrosis phenotype SIGNOR-PH3 SIGNOR up-regulates 9606 14965271 f amattioni "Fas-induced necrosis requires rip" SIGNOR-121901 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 RIPK2 protein O43353 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser446 DSIRLQIsNPDLKDR 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-196524 risperidone chemical CHEBI:8871 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-258524 risperidone chemical CHEBI:8871 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-258529 rivaroxaban chemical CHEBI:68579 ChEBI F10 protein P00742 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206550 RNF10 protein Q8N5U6 UNIPROT MEOX2 protein P50222 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 16335786 t miannu "RFN10 co-immunoprecipitates with MEOX2. RNF10 potentiates MEOX2 transcriptional activation" SIGNOR-236968 RNF111 protein Q6ZNA4 UNIPROT SKIL protein P12757 UNIPROT down-regulates ubiquitination 9606 17591695 t gcesareni "Arkadia interacts with snon and induces its ubiquitination irrespective of tgf-beta/activin signaling, but snon is efficiently degraded only when it forms a complex with both arkadia and phosphorylated smad2 or smad3" SIGNOR-156430 RNF43 protein Q68DV7 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates relocalization 9606 23151663 t gcesareni "Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation61 (see above), and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane" SIGNOR-199585 RNF8 protein O76064 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates ubiquitination 9606 20551964 t gcesareni "Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist." SIGNOR-166174 RNF8 protein O76064 UNIPROT H2AX protein P16104 UNIPROT up-regulates ubiquitination 9606 18001824 t gcesareni "Rnf8 can ubiquitylate histone h2a and h2ax," SIGNOR-159309 (R)-noradrenaline smallmolecule CHEBI:18357 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-258897 ROCK1 protein Q13464 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 19279717 t areggio "To date it is not clear whether any genes are transcribed downstream of these two GTPases for non-canonical signaling. The prevailing dogma remains that their primary roles are indeed solely for cytoskeletal modulation" SIGNOR-258975 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr445 QKQQREKtRWLNSGR 9606 BTO:0000671 10209029 t lperfetto "Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480" SIGNOR-66992 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000551 20145185 t 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-163730 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Thr576 NSCRSSTtTCPEQDF 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-249300 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -1 12686604 t lperfetto "We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro." SIGNOR-100188 ROCK1 protein Q13464 UNIPROT KCNK3 protein O14649 UNIPROT down-regulates phosphorylation Ser336 IPRDLSTsDTCVEQS 9606 BTO:0000887 21838752 t lperfetto "Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway." SIGNOR-176025 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Thr18 T-->A -1 21457715 t Giulio "Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation." SIGNOR-260308 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 ROCK1 protein Q13464 UNIPROT MYLK protein Q15746 UNIPROT up-regulates binding 9606 11283607 t gcesareni "Rock proteins are known to regulate mlc-phosphorylation, and apoptotic cells exhibit a gradual increase in levels of phosphorylated mlc concomitant with rock i cleavage." SIGNOR-106552 ROCK1 protein Q13464 UNIPROT PPP1R12B protein O60237 UNIPROT down-regulates phosphorylation Thr646 ARQTRRStQGVTLTD 9606 22937917 t lperfetto "Phosphorylation of ppp1r12b on threonine 646 by rho kinase inhibits the activity of the pp1c-ppp1r12b complex." SIGNOR-198812 ROCK2 protein O75116 UNIPROT LPP protein Q93052 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 22886954 f miannu "Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression" SIGNOR-191765 ROCK2 protein O75116 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates phosphorylation Thr38 QKRHARVtVKYDRRE 9606 BTO:0000887;BTO:0001260 12144526 t gcesareni "Phosphorylation levels of thr(38)-cpi-17 and thr(696)/thr(850) myosin phosphatase target subunit (mypt1) were measured during pdbu or dog stimulation using site specific antibodies. cpi-17 as a major downstream effector, is phosphorylated by pkc and rock during pdbu and dog stimulation." SIGNOR-90832 ROCK2 protein O75116 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates phosphorylation Thr38 QKRHARVtVKYDRRE 9606 BTO:0000938 BTO:0000887;BTO:0000142 12495628 t gcesareni "Phosphorylation levels of thr(38)-cpi-17 and thr(696)/thr(850) myosin phosphatase target subunit (mypt1) were measured during pdbu or dog stimulation using site specific antibodies. cpi-17 as a major downstream effector, is phosphorylated by pkc and rock during pdbu and dog stimulation." SIGNOR-96696 ropinirole chemical CHEBI:8888 ChEBI DRD3 protein P35462 UNIPROT "up-regulates activity" "chemical activation" -1 9057850 t miannu "Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively)" SIGNOR-258601 RPA2 protein P15927 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates binding 9606 20068082 t gcesareni "Ssdna lesions are then coated by replication protein a (rpa), recruiting atr/atrip (atr-interacting protein) complexes via recognition and association of rpa-ssdna by atrip." SIGNOR-163176 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 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 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 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 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 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10558990 t lperfetto "The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival." SIGNOR-180910 RPS6KA1 protein Q15418 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-137482 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 RPS6KA1 protein Q15418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto "S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity." SIGNOR-110917 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 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-70428 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 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-138467 RPS6KA1 protein Q15418 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata "Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo" SIGNOR-160904 RPS6KA1 protein Q15418 UNIPROT RPS6KA1 protein Q15418 UNIPROT "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-162681 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 RPS6KA2 protein Q15349 UNIPROT NR4A1 protein P22736 UNIPROT "up-regulates activity" phosphorylation Ser351 GRRGRLPsKPKQPPD 10116 BTO:0001009 11883936 t lperfetto "Phosphorylation of a residue in the DNA-binding region (Ser-350 of NGFI-B and 354 of Nur77) has been described in detail to have effect on the transcriptional function of the protein [11, 24]. Growth-related kinase pp90rsk, but not ERK1 (pp44mapk), was shown to phosphorylate recombinant Nur77 in vitro in the DNA binding domain, but not the amino-terminus, using an immune complex kinase as- say [11]." SIGNOR-249429 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT "down-regulates activity" phosphorylation Ser25 KRRSARLsAKPPAKV 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-249101 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT unknown phosphorylation Ser7 sSAEGAAK 10090 BTO:0000452 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 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin." SIGNOR-249215 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 RPS6KA4 protein O75676 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 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) 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-151436 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 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-70444 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 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-138483 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 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser636 SGDYMPMsPKSVSAP 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-236733 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 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-252798 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252799 RPS6K proteinfamily SIGNOR-PF26 SIGNOR EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 11500364 t lperfetto "We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity" SIGNOR-252775 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252807 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 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata "Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo" SIGNOR-252770 RPS6K proteinfamily SIGNOR-PF26 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 BTO:0000551 21423205 t lperfetto "Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin." SIGNOR-252802 RPS6K proteinfamily SIGNOR-PF26 SIGNOR YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto "We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue." SIGNOR-252804 (R)-salbutamol chemical CHEBI:8746 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-257866 (R)-salbutamol chemical CHEBI:8746 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-257865 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0000007 22575959 t "Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3." SIGNOR-260113 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 RSPO2 protein Q6UXX9 UNIPROT LGR4 protein Q9BXB1 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-174486 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 RUBCN protein Q92622 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates binding 9606 19270693 t gcesareni "The run or cysteine-rich domain of rubicon appears to be inhibitory to the binding of rubicon to beclin 1 and vps34" SIGNOR-184547 RUNX1 protein Q01196 UNIPROT CCL3 protein P10147 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 12771199 t lperfetto "We show that RUNX1 can specifically bind to both RUNX sites but that only the proximal RUNX site is essential for PMA/ PHA stimulation of the MIP-1a promoter in Jurkat T-cells. We also show that the endogenous MIP-1a promoter is constitutively bound by RUNX1." SIGNOR-251738 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 RUNX2 protein Q13950 UNIPROT BMP2 protein P12643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15765505 f gcesareni "Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development" SIGNOR-134515 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 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 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 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-258277 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206670 ruxolitinib chemical CHEBI:66919 ChEBI JAK3 protein P52333 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206673 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 RXRB protein P28702 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-79449 RXRB protein P28702 UNIPROT NR2F2 protein P24468 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-79452 S1PR1 protein P21453 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-256856 S1PR2 protein O95136 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-257007 S1PR3 protein Q99500 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-257388 sabcomeline chemical CHEBI:134846 ChEBI CHRM3 protein P20309 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000142 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-258677 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 SATB1 protein Q01826 UNIPROT CD52 protein P31358 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-255131 SATB1 protein Q01826 UNIPROT HSPA6 protein P17066 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-255134 SATB1 protein Q01826 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000725 23563689 f miannu "Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc" SIGNOR-224831 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000567 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 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YAP1 protein P46937 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23431053 t lperfetto "This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap." SIGNOR-217187 SCF-FBW7 complex SIGNOR-C135 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity" ubiquitination 9606 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-243757 SCF-SKP2 complex SIGNOR-C136 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity" ubiquitination 9606 20852628 t gcesareni "The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain" SIGNOR-243551 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 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 SCHEMBL5067 smallmolecule CID:57418127 PUBCHEM MTR protein Q99707 UNIPROT "up-regulates activity" "chemical activation" 10520212 t lperfetto "Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels." SIGNOR-253144 SCN4A protein P35499 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 BTO:0001103 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 SDC4 protein P31431 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1." SIGNOR-199632 SDHB protein P21912 UNIPROT SDHA/SDHB complex SIGNOR-C69 SIGNOR "form complex" binding 9606 23000077 t miannu "Complex ii (also known as succinate dehydrogenase (sdh) or succinate coenzyme q reductase (sqr)) is made up of only four subunits (sdha, sdhb, sdhc and sdhd) / sdha and sdhb constitute the catalytic core of the complex that on its own can oxidize succinate (which directly binds to sdha) to fumarate in the tca cycle." SIGNOR-192082 (-)-selegiline chemical CHEBI:9086 ChEBI MAOB protein P27338 UNIPROT "down-regulates activity" "chemical inhibition" -1 21377879 t Luana "All the compounds were found as extremely potent and selective towards MAO-B, (Table 2) with at least 100 times more potent than the positive control selegiline. " SIGNOR-258136 SEMA3C protein Q99985 UNIPROT PLXNA2 protein O75051 UNIPROT "up-regulates activity" binding 19666519 f 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 SEMA3F protein Q13275 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t esanto "In the nervous system, neuropilins mediate axon retraction and guidance by binding class iii semaphorins. We found that sema3f could compete with metabolically labeled vegf-c for the binding to np1-ig and np2-ig fusion proteins." SIGNOR-147608 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 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1E protein P28566 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-257519 SERPINA1 protein P01009 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-41180 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 SERPINE1 protein P05121 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 10368279 f gcesareni "Pai-1 is now being identified as a key player in the link between coagulation and the cell adhesion pathways involved in tissue remodeling and metastasis. Active pai-1 (but not its latent or cleaved forms) binds tightly to the adhesive glycoprotein vitronectin in the extracellular matrix." SIGNOR-68478 SERPINE1 protein P05121 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 10368279 f gcesareni "Pai-1 is the physiological inhibitor of the fibrinolytic pathway" SIGNOR-68481 SERPINE1 protein P05121 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 29474926 f miannu "Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding." SIGNOR-260588 sertindole chemical CHEBI:9122 ChEBI DRD3 protein P35462 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-258547 sertindole chemical CHEBI:9122 ChEBI HTR1E protein P28566 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-258543 SF3B1 protein O75533 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000664;BTO:0000565 25428262 f irozzo "We have shown that SF3B1 knockdown in four myeloid cell lines resulted in inhibition of cell growth and disruption of the cell cycle.