PATHWAY_ID PATHWAY_NAME 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 SCORE SIGNOR_ID SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.781 SIGNOR-110566 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.855 SIGNOR-175219 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.679 SIGNOR-255754 SIGNOR-AML "Acute Myeloid Leukemia" CBL protein P22681 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" ubiquitination 9606 15315962 t miannu "KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT." 0.62 SIGNOR-260104 SIGNOR-AML "Acute Myeloid Leukemia" CBLB protein Q13191 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" ubiquitination 9606 15315962 t miannu "KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT." 0.324 SIGNOR-260105 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-255632 SIGNOR-AML "Acute Myeloid Leukemia" KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" binding 9606 17259966 t miannu "The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells" 0.935 SIGNOR-254946 SIGNOR-AML "Acute Myeloid Leukemia" KIT protein P10721 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 9606 15526160 t miannu "C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit" 0.616 SIGNOR-254954 SIGNOR-AML "Acute Myeloid Leukemia" CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 29958106 f miannu "In adult hematopoiesis, allelic CBFβ-SMMHC expression alters hematopoietic stem cell (HSC) differentiation, with clonal expansion of the short-term HSCs and pre-leukemic myeloid progenitor cells" 0.7 SIGNOR-255736 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.7 SIGNOR-245048 SIGNOR-AML "Acute Myeloid Leukemia" KIT protein P10721 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr703 DHAEAALyKNLLHSK 10377264 t gcesareni "We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936." 0.652 SIGNOR-248283 SIGNOR-AML "Acute Myeloid Leukemia" CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1237 TEYSQGAsPQPQHQL 9606 11584018 t lperfetto "Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter." 0.355 SIGNOR-110908 SIGNOR-AML "Acute Myeloid Leukemia" CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1270 YQQKPYPsPKTIEDL 9606 11584018 t lperfetto "Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter." 0.355 SIGNOR-110912 SIGNOR-AML "Acute Myeloid Leukemia" CUX1 protein P39880 UNIPROT PIK3IP1 protein Q96FE7 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 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." 0.37 SIGNOR-260072 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.278 SIGNOR-260073 SIGNOR-AML "Acute Myeloid Leukemia" KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" 9534 BTO:0001538 7509796 t "Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells" 0.724 SIGNOR-255949 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188)" 0.2 SIGNOR-244300 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.776 SIGNOR-183507 SIGNOR-AML "Acute Myeloid Leukemia" ZBTB16 protein Q05516 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 BTO:0002882 9710637 f fcortellessa "PLZF overexpression leads to apoptosis." 0.7 SIGNOR-261686 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.7 SIGNOR-241998 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.605 SIGNOR-108499 SIGNOR-AML "Acute Myeloid Leukemia" PARP1 protein P09874 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni "Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process" 0.7 SIGNOR-111680 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.595 SIGNOR-74227 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0001516 12796379 t "FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation." 0.611 SIGNOR-261516 SIGNOR-AML "Acute Myeloid Leukemia" STAT5A protein P42229 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 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." 0.325 SIGNOR-261518 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 10090 14981546 f "These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation." 0.292 SIGNOR-261521 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0001516 14981546 t "These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation." 0.432 SIGNOR-261522 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14592841 f "Thus, induction of C/EBPα and PU.1 expression is inhibited in 32D cells due to the expression of FLT3/ITD" 0.639 SIGNOR-261529 SIGNOR-AML "Acute Myeloid Leukemia" CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 14592841 t "Activation of C/EBPα induces PU.1 expression, cell cycle arrest, and differentiation in 32D cells expressing FLT3/ITD" 0.528 SIGNOR-261531 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15574429 f "Expression of FLT3/ITD induces down-regulation of SHP-1 expression and activity" 0.364 SIGNOR-261532 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT FZD4 protein Q9ULV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002882 15650056 f "AML-typical Flt3 mutations induce the expression of Frizzled-4 on the mRNA and protein level, mimicking the effects of IL-3." 0.2 SIGNOR-261533 SIGNOR-AML "Acute Myeloid Leukemia" NOTCH proteinfamily SIGNOR-PF30 SIGNOR HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 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" 0.2 SIGNOR-261534 SIGNOR-AML "Acute Myeloid Leukemia" HES1 protein Q14469 UNIPROT FLT3 protein P36888 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 25234168 t "We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity." 0.2 SIGNOR-261563 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 10090 18192505 f "Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity" 0.2 SIGNOR-261536 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT ZBTB16 protein Q05516 UNIPROT "down-regulates activity" 10090 BTO:0002181 14982881 f "We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm." 0.314 SIGNOR-261537 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT NCOR2 protein Q9Y618 UNIPROT "down-regulates activity" relocalization 10090 14982881 f "We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm." 0.258 SIGNOR-261538 SIGNOR-AML "Acute Myeloid Leukemia" RELA protein Q04206 UNIPROT NCOR2 protein Q9Y618 UNIPROT "down-regulates activity" relocalization 10090 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." 0.402 SIGNOR-261539 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 15769897 t "we observed constitutive activation of Erk-1 and Erk-2, Akt, and of Shc by both Flt3-ITD and Flt3-D835Y" 0.449 SIGNOR-261540 SIGNOR-AML "Acute Myeloid Leukemia" STAT5A protein P42229 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 t "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" 0.66 SIGNOR-261551 SIGNOR-AML "Acute Myeloid Leukemia" STAT5A protein P42229 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 t "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" 0.264 SIGNOR-261552 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT PTPRJ protein Q12913 UNIPROT "down-regulates activity" 10090 22438257 f "Taken together, the described findings supported the notion that FLT3 ITD causes reduced DEP-1 activity compared with cells expressing WT FLT3 rather than alterations in mRNA or protein levels." 0.488 SIGNOR-261553 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT PARP1 protein P09874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 21228325 f "Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls " 0.25 SIGNOR-261554 SIGNOR-AML "Acute Myeloid Leukemia" PIM1 protein P11309 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation 9606 25280219 t "FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells" 0.701 SIGNOR-261557 SIGNOR-AML "Acute Myeloid Leukemia" MYC protein P01106 UNIPROT USP22 protein Q9UPT9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26049753 f "USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells." 0.493 SIGNOR-261560 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.533 SIGNOR-261561 SIGNOR-AML "Acute Myeloid Leukemia" MIR1-1 mirna URS000075CF56_9606 RNAcentral PAX7 protein P23759 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 24708856 t irozzo "In this study, bioinformatic prediction combined with pathway analysis and validation by qRT-PCR revealed that miR-155 expression positively correlates with the expression of the AP-1 genes c-JUN and FOS, which are known to induce myeloid differentiation" 0.4 SIGNOR-256124 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.807 SIGNOR-261562 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation." 0.2 SIGNOR-244296 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.6 SIGNOR-162314 SIGNOR-AML "Acute Myeloid Leukemia" MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser47 DGPGLERsPGEPGGA 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." 0.6 SIGNOR-162318 SIGNOR-AML "Acute Myeloid Leukemia" MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Thr530 YLSELPPtPLHVSED 9606 20027304 t "This phosphorylation increased sirt1 nuclear localization" gcesareni "Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53." 0.6 SIGNOR-162322 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.662 SIGNOR-195414 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.723 SIGNOR-242628 SIGNOR-AML "Acute Myeloid Leukemia" FZD4 protein Q9ULV1 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 27096005 t areggio "Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin." 0.601 SIGNOR-258955 SIGNOR-AML "Acute Myeloid Leukemia" DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 15735151 t 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." 0.809 SIGNOR-134285 SIGNOR-AML "Acute Myeloid Leukemia" EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto "P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation." 0.784 SIGNOR-252671 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.413 SIGNOR-59965 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.261 SIGNOR-252727 SIGNOR-AML "Acute Myeloid Leukemia" BAD protein Q92934 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 "BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203" 23725574 f irozzo "Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions." 0.7 SIGNOR-256260 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.7 SIGNOR-261683 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-261685 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.2 SIGNOR-259418 SIGNOR-AML "Acute Myeloid Leukemia" BAD protein Q92934 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 "BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203" 23725574 f irozzo "Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions." 0.7 SIGNOR-256259 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.7 SIGNOR-252938 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.7 SIGNOR-251508 SIGNOR-AML "Acute Myeloid Leukemia" CCND1 protein P24385 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000575 11731443 f "Cyclin D1 regulates mitogen-dependent progression through G1 phase in cultured cells, and its overexpression in malignant cells is thought to contribute to autonomous proliferation in vivo." 0.7 SIGNOR-260014 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto "Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1" 0.2 SIGNOR-245428 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-260133 SIGNOR-AML "Acute Myeloid Leukemia" GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 14563837 t gcesareni "Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc" 0.724 SIGNOR-118844 SIGNOR-AML "Acute Myeloid Leukemia" GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 BTO:0000150 16504004 t gcesareni "Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover." 0.787 SIGNOR-144818 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 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." 0.292 SIGNOR-260132 SIGNOR-AML "Acute Myeloid Leukemia" MCL1 protein Q07820 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17289999 t gcesareni "Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w" 0.735 SIGNOR-151787 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.698 SIGNOR-66949 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.28 SIGNOR-200133 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-260077 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." 0.2 SIGNOR-244292 SIGNOR-AML "Acute Myeloid Leukemia" RUNX1 protein Q01196 UNIPROT hsa-mir-223 mirna URS000037EC34_9606 RNAcentral "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." 0.4 SIGNOR-255817 SIGNOR-AML "Acute Myeloid Leukemia" SPI1 protein P17947 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 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." 0.4 SIGNOR-255816 SIGNOR-AML "Acute Myeloid Leukemia" INPP5D protein Q92835 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 12421919 t gcesareni "Two inositol phosphatases implicated in the degradation of PI(3, 4, 5)P3, namely the 5_ phosphatase Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and the 3_ phosphatase and tensin homolog deleted on chromosome ten" 0.8 SIGNOR-252428 SIGNOR-AML "Acute Myeloid Leukemia" NfKb-p65/p50 complex SIGNOR-C13 SIGNOR miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity" "transcriptional regulation" 9606 26055960 f miannu "Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation." 0.4 SIGNOR-255802 SIGNOR-AML "Acute Myeloid Leukemia" RUNX1 protein Q01196 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral "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" 0.4 SIGNOR-255800 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 10090 25477897 t miannu "The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC" 0.4 SIGNOR-255796 SIGNOR-AML "Acute Myeloid Leukemia" miR-155 mirna URS000062749E_9606 RNAcentral CEBPB protein P17676 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 25477897 t miannu "The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT3" 0.4 SIGNOR-255795 SIGNOR-AML "Acute Myeloid Leukemia" MIR1-1 mirna URS000075CF56_9606 RNAcentral IGF1 protein P05019 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 25477897 t miannu "The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT1" 0.4 SIGNOR-255793 SIGNOR-AML "Acute Myeloid Leukemia" KLF2 protein Q9Y5W3 UNIPROT mir-143 mirna URS0000008A99_9606 RNAcentral "up-regulates quantity" "transcriptional regulation" 9606 25477897 t miannu "Overexpression of miR-155 leads to the activation of the PI3K-Akt pathway through negative regulation of Src Homology 2 domain-containing Inositol-5-Phosphatase (SHIP1)." 0.4 SIGNOR-255769 SIGNOR-AML "Acute Myeloid Leukemia" miR-155 mirna URS000062749E_9606 RNAcentral FOS protein P01100 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." 0.4 SIGNOR-255766 SIGNOR-AML "Acute Myeloid Leukemia" miR-199a mirna URS0000759977_9606 RNAcentral MTOR protein P42345 UNIPROT "up-regulates activity" 9606 26055960 t miannu "Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation." 0.4 SIGNOR-255803 SIGNOR-AML "Acute Myeloid Leukemia" miR-132 mirna URS00001F4E81_9606 RNAcentral MECP2 protein P51608 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 23132946 f irozzo "In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability." 0.4 SIGNOR-255884 SIGNOR-AML "Acute Myeloid Leukemia" STAT5A protein P42229 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 23132946 f irozzo "We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells." 0.4 SIGNOR-255885 SIGNOR-AML "Acute Myeloid Leukemia" SPI1 protein P17947 UNIPROT miR-338 mirna URS000075E706_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 23132946 f irozzo "We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells." 0.4 SIGNOR-255886 SIGNOR-AML "Acute Myeloid Leukemia" TWIST1 protein Q15672 UNIPROT mir-10b mirna URS00004CAC40_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 23132946 f irozzo "We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells." 0.4 SIGNOR-255887 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 9606 16266983 f gcesareni "We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway." 0.432 SIGNOR-245064 SIGNOR-AML "Acute Myeloid Leukemia" PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-AML "Acute Myeloid Leukemia" 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)," 0.746 SIGNOR-244469 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-255704 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." 0.449 SIGNOR-251148 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." 0.449 SIGNOR-251147 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." 0.449 SIGNOR-251146 SIGNOR-AML "Acute Myeloid Leukemia" DOT1L protein Q8TEK3 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20854876 f irozzo "Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented." 0.402 SIGNOR-256143 SIGNOR-AML "Acute Myeloid Leukemia" MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." 0.2 SIGNOR-260127 SIGNOR-AML "Acute Myeloid Leukemia" MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." 0.2 SIGNOR-260126 SIGNOR-AML "Acute Myeloid Leukemia" RUNX1 protein Q01196 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 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." 0.692 SIGNOR-255709 SIGNOR-AML "Acute Myeloid Leukemia" MCL1 protein Q07820 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni "Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax" 0.626 SIGNOR-149774 SIGNOR-AML "Acute Myeloid Leukemia" BAK1 protein Q16611 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu "The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation." 0.7 SIGNOR-261493 SIGNOR-AML "Acute Myeloid Leukemia" MLL-AF4 "fusion protein" SIGNOR-FP4 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." 0.2 SIGNOR-255877 SIGNOR-AML "Acute Myeloid Leukemia" "AEP complex" complex SIGNOR-C117 SIGNOR HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" 9606 20854876 f irozzo "Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented." 0.408 SIGNOR-255879 SIGNOR-AML "Acute Myeloid Leukemia" MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 10090 BTO:0004052 23996074 t irozzo "In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL.The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1" 0.2 SIGNOR-255869 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-255882 SIGNOR-AML "Acute Myeloid Leukemia" MEN1 protein O00255 UNIPROT MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR "up-regulates activity" binding 10090 BTO:0004730 16239140 t irozzo "We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]." 0.2 SIGNOR-255866 SIGNOR-AML "Acute Myeloid Leukemia" MEN1 protein O00255 UNIPROT MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR "up-regulates activity" binding 10090 BTO:0004730 16239140 t irozzo "We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]." 0.2 SIGNOR-255867 SIGNOR-AML "Acute Myeloid Leukemia" MEN1 protein O00255 UNIPROT MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR "up-regulates activity" binding 10090 BTO:0004730 16239140 t irozzo "We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]." 0.2 SIGNOR-255868 SIGNOR-AML "Acute Myeloid Leukemia" "MLL Fusion" "fusion protein" SIGNOR-FP14 SIGNOR "AEP complex" complex SIGNOR-C117 SIGNOR "up-regulates activity" binding 9606 BTO:0005261 19956800 t miannu "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." 0.2 SIGNOR-260131 SIGNOR-AML "Acute Myeloid Leukemia" MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 10090 BTO:0004052 23996074 t irozzo "In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL. The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1" 0.2 SIGNOR-255870 SIGNOR-AML "Acute Myeloid Leukemia" DOT1L protein Q8TEK3 UNIPROT MCL1 protein Q07820 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27856324 f 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." 0.2 SIGNOR-255881 SIGNOR-AML "Acute Myeloid Leukemia" RUNX1 protein Q01196 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29958106 t miannu "RUNX1 represses MYC expression through direct binding at three downstream enhancer elements" 0.336 SIGNOR-260093 SIGNOR-AML "Acute Myeloid Leukemia" "AEP complex" complex SIGNOR-C117 SIGNOR MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" 9606 20854876 f irozzo "Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented." 0.384 SIGNOR-256144 SIGNOR-AML "Acute Myeloid Leukemia" BAX protein Q07812 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu "The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation." 0.7 SIGNOR-261494 SIGNOR-AML "Acute Myeloid Leukemia" MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR MECOM protein Q03112 UNIPROT "up-regulates quantity by expression" methylation 10090 BTO:0001271 22553314 t irozzo "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." 