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." SIGNOR-256003 SFN protein P31947 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates relocalization 9606 BTO:0000150;BTO:0001130 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 SFPQ protein P23246 UNIPROT "LMX1B/SFPQ/PSPC1 complex" complex SIGNOR-C106 SIGNOR "form complex" binding 10090 BTO:0000669 23308148 t miannu "LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo." SIGNOR-223970 SFPQ protein P23246 UNIPROT NONO/SFPQ complex SIGNOR-C62 SIGNOR "form complex" binding 9606 BTO:0000017 9756848 t miannu "We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i" SIGNOR-60560 SFPQ protein P23246 UNIPROT TOP1 protein P11387 UNIPROT up-regulates binding 9606 BTO:0000017 9756848 t miannu "We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i" SIGNOR-60563 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 10523516 t gcesareni "Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling." SIGNOR-71423 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000782 10347172 t gcesareni "Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling." SIGNOR-67806 SGI-1776 chemical CID:24795070 PUBCHEM PIM1 protein P11309 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206859 SGK1 protein O00141 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE 10090 BTO:0000011 19965929 t "We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1-/- cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone." SIGNOR-255925 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000007 11154281 t lperfetto "We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. 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." SIGNOR-236607 SGK1 protein O00141 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-252987 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000007 11154281 t lperfetto "We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. 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." SIGNOR-252989 SGK1 protein O00141 UNIPROT GLI1 protein P08151 UNIPROT down-regulates binding 9606 25790864 t gcesareni "SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family" SIGNOR-251672 SGK1 protein O00141 UNIPROT HTT protein P42858 UNIPROT down-regulates phosphorylation Ser419 GGRSRSGsIVELIAG 9606 BTO:0000938 BTO:0000142 14725621 t llicata "The serum- and glucocorticoid-induced kinase sgk inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin." SIGNOR-121349 SGK1 protein O00141 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser214 GGKERPGsKEEVDED 9606 BTO:0000007;BTO:0000567 16982696 t lperfetto "Second, sgk1 indirectly depolymerized mts through the phosphorylation of tau at ser214" SIGNOR-161288 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr346 GTRSRSHtSEGTRSR 9606 BTO:0000567 18787837 t llicata "Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1." SIGNOR-180821 SGK1 protein O00141 UNIPROT SMO protein Q99835 UNIPROT down-regulates binding 9606 25790864 t gcesareni "SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family" SIGNOR-251673 SGK2 protein Q9HBY8 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 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-249132 SGK3 protein Q96BR1 UNIPROT FLII protein Q13045 UNIPROT up-regulates phosphorylation Ser436 RLRRRKDsAQDDQAK 9606 19293151 t lperfetto "Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator." SIGNOR-184688 SGK3 protein Q96BR1 UNIPROT GSK3A protein P49840 UNIPROT "down-regulates activity" phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 16543730 t lperfetto "Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3." SIGNOR-249165 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 SH3RF1 protein Q7Z6J0 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni "We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2." SIGNOR-96952 SH3RF1 protein Q7Z6J0 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni "We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2." SIGNOR-96955 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K10 protein Q02779 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni "Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks." SIGNOR-97003 SH3RF1 protein Q7Z6J0 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 9482736 t gcesareni "Posh activates jnk1 in cos-1 cells." SIGNOR-55759 SHH protein Q15465 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887 17688959 f gcesareni "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-157291 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 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 SIAH1 protein Q8IUQ4 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 BTO:0000938 16174773 t lperfetto "Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system" SIGNOR-140612 SIAH2 protein O43255 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 BTO:0000938 16174773 t lperfetto "Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system" SIGNOR-140651 SIK1 protein P57059 UNIPROT CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation Ser167 MTPTQPEsFSSGSQD 9606 BTO:0000007;BTO:0000567 16817901 t miannu "These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities." SIGNOR-147669 silodosin chemical CHEBI:135929 ChEBI ADRA1A protein P35348 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206914 silodosin chemical CHEBI:135929 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-258449 silodosin chemical CHEBI:135929 ChEBI ADRA1D protein P25100 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-258451 sirolimus chemical CHEBI:9168 ChEBI CD80 protein P33681 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002042 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-255475 sirolimus chemical CHEBI:9168 ChEBI IRS1 protein P35568 UNIPROT up-regulates 9606 16452206 f gcesareni "The mtor inhibitory drug rapamycin up-regulates irs-1 protein levels and induces akt phosphorylation, protein kinase activity, and downstream signaling." SIGNOR-144159 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 SIRT1 protein Q96EB6 UNIPROT CRTC1 protein Q6UUV9 UNIPROT up-regulates deacetylation 9606 BTO:0000938 BTO:0000142 22179316 t miannu "Sirt1 deacetylates and activates torc1" SIGNOR-191568 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 19553684 f gcesareni "Collectively, these data indicate that SIRT1 controls PGC-1alpha gene expression in skeletal muscle and that MyoD is a key mediator of this action" SIGNOR-238790 SIRT1 protein Q96EB6 UNIPROT RELA protein Q04206 UNIPROT "down-regulates activity" deacetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 t gcesareni "SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310." SIGNOR-238817 SIRT2 protein Q8IXJ6 UNIPROT KAT2B protein Q92831 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 12887892 t gcesareni "Sir2 forms a complex with the acetyltransferase pcaf and myod and, when overexpressed, retards muscle differentiation." SIGNOR-104248 SIX1 protein Q15475 UNIPROT EZR protein P15311 UNIPROT "up-regulates quantity" "transcriptional activation" 9606 BTO:0001802 16488997 t "We now show that the gene encoding Ezrin is a direct transcriptional target of Six1." SIGNOR-259374 SIX1 protein Q15475 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 9826681 f gcesareni "We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4." SIGNOR-62104 SIX1 protein Q15475 UNIPROT Six1/Dach complex SIGNOR-C122 SIGNOR "form complex" binding 10090 14628042 t llicata "The phosphatase function of Eya switches the function of Six1-Dach from repression to activation," SIGNOR-238029 SKP1 protein P63208 UNIPROT CUL1 protein Q13616 UNIPROT up-regulates binding 9606 10023660 t gcesareni "The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin." SIGNOR-64511 SKP1 protein P63208 UNIPROT "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR "form complex" binding 10090 25533466 t miannu "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-255278 SKP1 protein P63208 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "form complex" binding 9606 10023660 t gcesareni "The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin." SIGNOR-64514 SL0101 chemical CID:10459196 PUBCHEM RPS6KA3 protein P51812 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207075 SLC16A3 protein O15427 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 f lperfetto "Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival." SIGNOR-242468 SLC16A4 protein O15374 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 f lperfetto "Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival." SIGNOR-256582 SLC27A2 protein O14975 UNIPROT "fatty acyl-CoA" smallmolecule CHEBI:37554 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0006301 10198260 t lperfetto "Very-long-chain acyl-CoA synthetases (VLCS) activate very-long-chain fatty acids (VLCFA) containing 22 or more carbons to their CoA derivatives." SIGNOR-260415 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 SMAD1/4 complex SIGNOR-C85 SIGNOR PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004058 12589053 f lperfetto "Overexpression of Smad6, a natural antagonist for Smad1, blocked PPARgamma expression and adipocytic differentiation induced by BMP2" SIGNOR-236233 SMAD1/4 complex SIGNOR-C85 SIGNOR RUNX2 protein Q13950 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15573378 f 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 SMAD2 protein Q15796 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR "form complex" binding 9606 26194464 t "MARCO ROSINA" "Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes." SIGNOR-255023 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 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 t miannu "Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes" SIGNOR-260440 SMAD3 protein P84022 UNIPROT FOXA1 protein P55317 UNIPROT "down-regulates activity" binding 9606 BTO:0004299 18003659 t 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. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function." SIGNOR-254168 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 9732876 t lperfetto "Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos" SIGNOR-253332 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR ATF2 protein P15336 UNIPROT "up-regulates activity" binding 9606 10085140 t lperfetto "Here we report that the transcription factor atf-2 (also called cre-bp1) is bound by a hetero-oligomer of smad3 and smad4 upon tgf-beta stimulation. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity." SIGNOR-65583 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR PPARG protein P37231 UNIPROT "down-regulates activity" 9606 17139329 f fferrentino "Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter" SIGNOR-253537 SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR "form complex" binding 9606 11274206 t gcesareni "the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4" SIGNOR-235178 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 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 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 SMAD6 protein O43541 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3" SIGNOR-64071 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 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 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-227556 SMAD7 protein O15105 UNIPROT SMURF proteinfamily SIGNOR-PF29 SIGNOR "up-regulates activity" relocalization 9606 19352540 t lperfetto "Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway." SIGNOR-253258 SMARCB1 protein Q12824 UNIPROT CCNA2 protein P20248 UNIPROT down-regulates 9606 12226744 f miannu "We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6." SIGNOR-92782 SMARCB1 protein Q12824 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates 9606 12226744 f miannu "We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6." SIGNOR-92785 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 28195531 t "While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion." SIGNOR-252029 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 BTO:0000007 28195531 t "While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus." SIGNOR-252030 SMO protein Q99835 UNIPROT GATA3 protein P23771 UNIPROT "up-regulates activity" 17139329 t fferrentino "That GATA is a downstream effector of the hedgehog pathway." SIGNOR-253527 SMO protein Q99835 UNIPROT GNAI1 protein P63096 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-199159 SMO protein Q99835 UNIPROT SRC protein P12931 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-178610 SMURF2 protein Q9HAU4 UNIPROT SKIL protein P12757 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0002181;BTO:0005493 11389444 t lperfetto "Tgf-beta also induces the association of smurf2 with the transcriptional co-repressor snon and we show that smad2 can function to mediate this interaction. This allows smurf2 hect domain to target snon for ubiquitin-mediated degradation by the proteasome." SIGNOR-236090 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto "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-120647 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 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 SNCA protein P37840 UNIPROT "ER stress" stimulus SIGNOR-ST9 SIGNOR up-regulates 9606 BTO:0000938 12666095 f lperfetto "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-249702 SNCA protein P37840 UNIPROT Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR up-regulates 9606 BTO:0000938 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 SND1 protein Q7KZF4 UNIPROT IGFBP3 protein P17936 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0003227 23878061 f irozzo "Therefore, we concluded that SND1 could affect SMMC-7721 cells proliferation by regulating IGFBP3 expression and IGF signaling pathway." SIGNOR-259140 SND1 protein Q7KZF4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 "BTO:0001596; BTO:0003904; BTO:0000971" 30365124 f irozzo "SND1 upregulation is a common phenomenon in different human malignant tissues. We found that SND1 overexpression significantly promoted cell proliferation and tumor growth in vitro and in vivo." SIGNOR-259135 SNTG1 protein Q9NSN8 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-255994 SOCS1 protein O15524 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000876 BTO:0001103 24890514 f apalma "Socs1 associates with CSF-1R pTyr-697 and pTyr721 binding sites to inhibit proliferation by an unknown mechanism" SIGNOR-255575 SOCS1 protein O15524 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 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 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT "down-regulates activity" binding 9606 23454976 t miannu "SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell." SIGNOR-255328 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR4 protein P31391 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-257584 "sorafenib tosylate" chemical CHEBI:50928 ChEBI KDR protein P35968 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-259225 "sorafenib tosylate" chemical CHEBI:50928 ChEBI RAF1 protein P04049 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant)." SIGNOR-259228 SOSTDC1 protein Q6X4U4 UNIPROT WNT10B protein O00744 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-242698 SOSTDC1 protein Q6X4U4 UNIPROT WNT11 protein O96014 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-242721 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 SOX2 protein P48431 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19882665 f miannu "We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression." SIGNOR-189036 SOX9 protein P48436 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15240568 f "SOX9 represses the expression of the CDX2 transcription factor, known to be mostly active in villus cells." SIGNOR-253322 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19254573 f fspada "Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation" SIGNOR-184280 SP1 protein P08047 UNIPROT CD151 protein P48509 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000594 20149781 f miannu "SP1 is required for basal activation and chromatin accessibility of CD151 promoter in liver cancer cells." SIGNOR-255195 SP1 protein P08047 UNIPROT CRX protein O43186 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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 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 SP1 protein P08047 UNIPROT CYP27A1 protein Q02318 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 11867220 f miannu "Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells." SIGNOR-255199 SP1 protein P08047 UNIPROT MET protein P08581 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944 9223667 t lperfetto "Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region." SIGNOR-241490 SP1 protein P08047 UNIPROT PHGDH protein O43175 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18378410 f miannu "Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y." SIGNOR-255208 SP1 protein P08047 UNIPROT THBD protein P07204 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321;BTO:0003160;BTO:0001061 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 SP4 protein Q02446 UNIPROT RHO protein P08100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 15781457 f miannu "Sp4 and Sp1 are activators of the rod opsin promoter" SIGNOR-225382 SP7 protein Q8TDD2 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 "BTO:0004058; BTO:0000165" 11792318 f "Giulio Giuliani" "To test whether Osx could activate typical osteoblast genes, we transfected an Osx expressing vector into both C2C12 and C3H10T1/2 cells. Our results showed that Osx produced an induction of osteocalcin RNA in both cell types." SIGNOR-255409 SP7 protein Q8TDD2 UNIPROT IFITM5 protein A6NNB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001593 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-254219 "sphingosine 1-phosphate(1-)" smallmolecule CHEBI:60119 ChEBI S1PR2 protein O95136 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-257578 SPI1 protein P17947 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20861919 f apalma "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-256372 SPI1 protein P17947 UNIPROT EGR2 protein P11161 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000802 16923394 f miannu "PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation" SIGNOR-256040 SPI1 protein P17947 UNIPROT miR-34 mirna MI0000268 miRBase "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000725 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 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 SPP1 protein P10451 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "up-regulates activity" binding 9606 BTO:0000801;BTO:0001336 24241034 t lperfetto "Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C." SIGNOR-253311 SPP1 protein P10451 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR up-regulates binding 9606 BTO:0001130 10835423 t gcesareni "Among others, vitronectin (vn)1- (11, 13, 14) and osteopontin (opn)-coated (15-20) substrates have been shown to support cell adhesion via avb3." SIGNOR-77910 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 SPRY2 protein O43597 UNIPROT CBLB protein Q13191 UNIPROT down-regulates binding 9606 11053437 t gcesareni "One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis." SIGNOR-83507 SPRY2 protein O43597 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates 9606 BTO:0000763 12234920 f gcesareni "Hspry2 prevents c-cbl-mediated ubiquitylation of egfrs. hspry2 interacts specifically with the c-cbl ring finger domain and displaces ubch7 from its binding site on the e3 ligase." SIGNOR-92926 SPRY2 protein O43597 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates 9606 BTO:0000567 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 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr453 PEALHYDyIDVEMSA 9534 BTO:0004055 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 SRC protein P12931 UNIPROT ANXA2 protein P07355 UNIPROT up-regulates phosphorylation Tyr24 HSTPPSAyGSVKAYT 9606 BTO:0001271 15302870 t lperfetto "Translocation requires the presence of the annexin 2 binding partner p11 (s100a10) and the phosphorylation of annexin 2 at tyr23 through a src-like tyrosine kinase-dependent mechanism both in vitro and in vivo." SIGNOR-127872 SRC protein P12931 UNIPROT AP2B1 protein P63010 UNIPROT down-regulates phosphorylation Tyr737 THRQGHIyMEMNFTN 9606 BTO:0000007 BTO:0000887;BTO:0001260 18938240 t gcesareni "The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin." SIGNOR-181743 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT "up-regulates activity" phosphorylation Tyr302 GYRDSGYyWEVPPSE 9534 BTO:0004055 9020159 t lperfetto "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" SIGNOR-236459 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "down-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" SIGNOR-246401 SRC protein P12931 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates phosphorylation Tyr341 SEEQLQLyWAMDSTF 9606 20525694 t gcesareni "Phosphorylation of a critical tyrosine (tyr-341) in the linker region of cbl-c by src or a phosphomimetic mutation of this tyrosine (y341e) is sufficient to increase the e3 activity of cbl-c." SIGNOR-165862 SRC protein P12931 UNIPROT CDCP1 protein Q9H5V8 UNIPROT unknown phosphorylation Tyr734 KDNDSHVyAVIEDTM 9606 BTO:0000667 14739293 t lperfetto "Phosphorylation of gp140 and p80 are mediated by Src family kinases at multiple Tyr residues including Tyr(734)." SIGNOR-246457 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr852 NDPTAPPyDSLLVFD 9606 BTO:0000848 16371504 t lperfetto "Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated." SIGNOR-143234 SRC protein P12931 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Tyr68 GQTVDDPyATFVKML 9606 19802004 t lperfetto "Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway" SIGNOR-188352 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr386 ASNGNLLyIGFRGLD 9606 BTO:0000938 16251431 t gcesareni "?7 Neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinases" SIGNOR-141307 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr302 DYGMMSDyGTARRTG -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-246504 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr96 QDHSHLLySTIPRMQ -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-246508 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr740 RNLYSGDyYRIQGRA 9606 16186108 t gcesareni "Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues." SIGNOR-140763 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr741 NLYSGDYyRIQGRAV 9606 16186108 t gcesareni "Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues." SIGNOR-140767 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 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 BTO:0000017 15647376 t llicata "N this study we have demonstrated that ezrin y145 is a direct target for phosphorylation by the tyrosine kinase src evidence from this study suggests that a positive feedback loop exists whereby src-mediated ezrin y145 phosphorylation sustains src activity._" SIGNOR-133227 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 BTO:0000150 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 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 BTO:0000671 15623525 t lperfetto "Src phosphorylates ezrin at tyrosine 477 and induces a phosphospecific association between ezrin and a kelch-repeat protein family member" SIGNOR-132907 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr242 FFQQQMIyDSPPSRA 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-236314 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr247 VKGKSDPyHATSGAL 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-148913 SRC protein P12931 UNIPROT GTF2I protein P78347 UNIPROT "up-regulates activity" phosphorylation Tyr652 KPELVISyLPPGMAS 9534 BTO:0004055 11934902 t lperfetto "c-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling" SIGNOR-247189 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1161 FGMTRDIyETDYYRK 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-45122 SRC protein P12931 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Tyr785 STFTNITyRGT 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-247207 SRC protein P12931 UNIPROT MMP3 protein P08254 UNIPROT "up-regulates activity" 23967200 f "C-Src-induced STAT3 activation regulates MMP3 levels" SIGNOR-251109 SRC protein P12931 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 11152665 t lperfetto "The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin" SIGNOR-85938 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 11113114 t gcesareni "Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity." SIGNOR-85005 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 12408982 t gcesareni "Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity." SIGNOR-95238 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 11113114 t gcesareni "Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity." SIGNOR-85009 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr334 RLFFVIEyVNGGDLM 9606 11713277 t llicata "Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain." SIGNOR-111928 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr95 KFPECGFyGMYDKIL 9606 17804414 t llicata "Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation." SIGNOR-157716 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0000007 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-120492 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 SRC protein P12931 UNIPROT SPTAN1 protein Q13813 UNIPROT up-regulates phosphorylation Tyr1176 AVQQQEVyGMMPRDE 9606 BTO:0000671 11971983 t llicata "Using mutagenesis on recombinant peptides, we identified the residue y1176 located in the calpain cleavage site of alpha ii-spectrin, near the sh3 domain, as an in vitro substrate for src kinase and lmw-ptp a. phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro." SIGNOR-86718 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 SRC protein P12931 UNIPROT TGFA protein P01135 UNIPROT "up-regulates activity" 9606 BTO:0000586 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 SRC protein P12931 UNIPROT TGFA protein P01135 UNIPROT up-regulates cleavage 9606 BTO:0000586 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 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 SREBF1 protein P36956 UNIPROT FASN protein P49327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f 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-142294 SREBF2 protein Q12772 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 17921436 f 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 SREBF2 protein Q12772 UNIPROT PON1 protein P27169 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001950 20728021 f 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 SRGAP3 protein O43295 UNIPROT RAC1 protein P63000 UNIPROT down-regulates 9606 12447388 f miannu "Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo." SIGNOR-95918 SRGAP3 protein O43295 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-260518 SRGAP3 protein O43295 UNIPROT RAC2 protein P15153 UNIPROT down-regulates 9606 12447388 f miannu "Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo." SIGNOR-95921 SRGAP3 protein O43295 UNIPROT RAC3 protein P60763 UNIPROT down-regulates 9606 12447388 f miannu "Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo." SIGNOR-95964 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Ser309 RPNKQEEsESPVERP 9606 22727668 t llicata "We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1" SIGNOR-197985 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Ser33 SETQHRGsAPHSESD 9606 22727668 t llicata "We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1" SIGNOR-197989 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Thr326 ENPPNKMtQEKLEES 9606 22727668 t llicata "We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1" SIGNOR-197993 SRPK1 protein Q96SB4 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 10196197 t gcesareni "These results suggest that the formation of complexes between sf2/asf and srpks, which is influenced by the phosphorylation state of sf2/asf, may have regulatory roles in the assembly and localization of this splicing factor." SIGNOR-66465 SRPK2 protein P78362 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 BTO:0000142 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 SRSF3 protein P84103 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates binding 9606 18364396 t miannu "9g8 and srp20 also enhance the tap rna-binding activity" SIGNOR-178111 (S,S)-asenapine chemical CHEBI:71257 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-258569 (S,S)-asenapine chemical CHEBI:71257 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-258568 SSTR2 protein P30874 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-256963 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1616 TPQSPSYsPTSPSYS -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-248803 STAT1 protein P42224 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 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-249496 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1696 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-248810 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1714 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-248822 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1717 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-248811 STAG2 protein Q8N3U4 UNIPROT CD69 protein Q07108 UNIPROT up-regulates 9606 14660624 f miannu "Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner." SIGNOR-119985 STAG2 protein Q8N3U4 UNIPROT TNF protein P01375 UNIPROT up-regulates 9606 14660624 f miannu "Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner." SIGNOR-119988 Starvation stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 BTO:0000567 23000343 f lperfetto "Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activationSTARV" SIGNOR-209796 