0.2 SIGNOR-255858 SIGNOR-AML "Acute Myeloid Leukemia" MLL-AF9 "fusion protein" SIGNOR-FP5 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." 0.2 SIGNOR-255876 SIGNOR-AML "Acute Myeloid Leukemia" RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24321385 t miannu "We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells" 0.284 SIGNOR-259973 SIGNOR-AML "Acute Myeloid Leukemia" BCOR protein Q6W2J9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo "Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes." 0.7 SIGNOR-256011 SIGNOR-AML "Acute Myeloid Leukemia" DOT1L protein Q8TEK3 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27856324 f 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." 0.2 SIGNOR-255880 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-255878 SIGNOR-AML "Acute Myeloid Leukemia" DOT1L protein Q8TEK3 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" binding 9606 BTO:0001939 26199140 t 1 miannu "Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1" 0.336 SIGNOR-239362 SIGNOR-AML "Acute Myeloid Leukemia" BCOR protein Q6W2J9 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo "Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes." 0.7 SIGNOR-256010 SIGNOR-AML "Acute Myeloid Leukemia" MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR BCOR protein Q6W2J9 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 12776190 t irozzo "As BCoR binds the C-terminus of AF9, it seems likely that BCoR will also bind chimeric MLL–AF9 proteins. As transcriptional repressors, BCoR or Pc3 bound to MLL–AF9 might interfere with the expression of genes required for normal hematopoiesis." 0.2 SIGNOR-256142 SIGNOR-AML "Acute Myeloid Leukemia" MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." 0.2 SIGNOR-260128 SIGNOR-AML "Acute Myeloid Leukemia" NPM1 protein P06748 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30205049 t miannu "In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation." 0.352 SIGNOR-260138 SIGNOR-AML "Acute Myeloid Leukemia" FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 t lperfetto "We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1" 0.767 SIGNOR-249638 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.752 SIGNOR-99712 SIGNOR-AML "Acute Myeloid Leukemia" MEIS1 protein O00470 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001271 19109563 f irozzo "These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase." 0.7 SIGNOR-255859 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.552 SIGNOR-245073 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.48 SIGNOR-245084 SIGNOR-AML "Acute Myeloid Leukemia" FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity" ubiquitination 9606 SIGNOR-C135 20852628 t gcesareni "We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it." 0.767 SIGNOR-243545 SIGNOR-AML "Acute Myeloid Leukemia" MYC protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12835716 t gcesareni "C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a" 0.771 SIGNOR-102743 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.7 SIGNOR-255678 SIGNOR-AML "Acute Myeloid Leukemia" CCND1 protein P24385 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18177723 f "andrea cerquone perpetuini" "Cyclin D1 is necessary for proliferation of different cell types, including myogenic cells." 0.7 SIGNOR-255412 SIGNOR-AML "Acute Myeloid Leukemia" DNMT3A protein Q9Y6K1 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19786833 f irozzo "Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc." 0.512 SIGNOR-255808 SIGNOR-AML "Acute Myeloid Leukemia" IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "chemical modification" 9606 29090344 t miannu "Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases." 0.8 SIGNOR-253135 SIGNOR-AML "Acute Myeloid Leukemia" IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "chemical modification" 9606 29090344 t miannu "Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases." 0.8 SIGNOR-253134 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.45 SIGNOR-255703 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-255705 SIGNOR-AML "Acute Myeloid Leukemia" MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f "The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size." 0.7 SIGNOR-255944 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 9575217 t lperfetto "Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein" 0.869 SIGNOR-249507 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.733 SIGNOR-248466 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C7 17964260 t lperfetto "Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300." 0.2 SIGNOR-244239 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto "We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity" 0.2 SIGNOR-244236 SIGNOR-AML "Acute Myeloid Leukemia" EP300 protein Q09472 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20660310 f amattioni "Switch to beta-catenin/p300-mediated gene expression is an essential first step in initiating normal cellular differentiation" 0.7 SIGNOR-229780 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.434 SIGNOR-255739 SIGNOR-AML "Acute Myeloid Leukemia" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR 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." 0.795 SIGNOR-252353 SIGNOR-AML "Acute Myeloid Leukemia" GRB2 protein P62993 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t "GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway." gcesareni "The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization." 0.904 SIGNOR-114704 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.665 SIGNOR-255982 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni "Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation." 0.523 SIGNOR-245057 SIGNOR-AML "Acute Myeloid Leukemia" "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR "down-regulates quantity by destabilization" "chemical inhibition" 9606 19029980 t "Retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation." 0.8 SIGNOR-259926 SIGNOR-AML "Acute Myeloid Leukemia" PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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." 0.2 SIGNOR-255725 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001545 17851558 t miannu "Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML." 0.411 SIGNOR-260124 SIGNOR-AML "Acute Myeloid Leukemia" "diarsenic trioxide" chemical CHEBI:30621 ChEBI PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR "down-regulates quantity by destabilization" "chemical inhibition" 9606 24344243 t "ATO was shown to degrade PML-RARa via its PML moiety further reinforcing the idea that APL is addicted to the PML-RARa oncoprotein" 0.8 SIGNOR-259924 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.422 SIGNOR-259927 SIGNOR-AML "Acute Myeloid Leukemia" midostaurin chemical CHEBI:63452 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 12124173 t "PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors." 0.8 SIGNOR-256308 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" 9606 28213513 f "Our finding that RUNX1 protein levels are dependent on FLT3-ITD signaling in AML cells and that, together, they synergize to generate AML. […]Our work demonstrated that Tyr phosphorylation within the ID region of RUNX1 is critical for its oncogenic potential," 0.363 SIGNOR-256307 SIGNOR-AML "Acute Myeloid Leukemia" HHEX protein Q03014 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR "up-regulates activity" 10090 BTO:0000089 26728554 f "Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal." 0.7 SIGNOR-256306 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.364 SIGNOR-259950 SIGNOR-AML "Acute Myeloid Leukemia" CDKN2A protein P42771 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f "Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation." 0.7 SIGNOR-259406 SIGNOR-AML "Acute Myeloid Leukemia" ASXL1 protein Q8IXJ9 UNIPROT CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 29967380 t miannu "Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice." 0.302 SIGNOR-260119 SIGNOR-AML "Acute Myeloid Leukemia" ASXL1 protein Q8IXJ9 UNIPROT NCOA1 protein Q15788 UNIPROT "up-regulates activity" binding 9606 16606617 t 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." 0.284 SIGNOR-255931 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.244 SIGNOR-249636 SIGNOR-AML "Acute Myeloid Leukemia" ASXL1 protein Q8IXJ9 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22897849 f miannu "ASXL1 siRNA in human primary CD34+ cells form cord blood results in upregulation of HOXA5 and HOXA9 with ASXL1 knockdown (KD) as revealed by quantitative real-time PCR" 0.433 SIGNOR-256127 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.723 SIGNOR-16433 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" 10090 BTO:0001516 23246379 f miannu "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells." 0.561 SIGNOR-260083 SIGNOR-AML "Acute Myeloid Leukemia" BCORL1 protein Q5H9F3 UNIPROT CTBP1 protein Q13363 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 17379597 t irozzo "BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay." 0.436 SIGNOR-259193 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.599 SIGNOR-256139 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.968 SIGNOR-34962 SIGNOR-AML "Acute Myeloid Leukemia" JUN protein P05412 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates activity" binding 9606 BTO:0004136 12393465 t apalma "These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1." 0.554 SIGNOR-255660 SIGNOR-AML "Acute Myeloid Leukemia" CEBPA protein P49715 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." 0.488 SIGNOR-253830 SIGNOR-AML "Acute Myeloid Leukemia" AP1 complex SIGNOR-C154 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto "AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation." 0.7 SIGNOR-252356 SIGNOR-AML "Acute Myeloid Leukemia" MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni "C-myc has emerged as one of the central regulators of mammalian cell proliferation." 0.7 SIGNOR-56572 SIGNOR-AML "Acute Myeloid Leukemia" AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR PTGS2 protein P35354 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004850 23645839 f miannu "AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells." 0.2 SIGNOR-255683 SIGNOR-AML "Acute Myeloid Leukemia" CEBPA protein P49715 UNIPROT SOX4 protein Q06945 UNIPROT down-regulates "transcriptional regulation" 9606 24183681 t apalma "In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding." 0.383 SIGNOR-255675 SIGNOR-AML "Acute Myeloid Leukemia" CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f "Simone Vumbaca" "we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells." 0.7 SIGNOR-255654 SIGNOR-AML "Acute Myeloid Leukemia" AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR PTPRC protein P08575 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001271 22740448 f miannu "Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced." 0.2 SIGNOR-255686 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-249633 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.47 SIGNOR-248348 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.47 SIGNOR-248349 SIGNOR-AML "Acute Myeloid Leukemia" "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" 0.8 SIGNOR-255685 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.47 SIGNOR-248347 SIGNOR-AML "Acute Myeloid Leukemia" SRSF2 protein Q01130 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27524244 t miannu "Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2." 0.279 SIGNOR-260076 SIGNOR-AML "Acute Myeloid Leukemia" AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR CDKN2A protein Q8N726 UNIPROT down-regulates "transcriptional regulation" 9606 12091906 t apalma "We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO." 0.2 SIGNOR-255677 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.7 SIGNOR-255669 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.2 SIGNOR-255671 SIGNOR-AML "Acute Myeloid Leukemia" AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates activity" binding 9606 BTO:0001271 11283671 t apalma "Here we show that AML1–ETO blocks C/EBPα –dependent activation of its own promoter and thereby inhibits autoregulation." 0.2 SIGNOR-255672 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16146838 f 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." 0.639 SIGNOR-249635 SIGNOR-AML "Acute Myeloid Leukemia" AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR JUN protein P05412 UNIPROT "down-regulates activity" binding 9606 BTO:0004136 12393465 t "RUNX1-RUNX1T1 fusion protein (AML-ETO)" apalma "Here we show that AML1-ETO blocks the transcriptional activity of PU.1 by displacing its coactivator c-Jun." 0.2 SIGNOR-255670 SIGNOR-AML "Acute Myeloid Leukemia" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23150757 t lperfetto "Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity" 0.968 SIGNOR-199371 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.968 SIGNOR-80528 SIGNOR-AML "Acute Myeloid Leukemia" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 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." 0.968 SIGNOR-196116 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.7 SIGNOR-254302 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni "Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation" 0.869 SIGNOR-56827 SIGNOR-AML "Acute Myeloid Leukemia" AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates activity" binding 9606 BTO:0001412 11283671 t irozzo "AML1–ETO inhibits CEBPA autoregulation in myeloid cells.[…]It was also demonstrated that AML1–ETO and C/EBPα physically interact in vivo." 0.2 SIGNOR-255700 SIGNOR-AML "Acute Myeloid Leukemia" CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma "For example, 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" 0.7 SIGNOR-255695 SIGNOR-AML "Acute Myeloid Leukemia" AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR JAK2 protein O60674 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001271 22740448 f miannu "Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced." 0.2 SIGNOR-260120 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-255676 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.47 SIGNOR-255679 SIGNOR-AML "Acute Myeloid Leukemia" CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" relocalization 9606 23416275 t fstefani "We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53." 0.769 SIGNOR-192697 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-255682 SIGNOR-AML "Acute Myeloid Leukemia" PTGS2 protein P35354 UNIPROT "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI "up-regulates quantity" "chemical modification" 9606 16540375 t "Arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES)" 0.8 SIGNOR-255684 SIGNOR-AML "Acute Myeloid Leukemia" CCNA1 protein P78396 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001884 15829981 f miannu "SiRNA mediated silencing of cyclin A1 in highly cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation. " 0.7 SIGNOR-255734 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.284 SIGNOR-255924 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.723 SIGNOR-16665 SIGNOR-AML "Acute Myeloid Leukemia" ASXL1 protein Q8IXJ9 UNIPROT RARA protein P10276 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 16606617 t irozzo "Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells." 0.442 SIGNOR-255910 SIGNOR-AML "Acute Myeloid Leukemia" CTBP1 protein Q13363 UNIPROT CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23303449 f irozzo "Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Additionally, the inhibitor of cyclin-dependent protein kinases (CDKs), p16INK4a, whose loss has been related to the pathogenesis of melanoma, was repressed by CtBP1 as well." 0.413 SIGNOR-259195 SIGNOR-AML "Acute Myeloid Leukemia" EZH2 protein Q15910 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20565746 t miannu "These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression." 0.397 SIGNOR-260068 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.2 SIGNOR-244259 SIGNOR-AML "Acute Myeloid Leukemia" NCOA1 protein Q15788 UNIPROT RARA protein P10276 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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." 0.709 SIGNOR-255932 SIGNOR-AML "Acute Myeloid Leukemia" ASXL1 protein Q8IXJ9 UNIPROT RARA protein P10276 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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." 0.442 SIGNOR-255933 SIGNOR-AML "Acute Myeloid Leukemia" PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 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." 0.796 SIGNOR-254950 SIGNOR-AML "Acute Myeloid Leukemia" ASXL1 protein Q8IXJ9 UNIPROT RXRA protein P19793 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 16606617 t irozzo "In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells." 0.282 SIGNOR-255911 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation" 0.912 SIGNOR-252837 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244152 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244156 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f lperfetto "It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor." 0.2 SIGNOR-244314 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto "AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬†" 0.2 SIGNOR-244311 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-244501 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.2 SIGNOR-248199 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.796 SIGNOR-252703 SIGNOR-AML "Acute Myeloid Leukemia" 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," 0.796 SIGNOR-252715 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244160 SIGNOR-AML "Acute Myeloid Leukemia" KDM5A protein P29375 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by destabilization" "transcriptional regulation" 9606 31374292 t miannu "The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL." 0.29 SIGNOR-260079 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-260080 SIGNOR-AML "Acute Myeloid Leukemia" BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 21900390 f miannu "RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK)." 0.661 SIGNOR-260082 SIGNOR-AML "Acute Myeloid Leukemia" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 10090 BTO:0000669 23452850 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate." 0.914 SIGNOR-235773 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 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." 0.2 SIGNOR-255812 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0005248 8758906 t irozzo "We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine." 0.2 SIGNOR-255999 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.829 SIGNOR-201703 SIGNOR-AML "Acute Myeloid Leukemia" KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR 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 phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism." 0.742 SIGNOR-252698 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 8642285 t irozzo "Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant.These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation." 0.2 SIGNOR-255813 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT "down-regulates activity" phosphorylation Tyr7 yDFKATAD 9606 BTO:0000007 20554525 t lperfetto "More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway." 0.2 SIGNOR-246285 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT "down-regulates activity" phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000007 20554525 t lperfetto "More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway." 0.2 SIGNOR-246281 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT "down-regulates activity" phosphorylation Tyr37 EECDQNWyKAELNGK 9606 20554525 t lperfetto "More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway." 0.2 SIGNOR-246289 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-247146 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT "down-regulates activity" phosphorylation Tyr52 DGFIPKNyIEMKPHP 9606 BTO:0000007 20554525 t lperfetto "More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway." 0.2 SIGNOR-246293 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-255820 SIGNOR-AML "Acute Myeloid Leukemia" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-AML "Acute Myeloid Leukemia" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." 