STAT1 protein P42224 UNIPROT SOCS1 protein O15524 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000552 19482358 f miannu "Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1" SIGNOR-226484 STAT1 protein P42224 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19643666 t lperfetto "Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways." SIGNOR-249565 STAT1 protein P42224 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 19041276 t lperfetto "Each STAT1 monomer becomes tyrosine phosphorylated at tyrosine 701 by the JAKs, dissociates from the receptor to form a STAT1-STAT1 homodimer which translocates to the nucleus" SIGNOR-249495 STAT3 protein P40763 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 BTO:0003298 BTO:0001103 30029643 f "Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway." SIGNOR-256257 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 f "Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA)" SIGNOR-254304 STAT3 protein P40763 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000150 11278729 t lperfetto "Coexpression of activated c-Src and Stat3 synergistically induced strong HGF promoter activity in SP1 cells" SIGNOR-251742 STAT3 protein P40763 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR "form complex" binding 9606 26194464 t "MARCO ROSINA" "Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes." SIGNOR-255024 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 11159537 f miannu "STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma." SIGNOR-253050 STAT5A protein P42229 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "STAT5 binds directly to the promoter region and potently mediates repression of MEF2C, probably via HDAC recruitment." SIGNOR-254207 STAT5A protein P42229 UNIPROT miR-155 mirna MI0000681 miRBase "up-regulates quantity by expression" "transcriptional regulation" 9606 25092144 f miannu "We could show that STAT5 is involved in miR-155 induction. STAT5 knockdown in FLT3-ITD model systems reduced miR-155 expression in vitro and in vivo. In silico analyses predicted an STAT binding site in the miR-155 promoter." SIGNOR-255817 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT "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-249606 STAT6 protein P42226 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000801 22025054 f lperfetto "IL-4R signals through a JAKSTAT6 pathway, and many of the genes associated with mouse M2 macrophages are regulated by STAT6, including arginase 1 (Arg1), macrophage mannose receptor 1 (Mrc1; also known as Cd206), resistin-like-? (Retnla; also known as Fizz1) and chitinase 3-like 3 (Chi3l3; also known as Ym1)." SIGNOR-249541 STAT6 protein P42226 UNIPROT MRC1 protein P22897 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-249535 STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" 10090 24948596 f "IL-4 was shown to inhibit lipid accumulation in adipose tissue by a mechanism that includes activation of Stat6, which suppresses PPARα transcriptional activity" SIGNOR-254682 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 STK11 protein Q15831 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 14657655 f gcesareni "Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent." SIGNOR-119892 STK11 protein Q15831 UNIPROT PRKAA1 protein Q13131 UNIPROT "up-regulates activity" phosphorylation Thr183 SDGEFLRtSCGSPNY -1 16054095 t lperfetto "The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase." SIGNOR-139297 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 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 STK11 protein Q15831 UNIPROT STRADA protein Q7RTN6 UNIPROT "up-regulates activity" phosphorylation Thr329 GLSDSLTtSTPRPSN 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-247560 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 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR Mob1 proteinfamily SIGNOR-PF42 SIGNOR "up-regulates activity" phosphorylation 9606 23431053 t miannu "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-256185 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR SAV1 protein Q9H4B6 UNIPROT "up-regulates activity" phosphorylation 9606 21084559 t miannu "Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst." SIGNOR-256184 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 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 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-175809 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr74 QINMLYGtITEFCTE 9606 BTO:0000007 18362890 t 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-177977 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 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-253000 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 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. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1." SIGNOR-252998 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Ser327 SEEDEMDsGTMVRAV 9534 BTO:0004055 12223493 t lperfetto "Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues" SIGNOR-247569 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Thr177 VAGQLTDtMAKRNTV 9534 BTO:0004055 12223493 t lperfetto "Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues" SIGNOR-247573 Stress_granules phenotype SIGNOR-PH124 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-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-260865 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 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 14701756 t gcesareni "These results suggest that chip can interact with the smad1/smad4 proteins and block bmp signal transduction through the ubiquitin-mediated degradation of smad proteins." SIGNOR-120731 SU11274 chemical CID:9549297 PUBCHEM MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207123 SUFU protein Q9UMX1 UNIPROT GLIS3 protein Q8NEA6 UNIPROT down-regulates binding 9606 21543335 t fspada "These data indicate that the inhibition of glis3-mediated transactivation by sufu appears to rely on the interaction with glis3 through the ygh motif and is not related to an effect on the general transcriptional machinery" SIGNOR-173573 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 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0004479 20570526 t Luana "Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors]," SIGNOR-257850 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 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-172917 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 21993628 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-176757 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 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-163947 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0004479 20570526 t Luana "Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors]," SIGNOR-257851 SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR PAX7 protein P23759 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165;BTO:0002314 20887952 t lperfetto "TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter." SIGNOR-235583 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 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr96 EENADDSyEPPPVEQ 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-96052 SYK protein P43405 UNIPROT BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 BTO:0000776 11226282 t lperfetto "We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity." SIGNOR-247586 SYK protein P43405 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates phosphorylation Tyr378 EPEPENDyEDVEEMD 9606 BTO:0000776 9104825 t llicata "Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis." SIGNOR-47338 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr783 EGRNPGFyVEANPMP 9606 BTO:0000776 8657103 t lperfetto "Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771." SIGNOR-246576 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT "up-regulates activity" phosphorylation Tyr174 YPTDNEDyEHDDEDD 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-246587 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr352 TEVYESPyADPEEIR 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-246613 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr525 ALRADENyYKAQTHG 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-246617 TAB3 protein Q8N5C8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 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-205452 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 tacedinaline chemical CHEBI:90195 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-258009 TACR1 protein P25103 UNIPROT GNAS protein Q5JWF2 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-256776 "tacrolimus (anhydrous)" chemical CHEBI:61049 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR 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-252308 "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 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser316 VEEEPLNsEDDVSDE 9606 BTO:0000007 11278496 t lperfetto "Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity." SIGNOR-105688 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates phosphorylation Ser321 LNSEDDVsDEEGQEL 9606 11278496 t llicata "Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity." SIGNOR-105745 TAK-875 chemical CID:24857286 PUBCHEM FFAR1 protein O14842 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-207182 "tamoxifen citrate" chemical CHEBI:9397 ChEBI ESR2 protein Q92731 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000150 20512796 t miannu "Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth." SIGNOR-259300 tamsulosin chemical CHEBI:9398 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-258474 tandutinib chemical CHEBI:90237 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207209 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" binding 9606 10497253 t lperfetto "Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7." SIGNOR-70950 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation Ser207 ISGYLVDsVAKTIDA 9606 BTO:0000007 11279118 t lperfetto "Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells" SIGNOR-106465 TAOK2 protein Q9UL54 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 BTO:0001130 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 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 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 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation 9606 24622840 t miannu "STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3." SIGNOR-260154 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 TBK1 protein Q9UHD2 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR up-regulates phosphorylation 9606 16888014 t lperfetto "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-217667 TBX2 protein Q13207 UNIPROT MYOD1 protein P15172 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-251560 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 TBX2 protein Q13207 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24470334 f "TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells" SIGNOR-251562 TBX2 protein Q13207 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 24470334 f "TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells" SIGNOR-251563 TBX3 protein O15119 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 25595898 f miannu "AKT phosphorylation potentiates the ability of TBX3 to repress the transcription of the E-cadherin gene" SIGNOR-223537 TBXA2R protein P21731 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-256887 TCL1A protein P56279 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-81683 TCL1A protein P56279 UNIPROT AKT3 protein Q9Y243 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-81434 TEAD1 protein P28347 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 21211055 f gcesareni "Tead1 can regulate transcription of the foxo3a gene through the binding to the m-cat element, demonstrated with independent chip-pcr analysis, emsa and luciferase reporter system assay. The over-expression and inhibition analysis suggest that foxo3a was positively regulated by tead1." SIGNOR-253003 TEAD1 protein P28347 UNIPROT MSLN protein Q13421 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17909009 f miannu "The presence of TEF-1 was required for MSLN protein overexpression as determined by TEF-1 knockdown experiments." SIGNOR-255395 TEK protein Q02763 UNIPROT PIK3R1 protein P27986 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-242634 TEK protein Q02763 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr1101 Y-->T 14665640 t gcesareni "our results identified a novel interaction between Tie2 with the adapter molecule ShcA and suggested that this interaction may play a role in the regulation of migration and three-dimensional organization of endothelial cells induced by angiopoietin-1" SIGNOR-242573 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "down-regulates activity" phosphorylation Tyr897 GACEHRGyLYLAIEY -1 11080633 t lperfetto "The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an activated-like conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated." SIGNOR-246662 terazosin chemical CHEBI:9445 ChEBI ADRA1D protein P25100 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001260 9379432 t miannu "Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication" SIGNOR-258670 terbutaline chemical CHEBI:9449 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-257870 testosterone smallmolecule CHEBI:17347 ChEBI AR protein P10275 UNIPROT "up-regulates activity" "chemical activation" 9606 15861399 t miannu "Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-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-251553 testosterone smallmolecule CHEBI:17347 ChEBI SRD5A1 protein P18405 UNIPROT "up-regulates activity" "chemical activation" 9606 15861399 t miannu "Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-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-251532 TFAP2B protein Q92481 UNIPROT ADIPOQ protein Q15848 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19325541 f miannu "A transcription factor, TFAP2B, has been shown to participate in the regulation of adipocyte metabolism, by facilitating glucose uptake and lipid accumulation, while simultaneously reducing insulin sensitivity, and recently a direct function for TFAP2B as an inhibitor of adiponectin expression was observed." SIGNOR-255421 TFAP2B protein Q92481 UNIPROT PTGDS protein P41222 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002605 15743775 f miannu "Deletion and mutation of the AP-2 element at -98 in the L-PGDS gene promoter result in a drastic decrease in the reporter activity (Figs. 1 and 2). Results from the EMSA and ChIP assay demonstrated that AP-2β bound to the AP-2 element both in vitro and in TE671 cells" SIGNOR-255425 TFDP1 protein Q14186 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates activity" binding 9606 14618416 t miannu "DP-1 is a heterodimerization partner for members of the E2F family of transcription factors; E2F/DP-1 regulates the expression of various cellular promoters, particularly gene products that are involved in the cell cycle." SIGNOR-253865 TG101209 chemical CHEBI:90304 ChEBI JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207263 TGFB1 protein P01137 UNIPROT ANKH protein Q9HCJ1 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-252201 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 