0.787 SIGNOR-244843 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t apalma "The GM-CSF receptor does not have intrinsic tyrosine kinase activity, but associates with the tyrosine kinase Jak2 that is required for Œ≤c transphosphorylation and the initiation of signaling and biological activity" 0.59 SIGNOR-255584 SIGNOR-AML "Acute Myeloid Leukemia" CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 19436055 t miannu "As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of Œ≤c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways" 0.473 SIGNOR-255585 SIGNOR-AML "Acute Myeloid Leukemia" CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 BTO:0000876 BTO:0001103 19436055 f apalma "As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of beta-c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways" 0.2 SIGNOR-255586 SIGNOR-AML "Acute Myeloid Leukemia" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t "Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK." 0.2 SIGNOR-252079 SIGNOR-AML "Acute Myeloid Leukemia" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser87 AAAGPALsPVPPVVH 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." 0.2 SIGNOR-244505 SIGNOR-AML "Acute Myeloid Leukemia" HOXA9 protein P31269 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo "Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function." 0.7 SIGNOR-255864 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-244494 SIGNOR-AML "Acute Myeloid Leukemia" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr56 FSSQPGHtPHPAASR 9606 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." 0.2 SIGNOR-244610 SIGNOR-AML "Acute Myeloid Leukemia" FOXO proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." 0.7 SIGNOR-252939 SIGNOR-AML "Acute Myeloid Leukemia" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-AML "Acute Myeloid Leukemia" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 8479541 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-39163 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" binding 10090 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. " 0.453 SIGNOR-255810 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 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. " 0.453 SIGNOR-255811 SIGNOR-AML "Acute Myeloid Leukemia" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.93 SIGNOR-134185 SIGNOR-AML "Acute Myeloid Leukemia" MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto "Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1." 0.93 SIGNOR-244417 SIGNOR-AML "Acute Myeloid Leukemia" KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." 0.878 SIGNOR-156906 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" 0.912 SIGNOR-252825 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" 0.912 SIGNOR-252826 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0004052 14500898 t irozzo "This up-regulation required BCR-ABL tyrosine kinase activity and led to IL-3Rbetac/beta chain tyrosine phosphorylation in the absence of detectable IL-3 production. These results suggested that cytokine-independent IL-3 receptor activation could be a dominant signaling component in BCR-ABL-induced leukemogenesis. However, the IL-3Rβc/β chain could act as a cofactor in BCR-ABL-induced leukemogenesis by activation of its many known oncogenic signaling pathways." 0.2 SIGNOR-256123 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR 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" 0.912 SIGNOR-252835 SIGNOR-AML "Acute Myeloid Leukemia" MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma "Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction" 0.7 SIGNOR-255108 SIGNOR-AML "Acute Myeloid Leukemia" PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 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]." 0.8 SIGNOR-252713 SIGNOR-AML "Acute Myeloid Leukemia" PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 24647478 t lperfetto "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478" 0.8 SIGNOR-252712 SIGNOR-AML "Acute Myeloid Leukemia" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" 9606 19951971 t lperfetto "PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain." 0.8 SIGNOR-249628 SIGNOR-AML "Acute Myeloid Leukemia" BCL2 protein P10415 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto "Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis" 0.7 SIGNOR-249611 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "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" 0.912 SIGNOR-252827 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR 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" 0.912 SIGNOR-252828 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 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" 0.912 SIGNOR-252829 SIGNOR-AML "Acute Myeloid Leukemia" 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)." 0.746 SIGNOR-134477 SIGNOR-AML "Acute Myeloid Leukemia" 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)" 0.746 SIGNOR-244480 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.746 SIGNOR-244421 SIGNOR-AML "Acute Myeloid Leukemia" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." 0.8 SIGNOR-175253 SIGNOR-AML "Acute Myeloid Leukemia" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9534 9637919 t lperfetto "In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation." 0.8 SIGNOR-58313 SIGNOR-AML "Acute Myeloid Leukemia" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" -1 9094314 t gcesareni "We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1)" 0.8 SIGNOR-243274 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.912 SIGNOR-252831 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto "Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export." 0.912 SIGNOR-252832 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation 9606 21440011 t lperfetto "Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs" 0.912 SIGNOR-252833 SIGNOR-AML "Acute Myeloid Leukemia" DNMT3A protein Q9Y6K1 UNIPROT CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 26350239 f miannu "Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family" 0.38 SIGNOR-255809 SIGNOR-AML "Acute Myeloid Leukemia" HOXA9 protein P31269 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." 0.619 SIGNOR-241162 SIGNOR-AML "Acute Myeloid Leukemia" DNMT3A protein Q9Y6K1 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24280869 f miannu "HOXA9 is significantly upregulated in both categories of DNMT3A modifications and this has been associated with poor prognosis in AML before (Figure 3d). In fact, almost the entire HOXA and HOXB cluster were significantly upregulated in AML samples with either epimutation or mutation in DNMT3A." 0.339 SIGNOR-256128 SIGNOR-AML "Acute Myeloid Leukemia" MEIS1 protein O00470 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo "Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function." 0.7 SIGNOR-255865 SIGNOR-AML "Acute Myeloid Leukemia" MEIS1 protein O00470 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo "To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells." 0.7 SIGNOR-255860 SIGNOR-AML "Acute Myeloid Leukemia" DNMT3A protein Q9Y6K1 UNIPROT MEIS1 protein O00470 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 28288143 f miannu "Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia." 0.329 SIGNOR-256125 SIGNOR-AML "Acute Myeloid Leukemia" DNMT3A protein Q9Y6K1 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 27639498 f irozzo "The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation." 0.7 SIGNOR-255714 SIGNOR-AML "Acute Myeloid Leukemia" 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI TET2 protein Q6N021 UNIPROT "up-regulates activity" binding 9606 25699704 t irozzo "A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity." 0.8 SIGNOR-255706 SIGNOR-AML "Acute Myeloid Leukemia" RUNX1 protein Q01196 UNIPROT HHEX protein Q03014 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 28213513 t "We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML." 0.272 SIGNOR-256305 SIGNOR-AML "Acute Myeloid Leukemia" CBLB protein Q13191 UNIPROT FLT3 protein P36888 UNIPROT "down-regulates activity" ubiquitination 10090 BTO:0001516 19276253 t miannu "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." 0.323 SIGNOR-260106 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18559972 f apalma "In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors." 0.263 SIGNOR-255698 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-255726 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-255732 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.413 SIGNOR-255733 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR 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)." 0.912 SIGNOR-252820 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni "Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity." 0.912 SIGNOR-252824 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR 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" 0.912 SIGNOR-252830 SIGNOR-AML "Acute Myeloid Leukemia" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 t lperfetto "The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity" 0.912 SIGNOR-252834 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.599 SIGNOR-256138 SIGNOR-AML "Acute Myeloid Leukemia" 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)," 0.885 SIGNOR-99750 SIGNOR-AML "Acute Myeloid Leukemia" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation -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." 0.787 SIGNOR-244831 SIGNOR-AML "Acute Myeloid Leukemia" FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 10080542 t gcesareni "Flt3 ligand (fl) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor flt3/flk2 belongs to class iii receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1" 0.885 SIGNOR-65564 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 10090 10080542 t gcesareni "FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc" 0.606 SIGNOR-245060 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni "in vitro kinase assays revealed that STAT5 is a direct target of Flt3" 0.611 SIGNOR-245069 SIGNOR-AML "Acute Myeloid Leukemia" ID1 protein P41134 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0004136 26084673 t apalma "We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation;" 0.335 SIGNOR-255942 SIGNOR-AML "Acute Myeloid Leukemia" GRB10 protein Q13322 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0001516 23246379 t "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation" 0.332 SIGNOR-255946 SIGNOR-AML "Acute Myeloid Leukemia" FLT3 protein P36888 UNIPROT GRB10 protein Q13322 UNIPROT "up-regulates activity" binding 10090 BTO:0001516 23246379 t "These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells." 0.361 SIGNOR-255947 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-255747 SIGNOR-AML "Acute Myeloid Leukemia" NFY complex SIGNOR-C1 SIGNOR ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18025157 f "We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein." 0.269 SIGNOR-255746 SIGNOR-AML "Acute Myeloid Leukemia" SP1 protein P08047 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18025157 f "We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein." 0.2 SIGNOR-255748 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-255749 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-255729 SIGNOR-AML "Acute Myeloid Leukemia" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto "Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions." 0.795 SIGNOR-252359 SIGNOR-AML "Acute Myeloid Leukemia" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto "In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity." 0.795 SIGNOR-252358 SIGNOR-AML "Acute Myeloid Leukemia" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 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." 0.795 SIGNOR-252357 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t "JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity" 0.2 SIGNOR-251356 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.2 SIGNOR-261507 SIGNOR-AML "Acute Myeloid Leukemia" KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000830 15526160 t miannu "Activation of PI3-kinase by c-Kit has been linked to mitogenesis, differentiation, survival, adhesion, secretion and actin cytoskeletal reorganization. In c-Kit, Y721 has been found to directly interact with PI3-kinase" 0.724 SIGNOR-254949 SIGNOR-AML "Acute Myeloid Leukemia" AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR KIT protein P10721 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29236325 f irozzo "We report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT." 0.2 SIGNOR-255699 SIGNOR-AML "Acute Myeloid Leukemia" AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 BTO:0004136 10208431 t miannu "The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. On physical interaction, AML1/ETO can form a complex with wild-type AML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex" 0.2 SIGNOR-260094 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 BTO:0001271 17318191 t lperfetto "Bcr-abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylationthe notion that y86 and y654 are located respectively within the n_ and c_terminal transcriptional domains of __catenin suggests that one or both residues might regulate the transactivating function of __catenin. In this regard, phosphorylation of y654 was reported to strengthen __catenin association with the basal transcription factor tata_binding protein (tbp)" 0.2 SIGNOR-153431 SIGNOR-AML "Acute Myeloid Leukemia" BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR NRAS protein P01111 UNIPROT "up-regulates activity" 9534 8402896 f miannu "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." 0.2 SIGNOR-261506 SIGNOR-AML "Acute Myeloid Leukemia" CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 t miannu "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." 0.871 SIGNOR-44557 SIGNOR-AML "Acute Myeloid Leukemia" CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 21059642 t "The effect has been demonstrated using Q01196-8" gcesareni "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." 0.616 SIGNOR-169334 SIGNOR-AML "Acute Myeloid Leukemia" "NUP98 Fusion" "fusion protein" SIGNOR-FP16 SIGNOR CDK6 protein Q00534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32344427 f miannu "NUP98-fusion proteins directly regulate leukemia-associated gene expression programs in AML. CDK6 expression is under direct transcriptional control of NUP98-fusions and NUP98-fusion AML is particularly sensitive to CDK6 inhibition." 0.2 SIGNOR-261505 SIGNOR-AML "Acute Myeloid Leukemia" WT1 protein P19544 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23042785 t 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." 0.381 SIGNOR-255904 SIGNOR-AML "Acute Myeloid Leukemia" STAT5A protein P42229 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 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" 0.326 SIGNOR-255631 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.7 SIGNOR-256583 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-249631 SIGNOR-AML "Acute Myeloid Leukemia" PTEN protein P60484 UNIPROT STAT5A protein P42229 UNIPROT down-regulates dephosphorylation 9606 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." 0.438 SIGNOR-166481 SIGNOR-AML "Acute Myeloid Leukemia" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 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" 0.2 SIGNOR-248545 SIGNOR-AML "Acute Myeloid Leukemia" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 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" 0.2 SIGNOR-248546 SIGNOR-AML "Acute Myeloid Leukemia" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 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" 0.2 SIGNOR-248544 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-255722 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-255577 SIGNOR-AML "Acute Myeloid Leukemia" 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" 0.681 SIGNOR-252700 SIGNOR-AML "Acute Myeloid Leukemia" "MLL Fusion" "fusion protein" SIGNOR-FP14 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." 0.2 SIGNOR-260129 SIGNOR-AML "Acute Myeloid Leukemia" MEN1 protein O00255 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16415155 f irozzo "We also found that menin is important for the proliferation of MLL oncoprotein-transformed myeloid cells, pointing to a paradoxically oncogenic role for the tumor suppressor menin in proliferation of transformed myeloid cells." 0.7 SIGNOR-255895 SIGNOR-AML "Acute Myeloid Leukemia" MEN1 protein O00255 UNIPROT "MLL Fusion" "fusion protein" SIGNOR-FP14 SIGNOR "up-regulates activity" binding 10090 BTO:0004730 16239140 t miannu "We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity." 0.2 SIGNOR-260130 SIGNOR-AML "Acute Myeloid Leukemia" MECOM protein Q03112 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates activity" binding 10090 17575132 t irozzo "The results that we present here support this model and show that EVI1 interacts with and inhibits RUNX1. As for GATA1, EVI1 seems to repress RUNX1 function by interacting specifically with its DNA-binding domain Runt, leading to destabilization and dissolution of the DNA-RUNX1 complex." 0.53 SIGNOR-255716 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr966 QICKGMEyLGTKRYI 9606 BTO:0000007 20304997 t lperfetto "Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity" 0.2 SIGNOR-236290 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 BTO:0000007 20304997 t lperfetto "Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity" 0.2 SIGNOR-236298 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t lperfetto "Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity" 0.2 SIGNOR-236506 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 t lperfetto "Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity" 0.2 SIGNOR-236294 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 t "16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition." lperfetto "Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b." 0.2 SIGNOR-235910 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 t "16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition." lperfetto "Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2." 0.2 SIGNOR-235885 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 t "Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction" 0.2 SIGNOR-251360 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t "Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop." 0.2 SIGNOR-251357 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t "Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity" 0.2 SIGNOR-251358 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Tyr317 TEQDLQLyCDFPNII 9606 BTO:0000007 19364823 t "16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling." lperfetto "Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2." 0.2 SIGNOR-236502 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 t "JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity" 0.2 SIGNOR-251359 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 t lperfetto "The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570." 0.2 SIGNOR-176058 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-176054 SIGNOR-AML "Acute Myeloid Leukemia" DOT1L protein Q8TEK3 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20854876 f irozzo "Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented." 0.449 SIGNOR-256141 SIGNOR-AML "Acute Myeloid Leukemia" CEBPA protein P49715 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto "The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder." 0.7 SIGNOR-249632 SIGNOR-AML "Acute Myeloid Leukemia" CEBPA protein P49715 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001056 11283671 t apalma "Here, we demonstrate that C/EBPα indeed activates its promoter in transient transfection assays in myeloid cells." 0.2 SIGNOR-255673 SIGNOR-AML "Acute Myeloid Leukemia" CDKN2A protein Q8N726 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" 9606 12091906 f apalma "P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes" 0.793 SIGNOR-255694 SIGNOR-AML "Acute Myeloid Leukemia" CCNA1 protein P78396 UNIPROT WT1 protein P19544 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19082485 f irozzo "This study identified WT1 as a repressed target of cyclin A1 and suggests that the suppression of WT1 in cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells." 0.39 SIGNOR-255905 SIGNOR-AML "Acute Myeloid Leukemia" CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR TP53 protein P04637 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 9834241 f miannu "CBFbeta-SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-damaging Agents Reduced p53 induction may be caused in part by direct inhibition of p53 gene transcription, because p53 mRNA levels were reduced by CBFβ-SMMHC. Attenuated p53 induction and slowed apoptosis may contribute to leukemogenesis by CBFβ-SMMHC." 