TGFB1 protein P01137 UNIPROT CCNA2 protein P20248 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 7592630 f gcesareni "Expression of one of these components, cyclin a, is inhibited by tgf-beta treatment. We have identified a 760-base pair fragment of the human cyclin a gene promoter that is sufficient to confer tgf-beta responsiveness." SIGNOR-29516 TGFB1 protein P01137 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001760 14739161 f lperfetto "Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12." SIGNOR-235602 TGFB1 protein P01137 UNIPROT MYOG protein P15173 UNIPROT down-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001760 14739161 f lperfetto "Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12." SIGNOR-235728 TGFB1 protein P01137 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18586026 f gcesareni "These data show that tgf-beta-induced nf-kappab activation is through tak1/mek-mediated aktactivation, which is essential for tgf-beta to support of osteoclast survival" SIGNOR-179179 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 22703233 t lperfetto "TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex." SIGNOR-249548 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 26194464 t "MARCO ROSINA" "TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI)." SIGNOR-255031 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 TGFBI protein Q15582 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 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-253268 TGFb proteinfamily SIGNOR-PF5 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates 9606 SIGNOR-C9 12524424 f fspada "Because tgf-beta inhibits adipogenesis by signaling through smad3, we examined physical and functional interactions of smad3 and smad4 with c/ebpbeta, c/ebpdelta, and ppargamma2." SIGNOR-97123 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Ser467 SVRCSSMs 9534 BTO:0001538 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 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr176 PFISEGTtLKDLIYD 9606 8576253 t lperfetto "Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta" SIGNOR-246732 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr200 LPLLVQRtIARTIVL -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-255962 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates phosphorylation 9606 26194464 t "MARCO ROSINA" "TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI)." SIGNOR-255032 TGM2 protein P21980 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 9606 BTO:0000150 16407273 t 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 THAP12 protein O43422 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 10542257 t lperfetto "The mammalian kinases PKR and HRI and the yeast kinase GCN2 specifically phosphorylate Ser-51 on the alpha subunit of the translation initiation factor eIF2. " SIGNOR-249029 THBS1 protein P07996 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-252271 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 TIAM1 protein Q13009 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-260577 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 12393875 t gcesareni "Lpa-induced rac activation requires tiam1" SIGNOR-94691 tiotropium chemical CHEBI:90960 ChEBI CHRM1 protein P11229 UNIPROT "down-regulates activity" "chemical inhibition" -1 8441333 t miannu "A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed ""kinetic receptor subtype selectivity"" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors." SIGNOR-258485 tiotropium chemical CHEBI:90960 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" -1 8441333 t miannu "A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed ""kinetic receptor subtype selectivity"" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors." SIGNOR-258484 tiotropium chemical CHEBI:90960 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" -1 8441333 t miannu "A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed ""kinetic receptor subtype selectivity"" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors." SIGNOR-258486 TLK1 protein Q9UKI8 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR -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-107037 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 24376897 t "The effect has been demonstrated using Q9UKI8-2" llicata "Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue." SIGNOR-203499 TLN1 protein Q9Y490 UNIPROT "A4/b7 integrin" complex SIGNOR-C187 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-257635 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 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 TLN1 protein Q9Y490 UNIPROT ITGB3 protein P05106 UNIPROT "up-regulates activity" binding 10090 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-257625 TLR7 protein Q9NYK1 UNIPROT IFNA1 protein P01562 UNIPROT "up-regulates quantity" 9606 BTO:0004625 15661881 f miannu "TLR7 in pDC is functionally associated with the production of IFN-α- and IFN-regulated cytokines, similar to the role of TLR9." SIGNOR-259248 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 TLRs proteinfamily SIGNOR-PF20 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 20404851 f lperfetto "The negative regulation of TLR-induced responses is important for sup- pressing inflammation and deleterious immune responses." SIGNOR-216304 TLRs proteinfamily SIGNOR-PF20 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR "up-regulates activity" binding 9606 BTO:0000782 24352680 t lperfetto "Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain" SIGNOR-216301 TNFAIP3 protein P21580 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 15258597 t "A20The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation." SIGNOR-259977 TNFAIP3 protein P21580 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates activity" deubiquitination 9606 18164316 t lperfetto "A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6" SIGNOR-160223 TNF protein P01375 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 21514273 f "via a ?-catenin-dependent pathway" fspada "Tumor necrosis factor-? (TNF-alpha) Is known to suppress adipocyte differentiation via a Beta-catenin-dependent pathway." SIGNOR-173421 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 TNF protein P01375 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 9606 8530143 f "andrea cerquone perpetuini" "Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation." SIGNOR-255689 TNF protein P01375 UNIPROT NOD2 protein Q9HC29 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003355 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 TNF protein P01375 UNIPROT SCN2A protein Q99250 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-253480 TNF protein P01375 UNIPROT SCN3A protein Q9NY46 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-253494 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 17151142 t miannu "TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling" SIGNOR-253591 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 21133840 t "simone vumbaca" "TNF alpha and IFN gamma exhibit a cross-talk at the level of TNFR1 to induce activation of macrophages" SIGNOR-256025 TNFRSF1A protein P19438 UNIPROT TRAF2 protein Q12933 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-256251 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT "up-regulates activity" phosphorylation Tyr284 LPQNDDHyVMQEHRK -1 16472662 t "Purified ACK1 undergoes autophosphorylation at Tyr284, and autophosphorylation increases kinase activity" SIGNOR-251184 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 TNKS2 protein Q9H2K2 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 19759537 t gcesareni "Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway." SIGNOR-188033 "tofacitinib citrate" chemical CHEBI:71197 ChEBI JAK3 protein P52333 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207311 Tomivosertib chemical CID:118598754 PUBCHEM MKNK1 protein Q9BUB5 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002522 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-261116 Tomivosertib chemical CID:118598754 PUBCHEM MKNK2 protein Q9HBH9 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002522 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 TOP2A protein P11388 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 20562910 f lperfetto "Topoisomerase IIalpha (topoIIalpha) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis." SIGNOR-242530 "torin 2" chemical CHEBI:90682 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000551 23436801 t "ATP-competitive inhibitor" gcesareni "Torin2, a second generation atp-competitive inhibitor that is potent and selective for mtor.." SIGNOR-201499 "torin 2" chemical CHEBI:90682 ChEBI RPS6KB1 protein P23443 UNIPROT down-regulates 9606 BTO:0000551 23436801 f gcesareni "Torin2 inhibited mtorc1-dependent t389 phosphorylation on s6k (rps6kb1)" SIGNOR-201502 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 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-258268 TP53 protein P04637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu "P53 is a nuclear transcription factor with a pro-apoptotic function" SIGNOR-255678 TP53 protein P04637 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 15077116 t gcesareni "P53 interacts with the pro-apoptotic mitochondrial membrane protein bak" SIGNOR-124122 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 14963330 t lperfetto "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" SIGNOR-178690 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 t gcesareni "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" SIGNOR-121895 TP53 protein P04637 UNIPROT BID protein P55957 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16151013 f "Nuclear p53" lperfetto "Bid is a p53 primary-response gene." SIGNOR-140248 TP53 protein P04637 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 19007744 f "Translocation from Mitochondria to Cytosol" lperfetto "P53 translocation precedes changes of mitochondrial membrane potential, cytochrome c release and caspase activation" SIGNOR-140251 TP53 protein P04637 UNIPROT DRAM2 protein Q6UX65 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 "BTO:0000018; BTO:0002203" 30755245 f irozzo "DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression." SIGNOR-259148 TP53 protein P04637 UNIPROT FASLG protein P48023 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 9841917 f "Nuclear p53" amattioni "Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53" SIGNOR-62379 TP53 protein P04637 UNIPROT NR4A3 protein Q92570 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0002552 30455429 f miannu "We showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. p53 transactivates the NR4A3 promoter in H1299 cells." SIGNOR-256200 TP53 protein P04637 UNIPROT OGG1 protein O15527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 16293709 f miannu "Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1." SIGNOR-255440 TP73 protein O15350 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 17700533 f miannu "Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death." SIGNOR-256665 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 TPO protein P07202 UNIPROT TG protein P01266 UNIPROT "up-regulates activity" "catalytic activity" 9606 BTO:0004709 23349248 t miannu "After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO)." SIGNOR-259914 TPR protein P12270 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates binding 9606 BTO:0000567 18981471 t miannu "Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20)." SIGNOR-181975 TPSAB1 protein Q15661 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" binding 10116 21999702 t lperfetto "Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2).|Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2." SIGNOR-251744 TRADD protein Q15628 UNIPROT BIRC2 protein Q13490 UNIPROT "up-regulates activity" binding 9606 BTO:0000007;BTO:0001412;BTO:0000567 8943045 t amattioni "The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD. N-terminal domain of tradd may become accessible to traf2, thereby permitting recruitment of the traf2/ciap1 heterocomplex." SIGNOR-45134 TRADD protein Q15628 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" binding 9606 14585074 t amattioni "Tradd recruits caspase-8" SIGNOR-118591 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT "up-regulates activity" binding 9606 18545270 t lperfetto "Tradd recruits fadd" SIGNOR-177958 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18997794 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-182137 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 TRAF6 protein Q9Y4K3 UNIPROT HK2 protein P52789 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 28980855 t "The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation." SIGNOR-260003 TRAF6 protein Q9Y4K3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" ubiquitination Lys134;Lys180 AEAWSPRkLPSSAST;SPAPSSTkPGPESSV 9606 BTO:0000007 18347055 t "K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B" SIGNOR-252252 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 trastuzumab antibody DB00072 DRUGBANK ERBB2 protein P04626 UNIPROT "down-regulates activity" binding 9606 BTO:0000150 29017563 t miannu "HER2+ breast cancer is associated with poor prognosis and high mortality rates, but the development of HER2-targeted therapies, such as originator trastuzumab (Herceptin®), has substantially improved patient survival." SIGNOR-259904 TRIB3 protein Q96RU7 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 BTO:0000759 12791994 t llicata "TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase." SIGNOR-252644 TRIB3 protein Q96RU7 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" binding 9606 BTO:0000007 BTO:0000759 12791994 t llicata "TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase." SIGNOR-237850 "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 "trichostatin A" chemical CHEBI:46024 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-257938 TRIM33 protein Q9UPN9 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 BTO:0000574;BTO:0002625;BTO:0000414 16751102 t lperfetto "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. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses." SIGNOR-236060 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 TRIM59 protein Q8IWR1 UNIPROT IRF7 protein Q92985 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-260374 trimipramine chemical CHEBI:9738 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-258740 trimipramine chemical CHEBI:9738 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 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-258741 TSC1/TSC2 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 TSC1/TSC2 complex SIGNOR-C101 SIGNOR MTOR protein P42345 UNIPROT "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-217907 TSC22D3 protein Q99576 UNIPROT FOXO1 protein Q12778 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-256146 TSC22D3 protein Q99576 UNIPROT FOXO3 protein O43524 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-256147 TSSK3 protein Q96PN8 UNIPROT TSSK3 protein Q96PN8 UNIPROT "up-regulates activity" phosphorylation S166 VLPKSHRELSQTFC -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 TSSK4 protein Q6SA08 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser133 EILSRRPsYRKILND 9606 BTO:0000007 15964553 t gcesareni "Tssk5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates creb at ser-133, and stimulates the cre/creb responsive pathway." SIGNOR-138289 TTK protein P33981 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 19332559 t llicata "Ttk/hmps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at thr18. phosphorylation at thr18 enhances p53-dependent activation of not only p21 but also lats2, two mediators of the postmitotic checkpoint." SIGNOR-184931 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 TUBB protein P07437 UNIPROT SMAD3 protein P84022 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-232113 TULP3 protein O75386 UNIPROT GPR161 protein Q8N6U8 UNIPROT "up-regulates activity" relocalization 10090 BTO:0003913 23332756 t "Upon knockdown of Tulp3 using siRNA in IMCD3 cells, ciliary localization of Gpr161 was severely reduced" SIGNOR-259938 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 TWIST1 protein Q15672 UNIPROT MMP2 protein P08253 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255525 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 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT "up-regulates activity" phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 10660534 t lperfetto "Rlk phosphorylated the N-terminal region of SLP-76, a region that has been previously shown to serve as a target for ZAP-70. Loss of N-terminal YESP/YEPP sites of SLP-76 or the Rlk kinase activity attenuated cooperativity between Rlk and SLP-76" SIGNOR-246929 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 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-74844 TXK protein P42681 UNIPROT TXK protein P42681 UNIPROT up-regulates phosphorylation Tyr91 KIQVKALyDFLPREP 9606 BTO:0000782 12081135 t lperfetto "Evidence of autophosphorylation in txk: y91 is an autophosphorylation site. the results suggest that phosphorylated txk is an active form to promote ifn-gamma synthesis" SIGNOR-89844 "tyrphostin AG 1478" chemical CHEBI:75404 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189377 "tyrphostin B42" chemical CHEBI:131968 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189386 "tyrphostin B42" chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT "down-regulates activity" 9606 11368440 t gcesareni "the Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel" SIGNOR-238293 "tyrphostin B42" chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT "down-regulates activity" "chemical inhibition" 9606 11368440 t gcesareni "the Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel" SIGNOR-238542 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207603 U69593 chemical CHEBI:73357 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-258827 UBA3 protein Q8TBC4 UNIPROT NAE complex SIGNOR-C131 SIGNOR "form complex" binding 9606 25504797 t lperfetto "the NEDD8 E1-activating enzyme (NAE) is a heterodimer of APPBP1 and UBA3 corresponding to the N-terminal and C-terminal of the single polypeptide of the ubiquitin E1 respectively" SIGNOR-242904 UBAP2L protein Q14157 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 25185265 t Sara "We identified UBAP2L as a novel BMI1-interacting protein. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex" SIGNOR-261315 UBE2I protein P63279 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates sumoylation Lys244 NQELLKVkTEPVDFL 9606 15208321 t miannu "Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263)" SIGNOR-126044 UBE2I protein P63279 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates sumoylation Lys263 CNVSVPIkDELLPVM 9606 15208321 t miannu "Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263)" SIGNOR-126048 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT "down-regulates activity" sumoylation Lys404 VSPTGIkNEKRGTS 9606 BTO:0000007 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 UBXN1 protein Q04323 UNIPROT NGLY1 protein Q96IV0 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15362974 t miannu "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-261060 UBXN1 protein Q04323 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 BTO:0000007 15362974 f miannu "Our working hypothesis is that SAKS1 acts as scaffolding protein to enhance the unfolding and proteolytic destruction of a subset of proteins. PNGase removes high-mannose-containing oligosaccharides from MGPs [30], and our results suggest this may be facilitated by the formation of a complex between PNGase, VCP, SAKS1 and ubiquitinated MGPs, as illustrated schematically in Figure 7(B). PNGase has been reported to bind to the S4 component of the proteasome [30], so that the deglycosylation of MGPs by PNGase, followed by VCP-catalysed unfolding, may facilitate their destruction by the proteasome." SIGNOR-261059 UBXN8 protein O00124 UNIPROT VCP protein P55072 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0000567 21949850 t SARA "The human protein named Rep8 or Ubxd6 as a new cofactor of p97. Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation." SIGNOR-261002 UCHL1 protein P09936 UNIPROT UBC protein P0CG48 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000938 9521656 t lperfetto "These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains" SIGNOR-249693 UIMC1 protein Q96RL1 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 17525342 t gcesareni "Rap80 specifically recruits brca1 to dna damage sites and functions with brca1 in g2/m checkpoint control" SIGNOR-155201 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 UHMK1 protein Q8TAS1 UNIPROT PAM protein P19021 UNIPROT unknown phosphorylation Ser946 DRLSTEGsDQEKEDD 9606 BTO:0004055 10574929 t lperfetto "Although P-CIP2 interacts with stathmin, it does not phosphorylate stathmin. Site-directed mutagenesis, phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM-Ser(949) is the major site phosphorylated by P-CIP2. B" SIGNOR-247009 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 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR CREB3L2 protein Q70SY1 UNIPROT up-regulates 9606 17178827 f miannu "Although bbf2h7 protein is not expressed under normal conditions, it is markedly induced at the translational level during er stress, suggesting that bbf2h7 might contribute to only the late phase of unfolded protein response signaling." SIGNOR-151312 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERN1 protein O75460 UNIPROT up-regulates 9606 31226023 f miannu "Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain" SIGNOR-260175 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERP44 protein Q9BS26 UNIPROT up-regulates 9606 11847130 f miannu "Like many ER folding factors, ERp44 transcripts are induced by agents that cause the accumulation of unfolded proteins in the ER." SIGNOR-261047 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HERPUD1 protein Q15011 UNIPROT "up-regulates quantity by expression" 9606 10922362 f miannu "We demonstrate a new target gene for upr-induced transcription, herp." SIGNOR-80156 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 USF1 protein P22415 UNIPROT FOSL1 protein P15407 UNIPROT "down-regulates activity" binding 10090 BTO:0000095 9160889 t 2 miannu "USF specifically interacts with Fra1. USF was repressing this modest Fra1 transactivation" SIGNOR-240975 USF1 protein P22415 UNIPROT GATA5 protein Q9BWX5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002922 22625849 f miannu "The present study provides the first evidence that USF1 activates GATA5 gene expression through the E-box motif and suggests a potential mechanism (disruption of the E-box) by which GATA5 promoter methylation reduces GATA5 expression in cancer." SIGNOR-255596 USF1 protein P22415 UNIPROT GCK protein P35557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 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 USP6 protein P35125 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 20418905 f miannu "These data confirm that tre17 activates nfkappab in a usp-dependent manner" SIGNOR-164949 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 USP7 protein Q93009 UNIPROT MDM4 protein O15151 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni "Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins." SIGNOR-139453 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 UTS2R protein Q9UKP6 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-257252 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 "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 "UV stress" stimulus SIGNOR-ST7 SIGNOR KRT14 protein P02533 UNIPROT up-regulates 9606 BTO:0000667 11875647 f miannu "UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK." SIGNOR-251900 "UV stress" stimulus SIGNOR-ST7 SIGNOR MAP3K4 protein Q9Y6R4 UNIPROT up-regulates 9606 9305639 f lperfetto "Overexpression of a dominant-negative MTK1 mutant [MTK1(K/R)] strongly inhibited the activation of the p38 pathway by environmental stresses (osmotic shock, UV and anisomycin)[]These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway" SIGNOR-226605 vatalanib chemical CHEBI:90620 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207642 vatalanib chemical CHEBI:90620 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-258309 VCAM1 protein P19320 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 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-253241 VCP protein P55072 UNIPROT DDX58 protein O95786 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys181 ALEKERNkFSELWIV 9606 BTO:0000007 26471729 t lperfetto "Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181." SIGNOR-261000 VCP protein P55072 UNIPROT NGLY1 protein Q96IV0 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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 VEGFD protein O43915 UNIPROT FLT4 protein P35916 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni "Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors." SIGNOR-55065 VEGFD protein O43915 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni "Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors." SIGNOR-55163 veliparib chemical CHEBI:62880 ChEBI PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189183 "Vicriviroc Malate" chemical CID:10218922 PUBCHEM CCR5 protein P51681 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207657 vildagliptin chemical CHEBI:135285 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000783 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 "Vincristine sulfate" chemical CHEBI:79401 ChEBI FN1 protein P02751 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000144 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-259252 Viral_replication stimulus SIGNOR-ST23 SIGNOR Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 31226023 f miannu "Double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses." SIGNOR-260587 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000527 21679342 t gcesareni "Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date." SIGNOR-174417 Volasertib chemical CID:10461508 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190290 vorinostat chemical CHEBI:45716 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-257920 VRK1 protein Q99986 UNIPROT H3C1 protein P68431 UNIPROT up-regulates phosphorylation Ser11 TKQTARKsTGGKAPR 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-158436 VRK1 protein Q99986 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 15378002 t flangone "Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription" SIGNOR-127069 VX-745 chemical CHEBI:90528 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207684 WASF3 protein Q9UPY6 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR "up-regulates activity" 9534 BTO:0000298 17623672 f "We have also shown that Abl targets and phosphorylates four tyrosine residues in WAVE3 and that the Abl-dependent phosphorylation of WAVE3 is critical for the stimulation of lamellipodia formation and cell migration." SIGNOR-259078 WASHC1 protein A8K0Z3 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-261020 WASHC2C protein Q9Y4E1 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-261016 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 WIF1 protein Q9Y5W5 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 10201374 t gcesareni "Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities." SIGNOR-66892 WIPF1 protein O43516 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR up-regulates 9606 BTO:0000007 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 WIPF1 protein O43516 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 BTO:0000007 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-260609 WLS protein Q5T9L3 UNIPROT WNT3A protein P56704 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 20826466 t "WNT secretion requires its binding to the carrier protein wntless (WLS);" SIGNOR-256599 WNT10A protein Q9GZT5 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 f fspada "We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b" SIGNOR-176187 WNT10A protein Q9GZT5 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-131616 WNT16 protein Q9UBV4 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-131677 WNT3A protein P56704 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates quantity by stabilization" 10090 17943183 f Regulation miannu "Wnt3a markedly stimulated matrix assembly of microfibrillar proteins, including Fbn-1, by cultured fibroblasts, suggesting that Wnts contribute to increased microfibrillar matrices in Tsk skin.Wnt3a stimulates Fbn-1 matrix formation." SIGNOR-251894 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 WNT3A protein P56704 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 22653731 t gcesareni "Structural basis of wnt recognition by frizzled." SIGNOR-197638 WNT5A protein P41221 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" 9606 BTO:0000007 21078818 f gcesareni "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-169666 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Ror1 and ror2 bind wnt5a." SIGNOR-199644 WNT5B protein Q9H1J7 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates 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-141440 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 "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 "WRC complex" complex SIGNOR-C191 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 20332100 f 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-253578 WRN protein Q14191 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 9606 19652551 f "Our work provides the first demonstration of the major importance of WRN in repair of a specific class of DSB in human cells." SIGNOR-258983 WSB1 protein Q9Y6I7 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates ubiquitination 9606 18093972 t lperfetto "Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by wd40 repeat/socs box protein wsb-1" SIGNOR-160032 WWTR1 protein Q9GZV5 UNIPROT BAK1 protein Q16611 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-255605 WWTR1 protein Q9GZV5 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-256668 WWTR1 protein Q9GZV5 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 t "YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201415 WWTR1 protein Q9GZV5 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates binding 9606 23431053 t "YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201459 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 WZ4002 chemical CHEBI:61400 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207827 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT "down-regulates activity" binding 9606 10548111 t amattioni "The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7)." SIGNOR-71954 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 11447297 t lperfetto "Xiap promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells. Both the association of XIAP with caspase-3 and the RING finger domain of XIAP were essential for ubiquitination. XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect." SIGNOR-109243 XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT "down-regulates quantity by destabilization" binding -1 11257231 t lperfetto "Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase." SIGNOR-105732 XL147 chemical CHEBI:71957 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252659 XXYLT1 protein Q8NBI6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22117070 t "Xylosylation in ER membrane" gcesareni "Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains." SIGNOR-177745 XXYLT1 protein Q8NBI6 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 22117070 t "Xylosylation in ER membrane" gcesareni "Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains." SIGNOR-254333 Y-27632 chemical CHEBI:75393 ChEBI ROCK1 protein Q13464 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207890 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003918 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-253873 YBX1 protein P67809 UNIPROT CXCR4 protein P61073 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001023 17072343 f miannu "YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C." SIGNOR-255611 YBX1 protein P67809 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17822788 f miannu "YB-1 binds to the MMP-13 promoter sequence and represses MMP-13 transactivation via the AP-1 site." SIGNOR-255615 YBX1 protein P67809 UNIPROT NDRG1 protein Q92597 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001023 17072343 f miannu "YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C." SIGNOR-255612 "Yellow AB" chemical CHEBI:82554 ChEBI PTCH1 protein Q13635 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000584 17970037 t gcesareni "Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation." SIGNOR-158650 YWHAH protein Q04917 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-109771 YWHAQ protein P27348 UNIPROT CDC25C protein P30307 UNIPROT down-regulates relocalization 9606 20068082 t gcesareni "Cdc25c: nuclear exclusion/cytoplasmic sequestration via binding to 14-3-3 proteins." SIGNOR-163237 YY1 protein P25490 UNIPROT PRC2 complex SIGNOR-C130 SIGNOR "up-regulates quantity by expression" 17158804 t "YY1 REPO domain is necessary and sufficient for PcG transcriptional repression, Polycomb recruitment to DNA, and methylation of histone H3 on lysine 27" SIGNOR-253595 YY1 protein P25490 UNIPROT SURF1 protein Q15526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10858544 f miannu "We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response." SIGNOR-254614 YY1 protein P25490 UNIPROT SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR "form complex" binding 10090 BTO:0000165;BTO:0002314 20887952 t lperfetto "TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter." SIGNOR-235580 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT "up-regulates activity" phosphorylation Tyr145 PVEDDADyEPPPSND 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-102515 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 9047237 t lperfetto "Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient." SIGNOR-46855 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr492 ALGADDSyYTARSAG 9606 BTO:0000782;BTO:0000776 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 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000782 16049944 t lperfetto "Zap-70 is modified by auto-phosphorylation of various tyrosine residues and is activated by specific phosphorylation of the tyrosine residue y-493" SIGNOR-139098 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 ZEB2 protein O60315 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255159 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 ziprasidone chemical CHEBI:10119 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-258833 "ZM 336372" chemical CID:5730 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207911 ZM447439 chemical CHEBI:91376 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207923 ZM447439 chemical CHEBI:91376 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207926 ZNF224 protein Q9NZL3 UNIPROT ALDOA protein P04075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17900823 f miannu "We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor." SIGNOR-255627 ZNF76 protein P36508 UNIPROT TBP protein P20226 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15280358 t miannu "we identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini. ZNF76 targets TBP for transcriptional repression." SIGNOR-224650 HERPUD1 protein Q15011 UNIPROT HSPA5 protein P11021 UNIPROT "up-regulates quantity by stabilization" relocalization 9606 BTO:0000567 29295953 f miannu "A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation. " SIGNOR-261346 ZNRF3 protein Q9ULT6 UNIPROT FZD5 protein Q13467 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-260118 ZNRF3 protein Q9ULT6 UNIPROT FZD6 protein O60353 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-260114 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 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 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-260112 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 23151663 t gcesareni "Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane." SIGNOR-199656 zotepine chemical CHEBI:32316 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000601 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-258558 zotepine chemical CHEBI:32316 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 20223878 t Luana "These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity." SIGNOR-257828 GOLGA7 protein Q7Z5G4 UNIPROT NRAS protein P01111 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-261354 GOLGA7 protein Q7Z5G4 UNIPROT ZDHHC9 protein Q9Y397 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16000296 t miannu "DHHC9 and GCP16 form a protein complex, and DHHC9 requires GCP16 for protein fatty acyltransferase activity and protein stability." SIGNOR-261353 LMAN2 protein Q12907 UNIPROT SERPINA1 protein P01009 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000599 20477988 t miannu "Identification of α1‐antitrypsin as interaction partner of VIP36. The complex formed by VIP36 and alpha1-AT in the Golgi recycled back to the ER. The combined data are most consistent with a function of VIP36 in post-ER quality control of alpha1-AT. We propose that VIP36 acts in post‐ER quality control in the Golgi by binding incompletely folded α1‐AT, which inadvertently escaped ER quality control, and by recycling it back to the ER for an additional round of quality control." SIGNOR-261356 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 NRF1 protein Q16656 UNIPROT BRK1 protein Q8WUW1 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0000934 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 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0000934 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-261368 QSOX2 protein Q6ZRP7 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18034316 f miannu "a pro-apoptotic member of the QSOX superfamily, QSOXN, was described (Wittke et al. 2003). QSOXN was shown to sensitize neuroblastoma cells to INFγ-induced apoptosis, by still unknown mechanisms. In this context, absence of QSOX in fetal epithelia may prevent apoptosis." SIGNOR-261365 REEP5 protein Q00765 UNIPROT CXCR1 protein P25024 UNIPROT "up-regulates activity" binding 9606 BTO:0000018 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 SELENOF protein O60613 UNIPROT UGGT2 protein Q9NYU1 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24415556 t miannu "The enzymatic activity of UGGT2 is enhanced by complex formation with Sep15" SIGNOR-261373 SELENOS protein Q9BQE4 UNIPROT DERL1 protein Q9BUN8 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15215856 t miannu "VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97." SIGNOR-261370 SELENOS protein Q9BQE4 UNIPROT VCP protein P55072 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15215856 t miannu "VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97." SIGNOR-261371 TGFBR1 protein P36897 UNIPROT VPS39 protein Q96JC1 UNIPROT "up-regulates activity" binding 9543 BTO:0001538 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 EXOSC1 protein Q9Y3B2 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-261381 ATP5F1B protein P06576 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-261397 ATP5F1C protein P36542 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-261405 ATP5F1D protein P30049 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-261402 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 ATP5MG protein O75964 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-261408 ARRB2 protein P32121 UNIPROT INPP5D protein Q92835 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 24817116 t lperfetto "We identified a new adaptor beta-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-261428 CD226 protein Q15762 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR up-regulates 9606 BTO:0000914 15039383 f lperfetto "CD226 and LFA-1 cooperate in cytotoxicity and cytokine secretion mediated by T and NK cells|These results were consistent with our observation that cross-linking CD226 with anti- CD226 mAb did not induce re-directed cytotoxicity against P815 by LFA-1-deficient LAD NK clones (Fig. 4D), suggesting a requirement for LFA-1 for CD226-mediated cytotoxicity." SIGNOR-261427 INTS11 protein Q5TA45 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261462 INTS12 protein Q96CB8 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261470 INTS13 protein Q9NVM9 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261469 INTS1 protein Q8N201 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261468 INTS2 protein Q9H0H0 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261466 INTS4 protein Q96HW7 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261467 INTS5 protein Q6P9B9 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261465 INTS6 protein Q9UL03 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261463 INTS7 protein Q9NVH2 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261464 INTS9 protein Q9NV88 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261471 AURKAIP1 protein Q9NWT8 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-261461 "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 27023846 f miannu "Mitochondrial ribosomes (mitoribosomes) perform protein synthesis inside mitochondria, the organelles responsible for energy conversion and adenosine triphosphate production in eukaryotic cells." SIGNOR-261487 BRK1 protein Q8WUW1 UNIPROT "Neurite outgrowth" phenotype SIGNOR-PH134 SIGNOR down-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-261491 "Integrator complex" complex SIGNOR-C265 SIGNOR FOSL1 protein P15407 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 25675981 f lperfetto "The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes." SIGNOR-261477 "Integrator complex" complex SIGNOR-C265 SIGNOR GADD45B protein O75293 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 25675981 f lperfetto "The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes." SIGNOR-261478 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 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 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 MCM2 protein P49736 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-198428 MCM3 protein P25205 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261673 MCM4 protein P33991 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261674 MCM5 protein P33992 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261675 MCM6 protein Q14566 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261676 MCM7 protein P33993 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261677 MCM complex SIGNOR-C268 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 19946136 f "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261678 "NUP98 Fusion" "fusion protein" SIGNOR-FP16 SIGNOR CDK6 protein Q00534 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0001271 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 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR CD44 protein P16070 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 9606 BTO:0004054 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. CD44 is also upregulated by NUP98‐HOXA9." SIGNOR-261502 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0004054 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 STAT5A protein P42229 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0001516 15003515 f "Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site." SIGNOR-261518 CDT1 protein Q9H211 UNIPROT MCM complex SIGNOR-C268 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 14672932 t "Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1." SIGNOR-261679 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0001516 15498859 t "Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells." SIGNOR-261517 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 CDT1 protein Q9H211 UNIPROT MCM2 protein P49736 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 14672932 t "Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1." SIGNOR-261681 RELA protein Q04206 UNIPROT Ncor2 protein Q9WU42 UNIPROT "down-regulates activity" relocalization 10090 BTO:0002181 14982881 t "Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. This indicates that shuttling of p65 was necessary for Flt3-ITD-mediated SMRT nuclear export." SIGNOR-261539 STAT5A protein P42229 UNIPROT CISH protein Q9NSE2 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0002882 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 CDT1 protein Q9H211 UNIPROT CDT1 protein Q9H211 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 14672932 t "We further show that Cdc6 physically associates with Cdt1 via its N-terminal noncatalytic domain, a region we had previously shown to be essential for Cdc6 function." SIGNOR-261682 CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0002882 14592841 t "Activation of C/EBPα induces PU.1 expression, cell cycle arrest, and differentiation in 32D cells expressing FLT3/ITD" SIGNOR-261531 FLT3 protein P36888 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 10090 BTO:0002882 18192505 f "Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity" SIGNOR-261536 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0002882 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 STAT5A protein P42229 UNIPROT SOCS2 protein O14508 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0002882 12468433 t "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-261547 STAT5A protein P42229 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0002882 12468433 t "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-261548 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 FLT3 protein P36888 UNIPROT XRCC5 protein P13010 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0000776 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 