0.2 SIGNOR-256132 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.7 SIGNOR-256233 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-255737 SIGNOR-AML "Acute Myeloid Leukemia" CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates activity" binding 9606 29958106 t miannu "The genes encoding CBFβ and RUNX1 are frequent targets of mutations in hematologic malignancies. The chromosome inversion inv(16)(p13;q22), found in 8% of acute myeloid leukemia (AML) cases, fuses the CBFB and MYH11 genes to produce the leukemic oncoprotein CBFβ-SMMHC. This fusion protein has higher affinity and altered stoichiometry for RUNX1 relative to the native CBFβ (Cao et al., 1997; Lukasik et al., 2002). During development, CBFβ-SMMHC expression blocks definitive hematopoiesis and embryos die at mid-gestation (Castilla et al., 1996), a similar phenotype to that of Runx1- and Cbfb-knock out embryos (Wang et al., 1996a; Wang et al., 1996b), indicating that CBFβ-SMMHC has a dominant negative effect on RUNX function." 0.2 SIGNOR-255743 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-256373 SIGNOR-AML "Acute Myeloid Leukemia" "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." 0.2 SIGNOR-260107 SIGNOR-AML "Acute Myeloid Leukemia" "MLL Fusion" "fusion protein" SIGNOR-FP14 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 9606 BTO:0001133 18977325 t miannu "Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed." 0.2 SIGNOR-260095 SIGNOR-AML "Acute Myeloid Leukemia" AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 t "We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo" 0.2 SIGNOR-256135 SIGNOR-AML "Acute Myeloid Leukemia" glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" 10090 BTO:0000222 18477450 f "Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK)." 0.8 SIGNOR-256137 SIGNOR-AML "Acute Myeloid Leukemia" AMPK complex SIGNOR-C15 SIGNOR 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." 0.415 SIGNOR-252880 SIGNOR-AML "Acute Myeloid Leukemia" FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN1B protein P46527 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 10783894 t gcesareni "AFX transcriptionally activates p27kip1, resulting in increased protein levels." 0.2 SIGNOR-252928 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.65 SIGNOR-128445 SIGNOR-AML "Acute Myeloid Leukemia" CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 16103124 t gcesareni "Moreover, app stabilized tip60 through cdk-dependent phosphorylation" 0.477 SIGNOR-139649 SIGNOR-AML "Acute Myeloid Leukemia" CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser90 LPGSRPGsPEREVPA 9606 16103124 t lperfetto "Moreover, app stabilized tip60 through cdk-dependent phosphorylation" 0.477 SIGNOR-139653 SIGNOR-AML "Acute Myeloid Leukemia" KAT5 protein Q92993 UNIPROT SRSF2 protein Q01130 UNIPROT down-regulates acetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 t miannu "In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation." 0.466 SIGNOR-170594 SIGNOR-AML "Acute Myeloid Leukemia" FOXO proteinfamily SIGNOR-PF27 SIGNOR IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." 0.2 SIGNOR-260088 SIGNOR-AML "Acute Myeloid Leukemia" AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT "down-regulates activity" 9606 30274374 f miannu "AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy." 0.572 SIGNOR-260096 SIGNOR-AML "Acute Myeloid Leukemia" AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001412 31900833 t miannu "Inactivation of AMPK suppressed the expression of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) in tumor cells. Compound C-induced AMPK suppression causes downregulation TET2 and FOXP3 expression, leading to death of parental and HQ-selected U937 cells. These results confirm the connection of AMPK with the TET2–FOXP3 axis in modulating the survival of AML cells and suggest that suppression of the AMPK–TET2–FOXP3 axis suppresses the progression of AML and HQ-induced malignant transformation of AML cells." 0.2 SIGNOR-260097 SIGNOR-AML "Acute Myeloid Leukemia" ASXL2 protein Q76L83 UNIPROT TET2 protein Q6N021 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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" 0.338 SIGNOR-260074 SIGNOR-AML "Acute Myeloid Leukemia" ETV6 protein P41212 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000960;BTO:0002062 15958056 f irozzo "We thus conclude that TEL is also an accelerator for erythroid differentiation upon cytokine stimulation in human hematopoietic cells. We demonstrated in the present study that TEL accelerates erythroid differentiation induced by a physiological cytokine EPO in human leukemia cell line UT-7/GM." 0.7 SIGNOR-256017 SIGNOR-AML "Acute Myeloid Leukemia" JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t lperfetto "Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction." 0.822 SIGNOR-238638 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.935 SIGNOR-21193 SIGNOR-AML "Acute Myeloid Leukemia" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu "Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257)." 0.2 SIGNOR-260084 SIGNOR-AML "Acute Myeloid Leukemia" KIT protein P10721 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 22806893 t irozzo "SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation." 0.688 SIGNOR-256140 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.65 SIGNOR-260075 SIGNOR-AML "Acute Myeloid Leukemia" KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0000141 18179858 t irozzo "KIT mutations within the carboxy-terminal region of the cytoplasmic tyrosine kinase domain (TK2), such as KITD816V, stabilize the KIT activation loop conformation in its active form.Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT. Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models." 0.724 SIGNOR-256121 SIGNOR-AML "Acute Myeloid Leukemia" 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." 0.2 SIGNOR-177485 SIGNOR-CRC "Colorectal Carcinoma" LRP5 protein O75197 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates quantity by destabilization" relocalization 9606 11336703 t lperfetto "Lrp-5, a close homolog of lrp-6 (hey et al., 1998), functions as a coreceptor for wnt proteins in mammalian cells and that it can transduce the canonical wnt signals, at least in part by binding and recruiting axin to membranes" 0.69 SIGNOR-227930 SIGNOR-CRC "Colorectal Carcinoma" SMAD3 protein P84022 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 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." 0.2 SIGNOR-256294 SIGNOR-CRC "Colorectal Carcinoma" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 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" 0.2 SIGNOR-248545 SIGNOR-CRC "Colorectal Carcinoma" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 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" 0.2 SIGNOR-248546 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.7 SIGNOR-256216 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t "Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK." 0.2 SIGNOR-252079 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 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." 0.896 SIGNOR-227885 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.896 SIGNOR-227901 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser2996 QECKRNLsDIDQSFN 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." 0.2 SIGNOR-170473 SIGNOR-CRC "Colorectal Carcinoma" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 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" 0.2 SIGNOR-248544 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 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" 0.896 SIGNOR-227878 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser87 AAAGPALsPVPPVVH 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." 0.2 SIGNOR-244505 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.2 SIGNOR-244494 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr56 FSSQPGHtPHPAASR 9606 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." 0.2 SIGNOR-244610 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244747 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244743 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.816 SIGNOR-235385 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.816 SIGNOR-235380 SIGNOR-CRC "Colorectal Carcinoma" IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 t lperfetto "Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor." 0.2 SIGNOR-26586 SIGNOR-CRC "Colorectal Carcinoma" IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -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." 0.2 SIGNOR-246252 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.2 SIGNOR-246256 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.847 SIGNOR-167156 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.847 SIGNOR-158636 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.7 SIGNOR-255678 SIGNOR-CRC "Colorectal Carcinoma" PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT "down-regulates activity" 9606 18794881 f lperfetto "The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3))." 0.738 SIGNOR-209856 SIGNOR-CRC "Colorectal Carcinoma" KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." 0.878 SIGNOR-156906 SIGNOR-CRC "Colorectal Carcinoma" KRAS protein P01116 UNIPROT PIK3CA protein P42336 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 phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism." 0.911 SIGNOR-175204 SIGNOR-CRC "Colorectal Carcinoma" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 10090 BTO:0000669 23452850 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate." 0.914 SIGNOR-235773 SIGNOR-CRC "Colorectal Carcinoma" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 8479541 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-39163 SIGNOR-CRC "Colorectal Carcinoma" CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma "For example, 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" 0.7 SIGNOR-255695 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto "We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities." 0.2 SIGNOR-170339 SIGNOR-CRC "Colorectal Carcinoma" BRAF protein P15056 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity" relocalization 9606 19861538 f miannu "The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression." 0.249 SIGNOR-251987 SIGNOR-CRC "Colorectal Carcinoma" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-CRC "Colorectal Carcinoma" 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)" 0.816 SIGNOR-254361 SIGNOR-CRC "Colorectal Carcinoma" DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT "up-regulates activity" 9606 BTO:0000007 12556884 f miannu "Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation." 0.7 SIGNOR-253376 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." 0.7 SIGNOR-254354 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.7 SIGNOR-255669 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000586 16293724 t lperfetto "Because phosphorylation of β-catenin by GSK-3β leads to its rapid ubiquitination and subsequent degradation in the proteosome, inactivation of GSK-3β is often a prerequisite for stimulating the accumulation, nuclear translocation, and functional activity of β-catenin" 0.896 SIGNOR-227893 SIGNOR-CRC "Colorectal Carcinoma" 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)" 0.846 SIGNOR-255960 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244591 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.829 SIGNOR-201703 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.829 SIGNOR-122075 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.829 SIGNOR-175256 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.829 SIGNOR-141647 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.846 SIGNOR-196022 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.752 SIGNOR-99712 SIGNOR-CRC "Colorectal Carcinoma" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9534 BTO:0000298 9482734 t lperfetto "Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin" 0.896 SIGNOR-227862 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.2 SIGNOR-244501 SIGNOR-CRC "Colorectal Carcinoma" BCL2 protein P10415 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto "Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis" 0.7 SIGNOR-249611 SIGNOR-CRC "Colorectal Carcinoma" CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f "Simone Vumbaca" "we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells." 0.7 SIGNOR-255654 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-254374 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.7 SIGNOR-254948 SIGNOR-CRC "Colorectal Carcinoma" 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)." 0.846 SIGNOR-255031 SIGNOR-CRC "Colorectal Carcinoma" TGFBR1 protein P36897 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 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" 0.313 SIGNOR-255033 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio "Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation." 0.7 SIGNOR-255120 SIGNOR-CRC "Colorectal Carcinoma" MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni "C-myc has emerged as one of the central regulators of mammalian cell proliferation." 0.7 SIGNOR-56572 SIGNOR-CRC "Colorectal Carcinoma" MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 f "andrea cerquone perpetuini" "We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation" 0.7 SIGNOR-255414 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." 0.7 SIGNOR-255579 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." 0.7 SIGNOR-255580 SIGNOR-CRC "Colorectal Carcinoma" SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14993291 f gcesareni "Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes" 0.689 SIGNOR-123087 SIGNOR-CRC "Colorectal Carcinoma" CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 21078818 t gcesareni "Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors." 0.917 SIGNOR-169632 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1196 GAVENPEyLTPQGGA 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" 0.2 SIGNOR-124856 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1222 PAFDNLYyWDQDPPE 9606 15156151 t gcesareni "Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227" 0.2 SIGNOR-124860 SIGNOR-CRC "Colorectal Carcinoma" LEF1 protein Q9UJU2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni "The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells." 0.7 SIGNOR-229764 SIGNOR-CRC "Colorectal Carcinoma" LEF1 protein Q9UJU2 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 17081971 f amattioni "The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells." 0.7 SIGNOR-229767 SIGNOR-CRC "Colorectal Carcinoma" LEF1 protein Q9UJU2 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19653274 f gcesareni "Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation" 0.642 SIGNOR-245351 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.7 SIGNOR-242649 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.2 SIGNOR-148605 SIGNOR-CRC "Colorectal Carcinoma" IGF1R protein P08069 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 10471495 t flangone "Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway." 0.805 SIGNOR-70477 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.71 SIGNOR-235168 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.847 SIGNOR-126757 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17967874 t lperfetto "In this study, we show that the increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15." 0.847 SIGNOR-158632 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.847 SIGNOR-167152 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation 9606 17157788 t miannu "Atm/atr are generally sensors of dna damage, but, together with the checkpoint kinases chk1 and chk2, they also function as response effectors by phosphorylation of key substrates, such as p53, brca1, and nbs1. In particular, p53 phosphorylation leads to protein accumulation and activation, which in turn promotes cell-cycle arrest or apoptosis." 0.847 SIGNOR-151138 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.792 SIGNOR-169645 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.792 SIGNOR-131574 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser9 EEPQSDPsVEPPLSQ 9606 11875057 t gcesareni "In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization." 0.847 SIGNOR-115348 SIGNOR-CRC "Colorectal Carcinoma" TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 9606 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." 0.846 SIGNOR-249548 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.689 SIGNOR-229311 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.514 SIGNOR-229308 SIGNOR-CRC "Colorectal Carcinoma" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates 9606 18481201 f lperfetto "Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation." 0.634 SIGNOR-244877 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 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" 0.896 SIGNOR-227870 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.896 SIGNOR-227889 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.896 SIGNOR-227897 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.896 SIGNOR-227905 SIGNOR-CRC "Colorectal Carcinoma" 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" 0.896 SIGNOR-227874 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 23151663 t lperfetto "Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells." 0.896 SIGNOR-227866 SIGNOR-CRC "Colorectal Carcinoma" CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 23151663 t gcesareni "Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus." 0.917 SIGNOR-199378 SIGNOR-CRC "Colorectal Carcinoma" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 22083140 t lperfetto "The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex." 0.896 SIGNOR-227881 SIGNOR-CRC "Colorectal Carcinoma" CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 15735151 t gcesareni "Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, 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" 0.917 SIGNOR-134219 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." 0.2 SIGNOR-170469 SIGNOR-CRC "Colorectal Carcinoma" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." 0.787 SIGNOR-244827 SIGNOR-CRC "Colorectal Carcinoma" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." 0.787 SIGNOR-244843 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 10567369 t lperfetto "An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2" 0.758 SIGNOR-244858 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9534 BTO:0004055 14993270 t lperfetto "We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling." 0.758 SIGNOR-244862 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244580 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244584 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244588 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates phosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000149 1706616 t gcesareni "However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2." 0.2 SIGNOR-21211 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1221 SPAFDNLyYWDQDPP 9606 BTO:0000149 1706616 t gcesareni "However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2." 0.2 SIGNOR-21199 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000149 1706616 t gcesareni "However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2." 0.2 SIGNOR-21203 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 14967450 t gcesareni "All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor" 0.851 SIGNOR-121968 SIGNOR-CRC "Colorectal Carcinoma" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation -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." 0.787 SIGNOR-244831 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11875057 t gcesareni "In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization." 0.847 SIGNOR-115340 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 11875057 t gcesareni "In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization." 0.847 SIGNOR-115344 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000552 15254178 t lperfetto "Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. We next aimed to identify novel factors that control damage-induced p53 phosphorylation in a keratinocyte model system, and discovered that the epithelial stem cell marker _Np63_ is a novel ATM regulator that controls p53 Serine-15 phosphorylation through transcription of the ATM kinase." 0.847 SIGNOR-126753 SIGNOR-CRC "Colorectal Carcinoma" IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." 0.2 SIGNOR-246248 SIGNOR-CRC "Colorectal Carcinoma" IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 t lperfetto "Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor." 0.2 SIGNOR-26582 SIGNOR-CRC "Colorectal Carcinoma" IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 t lperfetto "Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor." 0.2 SIGNOR-26590 SIGNOR-CRC "Colorectal Carcinoma" IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." 0.2 SIGNOR-246244 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser367 DTRSLEIsQSYTTTQ 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." 0.2 SIGNOR-170477 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser1893 PANLDSEsEHFFRCC 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." 0.2 SIGNOR-170465 SIGNOR-CRC "Colorectal Carcinoma" CTNNB1 protein P35222 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16510874 f gcesareni "Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp." 0.75 SIGNOR-19153 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" phosphorylation Tyr1248 PTAENPEyLGLDVPV -1 1706616 t " Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2." 0.2 SIGNOR-251128 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" phosphorylation Tyr1023 DLVDAEEyLVPQQGF 9606 1706616 t "Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2." 0.2 SIGNOR-251129 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" phosphorylation Tyr1222 PAFDNLYyWDQDPPE -1 1706616 t " Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2." 0.2 SIGNOR-251130 SIGNOR-CRC "Colorectal Carcinoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 t lperfetto "Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4." 0.2 SIGNOR-244739 SIGNOR-CRC "Colorectal Carcinoma" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-CRC "Colorectal Carcinoma" IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." 0.2 SIGNOR-246260 SIGNOR-CRC "Colorectal Carcinoma" IRS2 protein Q9Y4H2 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9606 22810696 t lperfetto "These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients." 0.688 SIGNOR-251492 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.647 SIGNOR-251493 SIGNOR-CRC "Colorectal Carcinoma" 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." 0.689 SIGNOR-251494 SIGNOR-CRC "Colorectal Carcinoma" IGF2 protein P01344 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" binding 9606 22810696 t lperfetto "These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients." 0.825 SIGNOR-251495 SIGNOR-CRC "Colorectal Carcinoma" DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 f lperfetto "the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively." 0.7 SIGNOR-242612 SIGNOR-CRC "Colorectal Carcinoma" ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT unknown phosphorylation Ser440 SPLLMILsQLLPQQR -1 10608806 t llicata "Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself." 0.2 SIGNOR-250576 SIGNOR-CRC "Colorectal Carcinoma" ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" phosphorylation Tyr1139 TCSPQPEyVNQPDVR -1 1706616 t " Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2." 0.2 SIGNOR-251127 SIGNOR-GBM "Glioblastoma Multiforme" 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." 0.848 SIGNOR-49477 SIGNOR-GBM "Glioblastoma Multiforme" 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." 0.848 SIGNOR-68990 SIGNOR-GBM "Glioblastoma Multiforme" 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." 0.892 SIGNOR-39237 SIGNOR-GBM "Glioblastoma Multiforme" 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." 0.892 SIGNOR-59472 SIGNOR-GBM "Glioblastoma Multiforme" HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto "BRAF kinase is a downstream target of KRAS and activates the MAPK pathway." 0.879 SIGNOR-160043 SIGNOR-GBM "Glioblastoma Multiforme" HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto "Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes." 0.879 SIGNOR-235478 SIGNOR-GBM "Glioblastoma Multiforme" 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" 0.817 SIGNOR-204357 SIGNOR-GBM "Glioblastoma Multiforme" PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-GBM "Glioblastoma Multiforme" 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)," 0.746 SIGNOR-244469 SIGNOR-GBM "Glioblastoma Multiforme" AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 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." 0.2 SIGNOR-251474 SIGNOR-GBM "Glioblastoma Multiforme" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244152 SIGNOR-GBM "Glioblastoma Multiforme" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244160 SIGNOR-GBM "Glioblastoma Multiforme" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244156 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000675 23616010 lperfetto "The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C_ (PKC_) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun" 0.2 SIGNOR-236767 SIGNOR-GBM "Glioblastoma Multiforme" PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" 0.2 SIGNOR-235782 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 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." 0.2 SIGNOR-236483 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1172 ISLDNPDyQQDFFPK 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" 0.2 SIGNOR-236531 SIGNOR-GBM "Glioblastoma Multiforme" PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" 0.2 SIGNOR-236772 SIGNOR-GBM "Glioblastoma Multiforme" PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 t miannu "PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated" 0.2 SIGNOR-250077 SIGNOR-GBM "Glioblastoma Multiforme" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 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" 0.2 SIGNOR-248544 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000762 12509763 t lperfetto "Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers." 0.2 SIGNOR-253214 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244591 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244747 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244743 SIGNOR-GBM "Glioblastoma Multiforme" 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" 0.829 SIGNOR-201703 SIGNOR-GBM "Glioblastoma Multiforme" 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" 0.829 SIGNOR-122075 SIGNOR-GBM "Glioblastoma Multiforme" 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" 0.829 SIGNOR-175256 SIGNOR-GBM "Glioblastoma Multiforme" 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" 0.829 SIGNOR-141647 SIGNOR-GBM "Glioblastoma Multiforme" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 16829981 t "Cbl binds directly to Tyr1045 receptors" gcesareni "Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2" 0.886 SIGNOR-147826 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." 0.7 SIGNOR-254354 SIGNOR-GBM "Glioblastoma Multiforme" GRB2 protein P62993 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t "GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway." gcesareni "The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization." 0.904 SIGNOR-114704 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-254374 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio "Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation." 0.7 SIGNOR-255120 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto "We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities." 0.2 SIGNOR-170339 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." 0.7 SIGNOR-255580 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 7518560 t lperfetto "Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc)." 0.924 SIGNOR-235721 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 t lperfetto "Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites" 0.924 SIGNOR-235738 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding -1 BTO:0000567 16729043 t lperfetto "We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K." 0.924 SIGNOR-236327 SIGNOR-GBM "Glioblastoma Multiforme" EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 12648462 t lperfetto "The mammalian ligands that bind the egf receptor (egfr [her1, erb-b1]) include egf, transforming growth factor- (tgf), heparin-binding egf-like growth factor (hb-egf), amphiregulin (ar), betacellulin (btc), epiregulin (epr), and epigen" 0.95 SIGNOR-22716 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1172 ISLDNPDyQQDFFPK 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." 0.2 SIGNOR-236467 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1197 STAENAEyLRVAPQS 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." 0.2 SIGNOR-236471 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." 0.2 SIGNOR-236475 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1092 TFLPVPEyINQSVPK 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." 0.2 SIGNOR-236479 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." 0.2 SIGNOR-236487 SIGNOR-GBM "Glioblastoma Multiforme" EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" binding 9606 12297050 t lperfetto "Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase." 0.95 SIGNOR-186159 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1092 TFLPVPEyINQSVPK 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" 0.2 SIGNOR-236523 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1016 DVVDADEyLIPQQGF 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" 0.2 SIGNOR-236527 SIGNOR-GBM "Glioblastoma Multiforme" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." 0.8 SIGNOR-175253 SIGNOR-GBM "Glioblastoma Multiforme" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9534 9637919 t lperfetto "In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation." 0.8 SIGNOR-58313 SIGNOR-GBM "Glioblastoma Multiforme" PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Ser241 SKQARANsFVGTAQY 9606 10455013 t lperfetto "Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1" 0.2 SIGNOR-236789 SIGNOR-GBM "Glioblastoma Multiforme" CREB1 protein P16220 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni "beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state" 0.7 SIGNOR-229777 SIGNOR-GBM "Glioblastoma Multiforme" 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" 0.936 SIGNOR-242637 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1110 GSVQNPVyHNQPLNP 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" 0.2 SIGNOR-236516 SIGNOR-GBM "Glioblastoma Multiforme" CBL protein P22681 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 20332299 t lperfetto "Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface." 0.886 SIGNOR-65642 SIGNOR-GBM "Glioblastoma Multiforme" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" -1 9094314 t gcesareni "We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1)" 0.8 SIGNOR-243274 SIGNOR-GBM "Glioblastoma Multiforme" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." 0.787 SIGNOR-244827 SIGNOR-GBM "Glioblastoma Multiforme" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." 0.787 SIGNOR-244843 SIGNOR-GBM "Glioblastoma Multiforme" 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" 0.272 SIGNOR-244934 SIGNOR-GBM "Glioblastoma Multiforme" 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." 0.272 SIGNOR-244938 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244580 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244584 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244588 SIGNOR-GBM "Glioblastoma Multiforme" PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Ser241 SKQARANsFVGTAQY 9606 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." 0.2 SIGNOR-250268 SIGNOR-GBM "Glioblastoma Multiforme" PTEN protein P60484 UNIPROT CREB1 protein P16220 UNIPROT "down-regulates activity" dephosphorylation Ser119 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." 0.438 SIGNOR-248543 SIGNOR-GBM "Glioblastoma Multiforme" CBL protein P22681 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto "Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner." 0.693 SIGNOR-110060 SIGNOR-GBM "Glioblastoma Multiforme" 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." 0.7 SIGNOR-233467 SIGNOR-GBM "Glioblastoma Multiforme" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation -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." 0.787 SIGNOR-244831 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 10635327 t llicata "Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR." 0.2 SIGNOR-251093 SIGNOR-GBM "Glioblastoma Multiforme" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-GBM "Glioblastoma Multiforme" PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." 0.8 SIGNOR-228145 SIGNOR-GBM "Glioblastoma Multiforme" 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." 0.2 SIGNOR-233520 SIGNOR-GBM "Glioblastoma Multiforme" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates 9606 18481201 f lperfetto "Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation." 0.634 SIGNOR-244877 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto "p85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation." 0.81 SIGNOR-33633 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 14967450 t lperfetto "The egf-r coimmunoprecipitated with p85 alpha" 0.81 SIGNOR-121959 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1197 STAENAEyLRVAPQS 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" 0.2 SIGNOR-235951 SIGNOR-GBM "Glioblastoma Multiforme" EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" 0.2 SIGNOR-235956 SIGNOR-GBM "Glioblastoma Multiforme" KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." 0.878 SIGNOR-156906 SIGNOR-GBM "Glioblastoma Multiforme" KRAS protein P01116 UNIPROT PIK3CA protein P42336 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 phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism." 0.911 SIGNOR-175204 SIGNOR-GBM "Glioblastoma Multiforme" PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 24647478 t "AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring" miannu "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks." 0.8 SIGNOR-65409 SIGNOR-GBM "Glioblastoma Multiforme" ELK1 protein P19419 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23426362 f lperfetto "AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions" 0.7 SIGNOR-233471 SIGNOR-GBM "Glioblastoma Multiforme" PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" 0.2 SIGNOR-236764 SIGNOR-GBM "Glioblastoma Multiforme" PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser25 VVLCSCPsPSMVRTQ 9606 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" 0.2 SIGNOR-236777 SIGNOR-GBM "Glioblastoma Multiforme" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 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" 0.2 SIGNOR-248545 SIGNOR-GBM "Glioblastoma Multiforme" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 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" 0.2 SIGNOR-248546 SIGNOR-GBM "Glioblastoma Multiforme" PIK3R1 protein P27986 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" 10116 21798082 f lperfetto "Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2)." 0.8 SIGNOR-175678 SIGNOR-GBM "Glioblastoma Multiforme" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-GBM "Glioblastoma Multiforme" 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" 0.2 SIGNOR-252081 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." 0.2 SIGNOR-252082 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." 0.2 SIGNOR-252083 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." 0.2 SIGNOR-252084 SIGNOR-GBM "Glioblastoma Multiforme" 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." 0.2 SIGNOR-252085 SIGNOR-GBM "Glioblastoma Multiforme" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 t gcesareni "Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency." 0.2 SIGNOR-252086 SIGNOR-GBM "Glioblastoma Multiforme" PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 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" 0.8 SIGNOR-147948 SIGNOR-GBM "Glioblastoma Multiforme" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 10090 BTO:0000669 23452850 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate." 0.914 SIGNOR-235773 SIGNOR-GBM "Glioblastoma Multiforme" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 8479541 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-39163 SIGNOR-GBM "Glioblastoma Multiforme" AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t lperfetto "In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis" 0.735 SIGNOR-252817 SIGNOR-GBM "Glioblastoma Multiforme" AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto "Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1." 0.735 SIGNOR-217586 SIGNOR-GBM "Glioblastoma Multiforme" mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f "The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size." 0.7 SIGNOR-256063 SIGNOR-GBM "Glioblastoma Multiforme" mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma "Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction" 0.7 SIGNOR-256064 SIGNOR-GBM "Glioblastoma Multiforme" PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" relocalization 9606 BTO:0001130 23633519 t lperfetto "Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring." 0.8 SIGNOR-236490 SIGNOR-GBM "Glioblastoma Multiforme" 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." 0.838 SIGNOR-235518 SIGNOR-GPCR_HCC GPCR_HCC LPR5/6 complex SIGNOR-C219 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9606 19107203 t "PPPSPxS motif in LRP6/5 must be phosphorylated." miannu "These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin." 0.714 SIGNOR-256177 SIGNOR-GPCR_HCC GPCR_HCC adrenaline smallmolecule CHEBI:33568 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" 0.8 SIGNOR-257878 SIGNOR-GPCR_HCC GPCR_HCC GCG protein P01275 UNIPROT GCGR protein P47871 UNIPROT up-regulates binding 9606 BTO:0000007 22863277 t milica "In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function." 0.781 SIGNOR-198504 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.8 SIGNOR-257582 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.8 SIGNOR-257585 SIGNOR-GPCR_HCC GPCR_HCC lanreotide chemical CHEBI:135901 ChEBI SSTR2 protein P30874 UNIPROT "up-regulates activity" "chemical activation" 9606 25060168 t miannu "Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2." 0.8 SIGNOR-259242 SIGNOR-GPCR_HCC GPCR_HCC lanreotide chemical CHEBI:135901 ChEBI SSTR5 protein P35346 UNIPROT "up-regulates activity" "chemical activation" 9606 26416534 t miannu "Lanreotide Autogel (known as lanreotide Depot in the USA) is a synthetic octapeptide analog of somatostatin with a longer half-life than the native molecule and with selectivity for somatostatin receptor (SSTR) 2 and, to a lesser extent, SSTR 5" 0.8 SIGNOR-259243 SIGNOR-GPCR_HCC GPCR_HCC ADRB2 protein P07550 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0." 0.662 SIGNOR-256809 SIGNOR-GPCR_HCC GPCR_HCC GCGR protein P47871 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 12626323 t "Glucagon signals through its receptor on the cell surface (Fig.1). The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gsα and Gq. The activation of Gsα leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA)." 0.514 SIGNOR-267715 SIGNOR-GPCR_HCC GPCR_HCC GNAS protein P63092 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "up-regulates activity" binding 9606 17652154 t gcesareni "Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR" 0.744 SIGNOR-267848 SIGNOR-GPCR_HCC GPCR_HCC Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "chemical modification" 9606 11376933 t miannu "To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis." 0.8 SIGNOR-267844 SIGNOR-GPCR_HCC GPCR_HCC CREB1 protein P16220 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni "beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state" 0.7 SIGNOR-229777 SIGNOR-GPCR_HCC GPCR_HCC CREB1 protein P16220 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana "Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state" 0.7 SIGNOR-261288 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.5 SIGNOR-256690 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.454 SIGNOR-256833 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.584 SIGNOR-256684 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.454 SIGNOR-256827 SIGNOR-GPCR_HCC GPCR_HCC GNAI1 protein P63096 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "down-regulates activity" binding 9606 15922020 t miannu "Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated." 0.636 SIGNOR-267853 SIGNOR-GPCR_HCC GPCR_HCC GNAI3 protein P08754 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "down-regulates activity" binding 9606 19703466 t miannu "Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)" 0.6 SIGNOR-267851 SIGNOR-GPCR_HCC GPCR_HCC acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM3 protein P20309 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." 