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 ZBTB16 protein Q05516 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 BTO:0002882 9710637 f fcortellessa "PLZF overexpression leads to apoptosis." SIGNOR-261686 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 RAD21 protein O60216 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates activity" relocalization 9606 BTO:0001545 26607380 t miannu "Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity." SIGNOR-261513 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates activity" relocalization 9606 BTO:0001545 26607380 t miannu "Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity." SIGNOR-261514 STAG2 protein Q8N3U4 UNIPROT RAD21 protein O60216 UNIPROT "up-regulates quantity by stabilization" binding 9606 28430577 t miannu "Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin" SIGNOR-261511 STAT5A protein P42229 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0001516 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 STAT5A protein P42229 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates quantity by expression" "transcriptional activation" 10090 BTO:0001516 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-261552 U2AF1 protein Q01081 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by repression" "transcriptional repression" 9606 BTO:0004911 31144421 f miannu " Our results further showed that knockdown of U2AF1 significantly inhibited cell growth and induced apoptosis in erythropoiesis. Additionally, knockdown of U2AF1 also delayed terminal erythroid differentiation. Western blot analysis revealed an increase in the protein levels of downstream targets of p53 following U2AF1 knockdown. The data further showed that depletion of U2AF1 altered alternatively spliced apoptosis-associated gene transcripts in CFU-E cells. Our findings elucidate the role of U2AF1 in human erythropoiesis and reveal the underlying mechanisms." SIGNOR-261512 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 PF-2545920 chemical CID:11581936 PUBCHEM PDE10A protein Q9Y233 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206001 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR "up-regulates activity" binding 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-256197 PF-3845 chemical CID:25154867 PUBCHEM FAAH protein O00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206049 arformoterol chemical CHEBI:408174 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" -1 20655218 t Luana "Table 1. Human β2- and β1-adrenoceptor binding and calculated log D7.4 values for formoterol, indacaterol, salmeterol, S1319 and the representative library members 11–41" SIGNOR-257882 ASPM protein Q8IZT6 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 16123590 f "Here, we report that downregulation of endogenous ASPM by siRNA decreases protein levels of endogenous BRCA1. ASPM localizes to the centrosome in interphase and to the spindle poles from prophase through telophase. These findings indicate that ASPM may be involved in mitotic spindle function, possibly, through regulation of BRCA1." SIGNOR-253936 ATOH1 protein Q92858 UNIPROT HES6 protein Q96HZ4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17826772 f miannu "Electrophoretic mobility shift assays and luciferase assays show that ATOH1 activates HES6 transcription through binding to three clustered E boxes of its promoter." SIGNOR-253754 PKI-587 chemical CID:44516953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205992 PIM1 protein P11309 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0004479 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 "BCR/ABL fusion" protein A9UF07 UNIPROT RAD52 protein P43351 UNIPROT "up-regulates activity" phosphorylation Y104 DLNNGKFYVGVCAFV 9606 BTO:0004408 23836560 t Manara "Have found that BCR-ABL1 interacts with the C-terminal portion of RAD52, resulting in tyrosine phosphorylation of Y104 located in RAD52 DNA II and enhanced nuclear foci formation" SIGNOR-260909 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 t lperfetto "Our data show that BCR-ABL also phosphorylates Grb2 in Tyr160Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation." SIGNOR-247146 BRCA1 protein P38398 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 15549093 f lperfetto "The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination" SIGNOR-251500 CAMK2G protein Q13555 UNIPROT PLCB3 protein Q01970 UNIPROT unknown phosphorylation Ser537 PSLEPQKsLGDEGLN 11325525 t llicata "CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment" SIGNOR-250702 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 CDC25A protein P30304 UNIPROT RAF1 protein P04049 UNIPROT down-regulates dephosphorylation 9606 7744247 t gcesareni "Cdc25a can act on substrates other than cdks, since it dephosphorylates the homeodomain transcription factor cut and interacts with and dephosphorylates the proto-oncogene raf-1, resulting in a significant decrease in raf-1 kinase activity" SIGNOR-32548 DDX5 protein P17844 UNIPROT DDX5/DDX17 complex SIGNOR-C40 SIGNOR "form complex" binding 9606 12595555 t miannu "The highly related dead box rna helicases p68 and p72 exist as heterodimers in cells" SIGNOR-98406 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 SIGNOR-C17 12058066 t gcesareni "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-89597 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser213 NLSPNPMsPAHNNLD 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-232134 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 SIGNOR-C18 23336272 t gcesareni "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." SIGNOR-200487 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 CDK5 protein Q00535 UNIPROT EZR protein P15311 UNIPROT "up-regulates activity" phosphorylation Thr235 YEKDDKLtPKIGFPW 9606 BTO:0000971 12769842 t llicata "Increased ezrin expression and activation by CDK5 coincident with acquisition of the senescent phenotype." SIGNOR-250665 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 CDK5R1 protein Q15078 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates binding 9606 BTO:0000567;BTO:0000938 BTO:0000142 15013773 t miannu "In brain, p35 or p25 exists with and activates cdk5" SIGNOR-123387 CDK6 protein Q00534 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 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-135189 CDK7 protein P50613 UNIPROT CDK11B protein P21127 UNIPROT "up-regulates activity" phosphorylation Thr595 GSPLKAYtPVVVTLW 9606 BTO:0000567 16327805 t gcesareni "We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase" SIGNOR-245871 Arry-380 chemical CID:42598643 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189882 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914168 t llicata "As receptor-activated smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by cdk8 and cdk9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote smad transcriptional action" SIGNOR-161654 CDKN1B protein P46527 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 SIGNOR-C16 17409098 t gcesareni "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-154191 [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 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 BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15694340 t lperfetto "Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2" SIGNOR-133759 CHEK1 protein O14757 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation 9606 20068082 t gcesareni "Chk1 directly phosphorylates essential s-phase kinases cdc7." SIGNOR-163161 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001321 15659650 t lperfetto "CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37" SIGNOR-217799 chelerythrine chemical CHEBI:78373 ChEBI MAPK8 protein P45983 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-190964 CHIR-124 chemical CID:11502647 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190973 CHN1 protein P15882 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates binding 9606 BTO:0000567;BTO:0000938 BTO:0000142 15013773 t miannu "_-chimaerin was identified to interact with the p35 activator of cdk5. The complex of _-chimaerin, cdk5 and p35 is enzymatically functional" SIGNOR-123439 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 CHUK protein O15111 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation 9606 BTO:0000093 18490760 t gcesareni "Insulin activation of mtor requires akt in a manner that involves ikkalpha, preferentially to ikkbeta, and tsc2 phosphorylation" SIGNOR-178664 Clinofibrate chemical CHEBI:31412 ChEBI HMGCR protein P04035 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191085 CLOCK protein O15516 UNIPROT CLOCK/ARNTL2 complex SIGNOR-C196 SIGNOR "form complex" binding 19605937 t lperfetto "Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription" SIGNOR-253711 CASP3 protein P42574 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni "Caspase-3 is responsible for apoptosis execution" SIGNOR-256638 CBL protein P22681 UNIPROT INSR protein P06213 UNIPROT down-regulates ubiquitination 9606 BTO:0000975 11498022 t gcesareni "Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor" SIGNOR-109688 COL3A1 protein P02461 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 BTO:0001103;BTO:0002319 21949456 t "Collagen is the major structural protein in skeletal muscle ECM;... type III collagen appears to be more evenly distributed between endomysium and epimysium" SIGNOR-254664 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 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 cortisone chemical CHEBI:16962 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 14817168 t allergy gcesareni SIGNOR-251691 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 CP protein P00450 UNIPROT SMO protein Q99835 UNIPROT down-regulates binding 9606 16885213 t gcesareni "Genetic and biochemical studies imply that smo can adopt an active conformation but that it is normally repressed by patched (ptch), a 12-transmembrane protein considered the receptor for hh" SIGNOR-148451 CREB1 protein P16220 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000876 10540320 f mianu "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 PSENEN protein Q9NZ42 UNIPROT RYK protein P34925 UNIPROT up-regulates cleavage 9606 BTO:0000938 19000841 t gcesareni "Ryk activity is modulated through cleavage of its icd by gamma-secretase" SIGNOR-182145 CREBBP protein Q92793 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR "form complex" binding 9606 11559745 t lperfetto "P300/cbp proteins: hats for transcriptional bridges and scaffolds" SIGNOR-110559 crizotinib chemical CHEBI:64310 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191136 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 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 CRTC2 protein Q53ET0 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" binding 9600 BTO:0000567 26652733 t "We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR)." SIGNOR-256101 CRYBB2 protein P43320 UNIPROT CRYBB1 protein P53674 UNIPROT "up-regulates activity" binding 9606 16319073 t miannu "At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency." SIGNOR-252153 CRYBB2 protein P43320 UNIPROT CRYBB2 protein P43320 UNIPROT "up-regulates activity" binding 9606 16319073 t miannu "βB2-crystallin is the major component of β-crystallin and is a dimer at low concentrations. At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency." SIGNOR-252154 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 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 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 beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms." SIGNOR-87433 CSNK1D protein P48730 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation 9606 15747065 t gcesareni "Cki_/_ binds and phosphorylates lef-1, and this phosphorylation disrupts lef-1_-catenin interaction" SIGNOR-134494 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 CDKN1B protein P46527 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 t gcesareni "P21 and p27 are key inhibitors of both cdk1 and cdk2." SIGNOR-128445 CSNK1E protein P49674 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser45 GATTTAPsLSGKGNP 9606 BTO:0000007 12176352 t gcesareni "Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45)." SIGNOR-244102 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 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 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT "up-regulates activity" phosphorylation Ser718 KEAEEESsEDD 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-250860 CSNK2A1 protein P68400 UNIPROT FKBP4 protein Q02790 UNIPROT "down-regulates activity" phosphorylation Thr143 EFKGEDLtEEEDGGI -1 9405642 t llicata "Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. | Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90" SIGNOR-250865 ACIN1 protein Q9UKV3 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 10490026 f "Cleaved by CASP3" amattioni "Acinus induces apoptotic chromatin condensation after cleavage by caspase-3 without inducing dna fragmentation." SIGNOR-70797 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser11 NDDIEVEsDEEQPRF 9606 8018564 t gcesareni "Max activity is affected by phosphorylation at two nh2-terminal sites, ser2 and ser11." SIGNOR-35768 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser376 LQESQAGsDTDVEEG 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-179879 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 CSNK2A1 protein P68400 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 t llicata "In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro." SIGNOR-250941 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 CSNK2A1 protein P68400 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-250949 ADAM10 protein O14672 UNIPROT BTC protein P35070 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-259839 CSNK2A1 protein P68400 UNIPROT SSB protein P05455 UNIPROT up-regulates phosphorylation Ser366 GKKTKFAsDDEHDEH 9606 18257391 t gcesareni "Prior studies indicate that hla is activated by phosphorylation of serine-366 by protein kinase ck2, neutralizing a negative effect of a short basic motif (sbm)" SIGNOR-160761 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT "up-regulates activity" phosphorylation Ser475 IDIEGVQsEGQDNGA 10029 BTO:0002640 15066279 t llicata "We show that inhibiting XRCC1 phosphorylation by mutation of the CK2 phosphorylation sites or preventing CK2 activity using a highly specific inhibitor ablates the rapid repair of cellular DNA single-strand breaks by XRCC1. |" SIGNOR-250972 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni "Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity." SIGNOR-147963 CSNK2A2 protein P19784 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser106 DDIDLFGsDDEEESE -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-250987 CSNK2A2 protein P19784 UNIPROT HNRNPC protein P07910 UNIPROT unknown phosphorylation Ser260 SEGGADDsAEEGDLL -1 12564933 t llicata "Protein kinase CK2 phosphorylates hnRNP-C1/C2 at S247" SIGNOR-251007 CSNK2A2 protein P19784 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 t llicata "In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro." SIGNOR-251028 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 CTCF protein P49711 UNIPROT TERT protein O14746 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 1632686 f miannu "CTCF binds the proximal exonic r