0.8 SIGNOR-257470 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.8 SIGNOR-257461 SIGNOR-GPCR_HCC GPCR_HCC AVPR1A protein P37288 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." 0.467 SIGNOR-257077 SIGNOR-GPCR_HCC GPCR_HCC ADRA1A protein P35348 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." 0.59 SIGNOR-257084 SIGNOR-GPCR_HCC GPCR_HCC CHRM3 protein P20309 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." 0.581 SIGNOR-257018 SIGNOR-GPCR_HCC GPCR_HCC CHRM3 protein P20309 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." 0.416 SIGNOR-257134 SIGNOR-GPCR_HCC GPCR_HCC CHRM3 protein P20309 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." 0.402 SIGNOR-257224 SIGNOR-GPCR_HCC GPCR_HCC ADRA1A protein P35348 UNIPROT GNA11 protein P29992 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 1334487 t "In this report, we demonstrate that in transfected cos-7 cells Gal4 and Ga16, like Gaq and Ga11, can activate PIPLC j3l and that all three al-ARs, alA, alB and alC, can activate endogenous PI-PLC by coupling to Gaq or Ga11." 0.578 SIGNOR-278121 SIGNOR-GPCR_HCC GPCR_HCC GNAQ protein P50148 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates binding 9606 8245028 t gcesareni "The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits." 0.772 SIGNOR-37149 SIGNOR-GPCR_HCC GPCR_HCC GNA11 protein P29992 UNIPROT PLCB1 protein Q9NQ66 UNIPROT "up-regulates activity" binding 9606 27515033 t scontino "TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C." 0.626 SIGNOR-267203 SIGNOR-GPCR_HCC GPCR_HCC GNA14 protein O95837 UNIPROT PLCB1 protein Q9NQ66 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 1334487 t "This suggests that both Gal4 and Gal6 can activate PLC b1." 0.472 SIGNOR-278119 SIGNOR-GPCR_HCC GPCR_HCC GNA15 protein P30679 UNIPROT PLCB1 protein Q9NQ66 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 1334487 t "This suggests that both Gal4 and Gal6 can activate PLC b1." 0.488 SIGNOR-278120 SIGNOR-GPCR_HCC GPCR_HCC PLCB1 protein Q9NQ66 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI "up-regulates quantity" "chemical modification" -1 23880553 t miannu "Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate." 0.8 SIGNOR-256496 SIGNOR-GPCR_HCC GPCR_HCC 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 18593525 t gcesareni "The increases in the membrane levels of nacholeate itself and of dag induce a translocation and overexpression of protein kinase c (pkc) and subsequent reductions of cyclin d, cyclin-dependent kinases 4 and 6 (cdks 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of e2f1 and knockdown of dihydrofolate reductase (dhfr) impairing dna synthesis." 0.8 SIGNOR-179279 SIGNOR-GPCR_HCC GPCR_HCC CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma "For example, 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" 0.7 SIGNOR-255695 SIGNOR-GPCR_HCC GPCR_HCC CTNNB1 protein P35222 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." 0.7 SIGNOR-256534 SIGNOR-GPCR_HCC GPCR_HCC 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)." 0.72 SIGNOR-255962 SIGNOR-GPCR_HCC GPCR_HCC CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 21078818 t gcesareni "Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors." 0.917 SIGNOR-169632 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.719 SIGNOR-235178 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.842 SIGNOR-256173 SIGNOR-GPCR_HCC GPCR_HCC BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." 0.787 SIGNOR-244827 SIGNOR-GPCR_HCC GPCR_HCC MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250289 SIGNOR-GPCR_HCC GPCR_HCC MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-GPCR_HCC GPCR_HCC PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9534 9637919 t lperfetto "In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation." 0.8 SIGNOR-58313 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.531 SIGNOR-256180 SIGNOR-GPCR_HCC GPCR_HCC GAB1 protein Q13480 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 11043767 t lperfetto "We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1." 0.515 SIGNOR-252676 SIGNOR-GPCR_HCC GPCR_HCC LEF1 protein Q9UJU2 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 17081971 f amattioni "The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells." 0.7 SIGNOR-229767 SIGNOR-GPCR_HCC GPCR_HCC NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24024136 t irozzo "In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs)." 0.687 SIGNOR-256276 SIGNOR-GPCR_HCC GPCR_HCC 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)." 0.746 SIGNOR-134477 SIGNOR-GPCR_HCC GPCR_HCC CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 23151663 t gcesareni "Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus." 0.917 SIGNOR-199378 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.7 SIGNOR-256265 SIGNOR-GPCR_HCC GPCR_HCC ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio "Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation." 0.7 SIGNOR-255120 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.649 SIGNOR-253332 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.71 SIGNOR-235168 SIGNOR-GPCR_HCC GPCR_HCC HMOX1 protein P09601 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000848 17148680 f irozzo "Here we investigated the effects of HO-1 overexpression in murine and human melanoma cells. The most important findings of our study are that 1) overexpression of HO-1 augments the proliferation [.]" 0.7 SIGNOR-256295 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.344 SIGNOR-254644 SIGNOR-GPCR_HCC GPCR_HCC ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-254374 SIGNOR-GPCR_HCC GPCR_HCC AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." 0.7 SIGNOR-251550 SIGNOR-GPCR_HCC GPCR_HCC NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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." 0.49 SIGNOR-256279 SIGNOR-GPCR_HCC GPCR_HCC HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto "BRAF kinase is a downstream target of KRAS and activates the MAPK pathway." 0.879 SIGNOR-160043 SIGNOR-GPCR_HCC GPCR_HCC PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" relocalization 9606 BTO:0001130 23633519 t lperfetto "Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring." 0.8 SIGNOR-236490 SIGNOR-GPCR_HCC GPCR_HCC GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.896 SIGNOR-227901 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.816 SIGNOR-235380 SIGNOR-GPCR_HCC GPCR_HCC HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni "Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene." 0.929 SIGNOR-38429 SIGNOR-GPCR_HCC GPCR_HCC MET protein P08581 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 22128289 t irozzo "For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS." 0.698 SIGNOR-256261 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.72 SIGNOR-32744 SIGNOR-GPCR_HCC GPCR_HCC GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.72 SIGNOR-32748 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.816 SIGNOR-235385 SIGNOR-GPCR_HCC GPCR_HCC KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates binding 9606 24997453 t miannu "Keap1 is an oxidative stress-sensing protein and is a negative regulator of nuclear factor-erythroid-2-related factor 2 (nrf2)." 0.818 SIGNOR-205229 SIGNOR-GPCR_HCC GPCR_HCC MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250552 SIGNOR-GPCR_HCC GPCR_HCC TCF4 protein P15884 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18852287 t "Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription." 0.373 SIGNOR-253324 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.72 SIGNOR-246732 SIGNOR-GPCR_HCC GPCR_HCC CTNNB1 protein P35222 UNIPROT TCF4 protein P15884 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11713476 t amattioni "beta-catenin interacts with the TCF/Lef family transcription factors." 0.692 SIGNOR-178042 SIGNOR-GPCR_HCC GPCR_HCC MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo "These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation." 0.7 SIGNOR-259110 SIGNOR-GPCR_HCC GPCR_HCC PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 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]." 0.8 SIGNOR-252713 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.828 SIGNOR-236107 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.649 SIGNOR-256181 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.719 SIGNOR-235183 SIGNOR-GPCR_HCC GPCR_HCC AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t lperfetto "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." 0.2 SIGNOR-244357 SIGNOR-GPCR_HCC GPCR_HCC AP1 complex SIGNOR-C154 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto "AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation." 0.7 SIGNOR-252356 SIGNOR-GPCR_HCC GPCR_HCC IGF1R protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni "Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively)" 0.702 SIGNOR-252690 SIGNOR-GPCR_HCC GPCR_HCC GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.896 SIGNOR-227897 SIGNOR-GPCR_HCC GPCR_HCC GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.896 SIGNOR-227905 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.812 SIGNOR-256174 SIGNOR-GPCR_HCC GPCR_HCC EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding -1 BTO:0000567 16729043 t lperfetto "We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K." 0.924 SIGNOR-236327 SIGNOR-GPCR_HCC GPCR_HCC TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto "Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals." 0.828 SIGNOR-235995 SIGNOR-GPCR_HCC GPCR_HCC LEF1 protein Q9UJU2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni "The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells." 0.7 SIGNOR-229764 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.9 SIGNOR-93199 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.71 SIGNOR-229560 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.7 SIGNOR-252292 SIGNOR-GPCR_HCC GPCR_HCC MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250290 SIGNOR-GPCR_HCC GPCR_HCC PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 24647478 t lperfetto "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478" 0.8 SIGNOR-252712 SIGNOR-GPCR_HCC GPCR_HCC GSTA1 protein P08263 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000018 29928434 f irozzo "Accordingly, downregulation of GSTA1 suppressed tumor growth. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line." 0.7 SIGNOR-256296 SIGNOR-GPCR_HCC GPCR_HCC 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)," 0.746 SIGNOR-244469 SIGNOR-GPCR_HCC GPCR_HCC AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 t lperfetto "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." 0.2 SIGNOR-244361 SIGNOR-GPCR_HCC GPCR_HCC BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-GPCR_HCC GPCR_HCC PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" 9606 19951971 t lperfetto "PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain." 0.8 SIGNOR-249628 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.7 SIGNOR-256264 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.2 SIGNOR-256178 SIGNOR-GPCR_HCC GPCR_HCC CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f "Simone Vumbaca" "we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells." 0.7 SIGNOR-255654 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.72 SIGNOR-246728 SIGNOR-GPCR_HCC GPCR_HCC MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250288 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.719 SIGNOR-235188 SIGNOR-GPCR_HCC GPCR_HCC ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." 0.7 SIGNOR-254354 SIGNOR-GPCR_HCC GPCR_HCC HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto "Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes." 0.879 SIGNOR-235478 SIGNOR-GPCR_HCC GPCR_HCC PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." 0.8 SIGNOR-175253 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.892 SIGNOR-39237 SIGNOR-GPCR_HCC GPCR_HCC PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." 0.8 SIGNOR-228145 SIGNOR-GPCR_HCC GPCR_HCC EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto "The egf-r coimmunoprecipitated with p85 alpha" 0.784 SIGNOR-252672 SIGNOR-GPCR_HCC GPCR_HCC IGF2 protein P01344 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" binding 9606 22810696 t lperfetto "These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients." 0.825 SIGNOR-251495 SIGNOR-GPCR_HCC GPCR_HCC EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 7518560 t lperfetto "Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc)." 0.924 SIGNOR-235721 SIGNOR-GPCR_HCC GPCR_HCC DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9606 20837657 t lperfetto "In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization." 0.716 SIGNOR-227911 SIGNOR-GPCR_HCC GPCR_HCC MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni "C-myc has emerged as one of the central regulators of mammalian cell proliferation." 0.7 SIGNOR-56572 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.2 SIGNOR-256179 SIGNOR-GPCR_HCC GPCR_HCC PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-GPCR_HCC GPCR_HCC LEF1 protein Q9UJU2 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19653274 f gcesareni "Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation" 0.642 SIGNOR-245351 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.71 SIGNOR-229557 SIGNOR-GPCR_HCC GPCR_HCC Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 t apalma "Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh." 0.2 SIGNOR-255891 SIGNOR-GPCR_HCC GPCR_HCC PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 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" 0.48 SIGNOR-144478 SIGNOR-GPCR_HCC GPCR_HCC LPAR6 protein P43657 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." 0.357 SIGNOR-257347 SIGNOR-GPCR_HCC GPCR_HCC GNA13 protein Q14344 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 23450633 t gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." 0.578 SIGNOR-192111 SIGNOR-GPCR_HCC GPCR_HCC 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" 0.813 SIGNOR-196740 SIGNOR-GPCR_HCC GPCR_HCC ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation 9606 15068801 t gcesareni "Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter." 0.296 SIGNOR-123717 SIGNOR-GPCR_HCC GPCR_HCC MAPK8 protein P45983 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto "The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71." 0.556 SIGNOR-236018 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.909 SIGNOR-250122 SIGNOR-GPCR_HCC GPCR_HCC JUN protein P05412 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 12553907 f "In contrast, c-Jun is required for the survival of liver tumor cells. Reduced tumor formation strictly correlated with high apoptotic indices in c-Jun-deficient tumors, suggesting that increased apoptosis in c-Jun-deficient liver tumors is the primary cause for impaired tumorigenesis." 0.7 SIGNOR-256560 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.7 SIGNOR-233467 SIGNOR-GPCR_HCC GPCR_HCC JUN protein P05412 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 23151663 f amattioni "Planar cell polarity (PCP) signalling is prominently involved in the regulation of cell polarity, cell motility and morphogenetic movements, throught the activation of JUN transcription factor." 0.7 SIGNOR-229760 SIGNOR-GPCR_HCC GPCR_HCC CXCL12 protein P48061 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 11859124 t gcesareni "To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells." 0.814 SIGNOR-115029 SIGNOR-GPCR_HCC GPCR_HCC CXCR4 protein P61073 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 33073183 t "Marta Tosoni" "Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner" 0.564 SIGNOR-278102 SIGNOR-GPCR_HCC GPCR_HCC CXCR4 protein P61073 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 33073183 t "Marta Tosoni" "Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner" 0.482 SIGNOR-278104 SIGNOR-GPCR_HCC GPCR_HCC "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates "chemical activation" 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-element driven reporter gene (CRE-luc)." 0.8 SIGNOR-141786 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.584 SIGNOR-176560 SIGNOR-GPCR_HCC GPCR_HCC PRKCA protein P17252 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 25058461 t miannu "As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha." 0.411 SIGNOR-278492 SIGNOR-GPCR_HCC GPCR_HCC "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR6 protein P43657 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." 0.8 SIGNOR-257533 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-222-5p mirna URS0000153377_9606 RNAcentral GNAI3 protein P08754 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003227 25444921 t Parnian "MiR-222 directly binds to the 3′UTR of GNAI3 and post-transcriptionally regulates GNAI3 expression." 0.4 SIGNOR-278031 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-320d mirna URS0000010C72_9606 RNAcentral GNAI1 protein P63096 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003227 23691483 t Parnian "GNAI1 was a target of miR-320a/c/d in HCC cells.| Western blot assays revealed that miR-320a/c/d dramatically down-regulated the endogenous GNAI1 protein level, which indicates that these miRNAs may directly target GNAI1 in HCC cells.| Taken together, these observations indicate that miR-320a/c/d facilitate the migration and invasion of HCC cells." 0.4 SIGNOR-278028 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-320a-5p mirna URS000042A57E_9606 RNAcentral GNAI1 protein P63096 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003227 23691483 t Parnian "GNAI1 was a target of miR-320a/c/d in HCC cells.| Western blot assays revealed that miR-320a/c/d dramatically down-regulated the endogenous GNAI1 protein level, which indicates that these miRNAs may directly target GNAI1 in HCC cells." 0.4 SIGNOR-278026 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-320c mirna URS0000010D30_9606 RNAcentral GNAI1 protein P63096 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003227 23691483 t Parnian "GNAI1 was a target of miR-320a/c/d in HCC cells.| Western blot assays revealed that miR-320a/c/d dramatically down-regulated the endogenous GNAI1 protein level, which indicates that these miRNAs may directly target GNAI1 in HCC cells.| Taken together, these observations indicate that miR-320a/c/d facilitate the migration and invasion of HCC cells." 0.4 SIGNOR-278027 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-30d-5p mirna URS000005CF5F_9606 RNAcentral GNAI2 protein P04899 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003227 20054866 t Parnian "MiR-30d Post-transcriptionally Down-regulates GNAI2 Expression by Directly Targeting Its 3' -UTR.| Taken together, these observations suggest that miR-30d is a positive metastatic regulator for HCC." 0.4 SIGNOR-278030 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.433 SIGNOR-148490 SIGNOR-GPCR_HCC GPCR_HCC CXCR4 protein P61073 UNIPROT GNAI2 protein P04899 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 33073183 t "Marta Tosoni" "Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner" 0.488 SIGNOR-278103 SIGNOR-GPCR_HCC GPCR_HCC GNAI2 protein P04899 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR down-regulates 9606 BTO:0001950 20054866 t "Marta Tosoni" "GNAI2 can significantly inhibit HCC cell migration and invasion" 0.7 SIGNOR-278881 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-338-3p mirna URS00000254A6_9606 RNAcentral SMO protein Q99835 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004169 29069716 t Parnian "MiR-338-3p suppresses the invasiveness and metastasis of HCC cells by directly targeting the Smoothened (SMO) protein" 0.4 SIGNOR-277973 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.433 SIGNOR-199162 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.521 SIGNOR-148487 SIGNOR-GPCR_HCC GPCR_HCC "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral "down-regulates activity" "chemical activation" 9606 BTO:0000599 25965999 f Parnian "We found that treatment of HepG2 cells with LPA (12 h) moderately reduced miR-122 levels" 0.4 SIGNOR-280507 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-199a-5p mirna URS0000554A4F_9606 RNAcentral FZD7 protein O75084 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0003227 25313882 t Parnian "These results suggested that miR-199a could significantly suppress the expression of FZD7 through targeting the 3'UTR of its mRNA." 0.4 SIGNOR-277958 SIGNOR-GPCR_HCC GPCR_HCC Frizzled proteinfamily SIGNOR-PF11 SIGNOR CTNNB1 protein P35222 UNIPROT "up-regulates activity" 18697834 f "Simone Vumbaca" "[…] we suggest that Wnt1, Wnt3a and Wnt5a result in the accumulation of Act-β-Cat" 0.2 SIGNOR-255652 SIGNOR-GPCR_HCC GPCR_HCC CTNNB1 protein P35222 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0001950 15480989 f parnian "These observations suggest that the Wnt/β-catenin signal transduction pathway is involved much more commonly in the molecular pathogenesis of HCC than previously recognized because FZD7 overexpression occurred early in the disease process, stabilized wild-type β-catenin levels, and contributed to enhanced tumor cell migration." 0.7 SIGNOR-280436 SIGNOR-GPCR_HCC GPCR_HCC WNT3 protein P56703 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 9606 BTO:0001950 18313787 t parnian "These experiments suggest that activation of the Wnt/β-catenin pathway by Wnt3 is mediated in part through FZD7 in HCC cells." 0.746 SIGNOR-280437 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-27a-5p mirna URS00001B341F_9606 RNAcentral FZD7 protein O75084 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0004050 24018051 t Parnian "Our observations indicate that FZD7 is a target of miR-27a and miR-27a mediates FZD7 expression via posttranslational suppression." 0.4 SIGNOR-277966 SIGNOR-GPCR_HCC GPCR_HCC FZD7 protein O75084 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0004050 24018051 f Parnian "Knockdown of FZD7 led to decrease the expressions of the MDR1 mRNA and P-gp protein, indicating that FZD7 is involved in the regulation of multidrug resistance in HCC." 0.272 SIGNOR-277983 SIGNOR-GPCR_HCC GPCR_HCC FZD7 protein O75084 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 22179044 t apalma "In non-canonical Wnt signalling, Wnt proteins bind Fzd and glypican-4, to activate Dsh at the cell membrane, leading to activation of Rho and JNK" 0.665 SIGNOR-255893 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral MET protein P08581 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000599 25965999 t Parnian "These results show that miR-122 directly inhibits c-Met translation by targeting the 3’UTR region." 0.4 SIGNOR-279816 SIGNOR-GPCR_HCC GPCR_HCC GNA12 protein Q03113 UNIPROT hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000599 25965999 f parnian "Our data indicates that Gα12 overexpressed in liver cancer mostly greatly dysregulates the expression of miR-122." 0.4 SIGNOR-280438 SIGNOR-GPCR_HCC GPCR_HCC LPAR6 protein P43657 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." 0.363 SIGNOR-257286 SIGNOR-GPCR_HCC GPCR_HCC GNA12 protein Q03113 UNIPROT MET protein P08581 UNIPROT "up-regulates activity" 9606 BTO:0000599 25965999 f parnian "All of these results indicate that increased levels of Gα12 causes the induction of c-Met by deregulating miR-122." 0.2 SIGNOR-280439 SIGNOR-GPCR_HCC GPCR_HCC MET protein P08581 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001033 22035268 f miannu "C-Met expression and activation appears to be one of the common mechanisms of resistance to other targeted therapies. Given these multiple roles of c-Met in prostate cancer, several c-Met inhibitors have been developed. Evidence to date suggests that aberrant activation of the HGF/c-Met axis in prostate cancer epithelial cells appears to be a relatively late event in tumor progression. C-Met expression increases in advanced stages of the disease, with the highest expression observed in bone metastases." 0.7 SIGNOR-263658 SIGNOR-GPCR_HCC GPCR_HCC "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral "down-regulates activity" 9606 BTO:0000599 25965999 f parnian "S1P treatment also significantly decreased miR-122 level" 0.4 SIGNOR-280441 SIGNOR-GPCR_HCC GPCR_HCC has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral LRP6 protein O75581 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000599 25240815 t Parnian "These results provided strong evidence that LRP6 is a target of miR-126-3p in HCC and mediates the metastasis function of miR-126-3p in HCC. | MiR-126-3p inhibits HCC metastasis by directly targeting LRP6." 0.4 SIGNOR-278836 SIGNOR-GPCR_HCC GPCR_HCC has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral Metastasis phenotype SIGNOR-PH107 SIGNOR down-regulates 9606 BTO:0000599 25240815 f parnian "Both gain- of function and loss- of function assays indicate that miR-126-3p suppresses metastasis and angiogenesis in HCC cells." 0.4 SIGNOR-280442 SIGNOR-GPCR_HCC GPCR_HCC has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 9606 BTO:0000599 25240815 f parnian "Both gain- of function and loss- of function assays indicate that miR-126-3p suppresses metastasis and angiogenesis in HCC cells." 0.4 SIGNOR-280443 SIGNOR-GPCR_HCC GPCR_HCC LRP6 protein O75581 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0004050 22570728 t parnian "LRP6 enhanced both cell migration and invasion in vitro" 0.7 SIGNOR-280444 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-202-5p mirna URS00003D8730_9606 RNAcentral LRP6 protein O75581 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000599 24704686 t Parnian "Taken together, our results suggested that LRP6 mRNA is a direct target of miR-202 in HCC cells." 0.4 SIGNOR-278841 SIGNOR-GPCR_HCC GPCR_HCC hsa-miR-610 mirna URS00004DC583_9606 RNAcentral LRP6 protein O75581 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0005814 25491321 t Parnian "Results indicate that miR-610 negatively regulated these proteins via directly binding to their 3’UTRs. These data further confirm that miR-610 suppresses HCC cell tumorigenicity by inhibiting the activity of β-catenin via targeting LRP6 and TBL1X." 0.4 SIGNOR-278839 SIGNOR-GPCR_HCC GPCR_HCC GPER1 protein Q99527 UNIPROT hsa-miR-21-5p mirna URS000039ED8D_9606 RNAcentral "up-regulates activity" "post transcriptional regulation" 9606 BTO:0000599 25969534 f Parnian "MiR-21 transcription is regulated by DHEA through GPER." 0.4 SIGNOR-279814 SIGNOR-GPCR_HCC GPCR_HCC GPER1 protein Q99527 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 10696571 t "GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; the activated receptor induces a conformational change in the associated G protein α-subunit leading to release of GDP followed by binding of GTP and α-subunit dissociation from the receptor." 0.381 SIGNOR-251102 SIGNOR-GPCR_HCC GPCR_HCC dehydroepiandrosterone chemical CHEBI:28689 ChEBI hsa-miR-21-5p mirna URS000039ED8D_9606 RNAcentral "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0000599 25969534 f Parnian "Together, these data suggest that the rapid DHEA-induced increase in pri-miR-21 and miR-21 is a transcriptional response that requires GPCR signaling, EGFR activation, Src kinase activity, intact PM structure, and MAPK and PI3K activity." 0.4 SIGNOR-279813 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.79 SIGNOR-118609 SIGNOR-GPCR_HCC GPCR_HCC 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." 0.943 SIGNOR-118615 SIGNOR-HT "Hepatocellular Tumor" 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." 0.2 SIGNOR-256178 SIGNOR-HT "Hepatocellular Tumor" 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." 0.531 SIGNOR-256180 SIGNOR-HT "Hepatocellular Tumor" 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." 0.649 SIGNOR-256181 SIGNOR-HT "Hepatocellular Tumor" MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250288 SIGNOR-HT "Hepatocellular Tumor" 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" 0.719 SIGNOR-235188 SIGNOR-HT "Hepatocellular Tumor" EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto "The egf-r coimmunoprecipitated with p85 alpha" 0.784 SIGNOR-252672 SIGNOR-HT "Hepatocellular Tumor" 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." 0.71 SIGNOR-235168 SIGNOR-HT "Hepatocellular Tumor" EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 7518560 t lperfetto "Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc)." 0.924 SIGNOR-235721 SIGNOR-HT "Hepatocellular Tumor" 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." 0.71 SIGNOR-229560 SIGNOR-HT "Hepatocellular Tumor" 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" 0.649 SIGNOR-253332 SIGNOR-HT "Hepatocellular Tumor" 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." 0.72 SIGNOR-32748 SIGNOR-HT "Hepatocellular Tumor" 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." 0.2 SIGNOR-256179 SIGNOR-HT "Hepatocellular Tumor" 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" 0.719 SIGNOR-235178 SIGNOR-HT "Hepatocellular Tumor" 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." 0.828 SIGNOR-236107 SIGNOR-HT "Hepatocellular Tumor" 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" 0.719 SIGNOR-235183 SIGNOR-HT "Hepatocellular Tumor" CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma "For example, 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" 0.7 SIGNOR-255695 SIGNOR-HT "Hepatocellular Tumor" 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." 0.842 SIGNOR-256173 SIGNOR-HT "Hepatocellular Tumor" LPR5/6 complex SIGNOR-C219 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9606 19107203 t "PPPSPxS motif in LRP6/5 must be phosphorylated." miannu "These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin." 0.714 SIGNOR-256177 SIGNOR-HT "Hepatocellular Tumor" Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 t apalma "Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh." 0.2 SIGNOR-255891 SIGNOR-HT "Hepatocellular Tumor" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.896 SIGNOR-227897 SIGNOR-HT "Hepatocellular Tumor" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.896 SIGNOR-227901 SIGNOR-HT "Hepatocellular Tumor" GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.896 SIGNOR-227905 SIGNOR-HT "Hepatocellular Tumor" DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9606 20837657 t lperfetto "In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization." 0.716 SIGNOR-227911 SIGNOR-HT "Hepatocellular Tumor" CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f "Simone Vumbaca" "we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells." 0.7 SIGNOR-255654 SIGNOR-HT "Hepatocellular Tumor" 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." 0.812 SIGNOR-256174 SIGNOR-HT "Hepatocellular Tumor" 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." 0.9 SIGNOR-93199 SIGNOR-HT "Hepatocellular Tumor" TCF4 protein P15884 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18852287 t "Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription." 0.373 SIGNOR-253324 SIGNOR-HT "Hepatocellular Tumor" EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding -1 BTO:0000567 16729043 t lperfetto "We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K." 0.924 SIGNOR-236327 SIGNOR-HT "Hepatocellular Tumor" CTNNB1 protein P35222 UNIPROT TCF4 protein P15884 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11713476 t amattioni "beta-catenin interacts with the TCF/Lef family transcription factors." 0.692 SIGNOR-178042 SIGNOR-HT "Hepatocellular Tumor" 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." 0.71 SIGNOR-229557 SIGNOR-HT "Hepatocellular Tumor" CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 23151663 t gcesareni "Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus." 0.917 SIGNOR-199378 SIGNOR-HT "Hepatocellular Tumor" CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 21078818 t gcesareni "Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors." 0.917 SIGNOR-169632 SIGNOR-HT "Hepatocellular Tumor" LEF1 protein Q9UJU2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni "The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells." 0.7 SIGNOR-229764 SIGNOR-HT "Hepatocellular Tumor" LEF1 protein Q9UJU2 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19653274 f gcesareni "Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation" 0.642 SIGNOR-245351 SIGNOR-HT "Hepatocellular Tumor" LEF1 protein Q9UJU2 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 17081971 f amattioni "The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells." 0.7 SIGNOR-229767 SIGNOR-HT "Hepatocellular Tumor" MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni "C-myc has emerged as one of the central regulators of mammalian cell proliferation." 0.7 SIGNOR-56572 SIGNOR-HT "Hepatocellular Tumor" MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo "These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation." 0.7 SIGNOR-259110 SIGNOR-HT "Hepatocellular Tumor" PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." 0.8 SIGNOR-228145 SIGNOR-HT "Hepatocellular Tumor" 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" 0.7 SIGNOR-252292 SIGNOR-HT "Hepatocellular Tumor" AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 t lperfetto "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." 0.2 SIGNOR-244361 SIGNOR-HT "Hepatocellular Tumor" AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t lperfetto "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." 0.2 SIGNOR-244357 SIGNOR-HT "Hepatocellular Tumor" KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates binding 9606 24997453 t miannu "Keap1 is an oxidative stress-sensing protein and is a negative regulator of nuclear factor-erythroid-2-related factor 2 (nrf2)." 0.818 SIGNOR-205229 SIGNOR-HT "Hepatocellular Tumor" PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 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]." 0.8 SIGNOR-252713 SIGNOR-HT "Hepatocellular Tumor" 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." 0.7 SIGNOR-256265 SIGNOR-HT "Hepatocellular Tumor" 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." 0.7 SIGNOR-256264 SIGNOR-HT "Hepatocellular Tumor" NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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." 0.49 SIGNOR-256279 SIGNOR-HT "Hepatocellular Tumor" NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24024136 t irozzo "In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs)." 0.687 SIGNOR-256276 SIGNOR-HT "Hepatocellular Tumor" 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." 0.344 SIGNOR-254644 SIGNOR-HT "Hepatocellular Tumor" IGF2 protein P01344 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" binding 9606 22810696 t lperfetto "These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients." 0.825 SIGNOR-251495 SIGNOR-HT "Hepatocellular Tumor" IGF1R protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni "Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively)" 0.702 SIGNOR-252690 SIGNOR-HT "Hepatocellular Tumor" GAB1 protein Q13480 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 11043767 t lperfetto "We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1." 0.515 SIGNOR-252676 SIGNOR-HT "Hepatocellular Tumor" MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250289 SIGNOR-HT "Hepatocellular Tumor" MET protein P08581 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 22128289 t irozzo "For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS." 0.698 SIGNOR-256261 SIGNOR-HT "Hepatocellular Tumor" MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250290 SIGNOR-HT "Hepatocellular Tumor" MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250552 SIGNOR-HT "Hepatocellular Tumor" HMOX1 protein P09601 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000848 17148680 f irozzo "Here we investigated the effects of HO-1 overexpression in murine and human melanoma cells. The most important findings of our study are that 1) overexpression of HO-1 augments the proliferation [.]" 0.7 SIGNOR-256295 SIGNOR-HT "Hepatocellular Tumor" GSTA1 protein P08263 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000018 29928434 f irozzo "Accordingly, downregulation of GSTA1 suppressed tumor growth. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line." 0.7 SIGNOR-256296 SIGNOR-HT "Hepatocellular Tumor" 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)." 0.746 SIGNOR-134477 SIGNOR-HT "Hepatocellular Tumor" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-254374 SIGNOR-HT "Hepatocellular Tumor" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-HT "Hepatocellular Tumor" HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni "Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene." 0.929 SIGNOR-38429 SIGNOR-HT "Hepatocellular Tumor" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9534 9637919 t lperfetto "In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation." 0.8 SIGNOR-58313 SIGNOR-HT "Hepatocellular Tumor" PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 24647478 t lperfetto "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478" 0.8 SIGNOR-252712 SIGNOR-HT "Hepatocellular Tumor" PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" relocalization 9606 BTO:0001130 23633519 t lperfetto "Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring." 0.8 SIGNOR-236490 SIGNOR-HT "Hepatocellular Tumor" AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." 0.7 SIGNOR-251550 SIGNOR-HT "Hepatocellular Tumor" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-HT "Hepatocellular Tumor" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." 0.7 SIGNOR-254354 SIGNOR-HT "Hepatocellular Tumor" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." 0.787 SIGNOR-244827 SIGNOR-HT "Hepatocellular Tumor" 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." 0.892 SIGNOR-39237 SIGNOR-HT "Hepatocellular Tumor" PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-HT "Hepatocellular Tumor" HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto "Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes." 0.879 SIGNOR-235478 SIGNOR-HT "Hepatocellular Tumor" 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)," 0.746 SIGNOR-244469 SIGNOR-HT "Hepatocellular Tumor" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" 9606 19951971 t lperfetto "PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain." 0.8 SIGNOR-249628 SIGNOR-HT "Hepatocellular Tumor" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio "Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation." 0.7 SIGNOR-255120 SIGNOR-HT "Hepatocellular Tumor" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." 0.8 SIGNOR-175253 SIGNOR-HT "Hepatocellular Tumor" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-HT "Hepatocellular Tumor" HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto "BRAF kinase is a downstream target of KRAS and activates the MAPK pathway." 0.879 SIGNOR-160043 SIGNOR-HT "Hepatocellular Tumor" 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." 0.72 SIGNOR-32744 SIGNOR-HT "Hepatocellular Tumor" 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)." 0.72 SIGNOR-255962 SIGNOR-HT "Hepatocellular Tumor" 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" 0.72 SIGNOR-246728 SIGNOR-HT "Hepatocellular Tumor" 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" 0.816 SIGNOR-235385 SIGNOR-HT "Hepatocellular Tumor" 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" 0.816 SIGNOR-235380 SIGNOR-HT "Hepatocellular Tumor" TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto "Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals." 0.828 SIGNOR-235995 SIGNOR-HT "Hepatocellular Tumor" 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" 0.72 SIGNOR-246732 SIGNOR-HT "Hepatocellular Tumor" AP1 complex SIGNOR-C154 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto "AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation." 0.7 SIGNOR-252356 SIGNOR-LBC "Luminal Breast Cancer" FGFR1 protein P11362 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 9606 12270934 f lperfetto "Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors" 0.31 SIGNOR-244865 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.868 SIGNOR-236944 SIGNOR-LBC "Luminal Breast Cancer" FRS2 protein Q8WU20 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 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." 0.805 SIGNOR-236953 SIGNOR-LBC "Luminal Breast Cancer" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 10090 BTO:0000669 23452850 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate." 0.914 SIGNOR-235773 SIGNOR-LBC "Luminal Breast Cancer" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 8479541 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-39163 SIGNOR-LBC "Luminal Breast Cancer" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 t lperfetto "Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir)." 0.914 SIGNOR-236752 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSEDLSAyASISFQK 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." 0.914 SIGNOR-235983 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto "Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir)." 0.914 SIGNOR-236756 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 11416002 t lperfetto "All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells" 0.914 SIGNOR-235971 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto "Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir)." 0.914 SIGNOR-236741 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr632 GRKGSGDyMPMSPKS 10116 11416002 t lperfetto "All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells" 0.914 SIGNOR-236709 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 t lperfetto "Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir)." 0.914 SIGNOR-236745 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr941 EETGTEEyMKMDLGP 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)." 0.914 SIGNOR-235975 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr989 VPSSRGDyMTMQMSC 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)." 0.914 SIGNOR-235979 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr465 GEEELSNyICMGGKG 10116 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)." 0.914 SIGNOR-236713 SIGNOR-LBC "Luminal Breast Cancer" INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 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." 0.914 SIGNOR-236725 SIGNOR-LBC "Luminal Breast Cancer" IRS1 protein P35568 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9606 20966354 t lperfetto "Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin." 0.724 SIGNOR-168985 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.806 SIGNOR-236614 SIGNOR-LBC "Luminal Breast Cancer" JUN protein P05412 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." 0.343 SIGNOR-254876 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.7 SIGNOR-233467 SIGNOR-LBC "Luminal Breast Cancer" KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." 0.878 SIGNOR-156906 SIGNOR-LBC "Luminal Breast Cancer" KRAS protein P01116 UNIPROT PIK3CA protein P42336 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 phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism." 0.911 SIGNOR-175204 SIGNOR-LBC "Luminal Breast Cancer" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23150757 t lperfetto "Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity" 0.968 SIGNOR-199371 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.968 SIGNOR-80528 SIGNOR-LBC "Luminal Breast Cancer" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 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." 0.968 SIGNOR-196116 SIGNOR-LBC "Luminal Breast Cancer" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "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" 0.758 SIGNOR-258989 SIGNOR-LBC "Luminal Breast Cancer" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-LBC "Luminal Breast Cancer" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887 11160134 t lperfetto "Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation." 0.2 SIGNOR-244784 SIGNOR-LBC "Luminal Breast Cancer" mTORC1 complex SIGNOR-C3 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." 0.7 SIGNOR-209919 SIGNOR-LBC "Luminal Breast Cancer" mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f "The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size." 0.7 SIGNOR-256063 SIGNOR-LBC "Luminal Breast Cancer" mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma "Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction" 0.7 SIGNOR-256064 SIGNOR-LBC "Luminal Breast Cancer" 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)," 0.746 SIGNOR-244469 SIGNOR-LBC "Luminal Breast Cancer" 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)." 0.746 SIGNOR-134477 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.746 SIGNOR-244421 SIGNOR-LBC "Luminal Breast Cancer" PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-LBC "Luminal Breast Cancer" 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)" 0.746 SIGNOR-244480 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.746 SIGNOR-244396 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.272 SIGNOR-244934 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.272 SIGNOR-244938 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.821 SIGNOR-236436 SIGNOR-LBC "Luminal Breast Cancer" 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," 0.821 SIGNOR-244429 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.724 SIGNOR-104911 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.7 SIGNOR-242649 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.633 SIGNOR-166478 SIGNOR-LBC "Luminal Breast Cancer" PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT "down-regulates activity" 9606 18794881 f lperfetto "The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3))." 0.738 SIGNOR-209856 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.633 SIGNOR-244439 SIGNOR-LBC "Luminal Breast Cancer" RB1 protein P06400 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21524151 f miannu "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." 0.7 SIGNOR-262533 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.92 SIGNOR-37305 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.7 SIGNOR-245483 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.802 SIGNOR-235355 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.802 SIGNOR-232208 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.829 SIGNOR-122075 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.829 SIGNOR-141647 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.829 SIGNOR-175256 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.829 SIGNOR-201703 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.968 SIGNOR-34962 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.7 SIGNOR-255669 SIGNOR-LBC "Luminal Breast Cancer" TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 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." 0.918 SIGNOR-235895 SIGNOR-LBC "Luminal Breast Cancer" TSC complex SIGNOR-C101 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto "These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor" 0.627 SIGNOR-251527 SIGNOR-LBC "Luminal Breast Cancer" FGF1 protein P05230 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates binding 9606 11030354 t lperfetto "Crystal structure of a ternary fgf-fgfr-heparin complex reveals a dual role for heparin in fgfr binding and dimerization." 0.915 SIGNOR-83143 SIGNOR-LBC "Luminal Breast Cancer" INS protein P01308 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" binding 9606 2550426 t lperfetto "Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds." 0.934 SIGNOR-23001 SIGNOR-LBC "Luminal Breast Cancer" CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "chemical modification" 9606 395188 t lperfetto "Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors, androstenedione and testosterone, to yield estrone and estradiol, respectively. In men, the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species." 0.8 SIGNOR-251528 SIGNOR-LBC "Luminal Breast Cancer" 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR1 protein P03372 UNIPROT up-regulates "chemical activation" 9606 BTO:0000150 17478088 t gcesareni "Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters." 0.8 SIGNOR-154660 SIGNOR-LBC "Luminal Breast Cancer" ESR1 protein P03372 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 18247370 t miannu "The primary conclusion of the results reported here is that ERα and c‐jun, c‐fos and ATF‐2, but not Fra‐2 AP‐1 factors interact “in vivo” with specific estrogen‐responsive regulatory sequences and AP‐1 cis‐elements within the F promoter of the human ERα gene in osteoblast‐like SaOS‐2 cells." 0.725 SIGNOR-263656 SIGNOR-LBC "Luminal Breast Cancer" AP1 complex SIGNOR-C154 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto "AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation." 0.7 SIGNOR-252356 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244156 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244160 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244152 SIGNOR-LBC "Luminal Breast Cancer" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation -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." 0.787 SIGNOR-244831 SIGNOR-LBC "Luminal Breast Cancer" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." 0.787 SIGNOR-244827 SIGNOR-LBC "Luminal Breast Cancer" BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 21900390 f miannu "RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK)." 0.661 SIGNOR-260082 SIGNOR-LBC "Luminal Breast Cancer" 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." 0.2 SIGNOR-244251 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." 0.7 SIGNOR-251550 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t lperfetto "In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis" 0.789 SIGNOR-251526 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f miannu "c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo." 0.7 SIGNOR-254952 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-257606 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 f "Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation" 0.7 SIGNOR-254353 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto "Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1." 0.735 SIGNOR-217586 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t lperfetto "In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis" 0.735 SIGNOR-252817 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188)" 0.2 SIGNOR-244300 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." 0.2 SIGNOR-244292 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation." 0.2 SIGNOR-244296 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 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." 0.2 SIGNOR-244255 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." 0.2 SIGNOR-244247 SIGNOR-LBC "Luminal Breast Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 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." 0.2 SIGNOR-244243 SIGNOR-LBC "Luminal Breast Cancer" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-LBC "Luminal Breast Cancer" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." 0.787 SIGNOR-244843 SIGNOR-LBC "Luminal Breast Cancer" CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates activity" binding 9606 11154267 t lperfetto "Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity" 0.83 SIGNOR-245459 SIGNOR-LBC "Luminal Breast Cancer" CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates activity" binding 9606 8891723 t lperfetto "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." 0.83 SIGNOR-217514 SIGNOR-LBC "Luminal Breast Cancer" CDKN2A protein P42771 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f "Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation." 0.7 SIGNOR-259406 SIGNOR-LBC "Luminal Breast Cancer" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." 0.864 SIGNOR-216988 SIGNOR-LBC "Luminal Breast Cancer" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." 0.864 SIGNOR-250759 SIGNOR-LBC "Luminal Breast Cancer" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." 0.864 SIGNOR-216992 SIGNOR-LBC "Luminal Breast Cancer" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." 0.864 SIGNOR-250760 SIGNOR-LBC "Luminal Breast Cancer" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." 0.864 SIGNOR-250762 SIGNOR-LBC "Luminal Breast Cancer" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto "We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein." 0.864 SIGNOR-216957 SIGNOR-LBC "Luminal Breast Cancer" E2F1 protein Q01094 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto "In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F" 0.7 SIGNOR-245477 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t "We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction" 0.2 SIGNOR-259919 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto "We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities." 0.2 SIGNOR-170339 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR E2F1 protein Q01094 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." 0.2 SIGNOR-233526 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t lperfetto "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" 0.2 SIGNOR-244647 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 t lperfetto "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" 0.2 SIGNOR-244651 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 BTO:0000567 17615152 t lperfetto "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo." 0.2 SIGNOR-244655 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 t lperfetto "Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling" 0.2 SIGNOR-244541 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000675 23616010 lperfetto "The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C_ (PKC_) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun" 0.2 SIGNOR-236767 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000762 12509763 t lperfetto "Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers." 0.2 SIGNOR-253214 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9534 BTO:0004055 14993270 t lperfetto "We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling." 0.758 SIGNOR-244862 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 10567369 t lperfetto "An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2" 0.758 SIGNOR-244858 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio "Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation." 0.7 SIGNOR-255120 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." 0.7 SIGNOR-254354 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-254374 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." 0.7 SIGNOR-255580 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244591 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244580 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244584 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244588 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244743 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244747 SIGNOR-LBC "Luminal Breast Cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." 0.7 SIGNOR-255579 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.7 SIGNOR-256216 SIGNOR-LBC "Luminal Breast Cancer" 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" 0.7 SIGNOR-254948 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" CDK1 protein P06493 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 26352374 t miannu "Drp1 is phosphorylated at the Ser616 position and activated predominantly by CDK1." 0.468 SIGNOR-279394 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR TCR complex SIGNOR-C153 SIGNOR "up-regulates activity" binding 9606 31001252 t scontino "The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes." 0.2 SIGNOR-267992 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" "Class I MHC:Antigen" complex SIGNOR-C426 SIGNOR CD8A protein P01732 UNIPROT "up-regulates activity" binding 9606 21954283 t scontino "Molecular recognition of pMHCI complexes is mediated primarily by clonally distributed TCRs expressed on the surface of CTLs. The coreceptor CD8 contributes to this antigen-recognition process by binding to a largely invariant region of the MHCI molecule and by promoting intracellular signaling, the effects of which serve to enhance TCR stimuli triggered by cognate ligands." 0.2 SIGNOR-267991 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" "Class I MHC:Antigen" complex SIGNOR-C426 SIGNOR TCR complex SIGNOR-C153 SIGNOR "up-regulates activity" binding 9606 31001252 t scontino "The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes." 0.2 SIGNOR-267993 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR CD4 protein P01730 UNIPROT "up-regulates activity" binding 9606 31001252 t scontino "Extracellular domain of¬†CD4, which is responsible for the recognition of its ligands, is composed of four globular Ig-like domains (D1-D4). The N-terminal D1 domain binds to a segment of the non-polymorphic Œ≤2 domain of MHC class II. CD4 is required for the recognition of most antigens in vivo. The presence of the CD4 coreceptor enhances T cell sensitivity to antigens" 0.2 SIGNOR-267990 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LCK protein P06239 UNIPROT TCR complex SIGNOR-C153 SIGNOR "up-regulates activity" phosphorylation 10090 2470098 t "Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex." 0.2 SIGNOR-259932 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor" 0.759 SIGNOR-198755 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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" 0.807 SIGNOR-251520 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" CD28 protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 24098653 t fspada "Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation" 0.706 SIGNOR-202706 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" dephosphorylation Tyr505 FTATEGQyQPQP 9606 11259588 t "Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity" 0.801 SIGNOR-248350 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.734 SIGNOR-248352 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" FYN protein P06241 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 16938345 t gcesareni "Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk." 0.751 SIGNOR-148931 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" FYN protein P06241 UNIPROT LCP2 protein Q13094 UNIPROT down-regulates phosphorylation 9606 9047237 t lperfetto "P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation" 0.758 SIGNOR-46851 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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" 0.758 SIGNOR-251381 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.809 SIGNOR-102507 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr493 LGADDSYyTARSAGK -1 8756661 t lperfetto "these data suggest that phosphorylation of ZAP-70 is initiated by a heterologous trans-phosphorylation of ZAP-70 by Lck on Tyr- 493." 0.621 SIGNOR-226628 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.775 SIGNOR-247018 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni "Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation." 0.762 SIGNOR-149182 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LAT protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." 0.811 SIGNOR-246060 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LAT protein O43561 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." 0.412 SIGNOR-252734 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 24647478 t lperfetto "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478" 0.8 SIGNOR-252712 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." 0.8 SIGNOR-175253 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" 0.66 SIGNOR-244281 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto "We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation" 0.889 SIGNOR-209773 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LCK protein P06239 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr42 DSMKDEEyEQMVKEL 14534291 t lperfetto "Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors" 0.588 SIGNOR-249374 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" CD3 complex SIGNOR-C432 SIGNOR ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9534 1423621 t "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." 0.699 SIGNOR-252304 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates "chemical modification" 9606 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." 0.8 SIGNOR-176606 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.562 SIGNOR-99310 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.422 SIGNOR-126066 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 12954613 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." gcesareni "C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates." 0.8 SIGNOR-100254 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.32 SIGNOR-248936 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PLCG1 protein P19174 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI up-regulates "chemical modification" 9606 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." 0.8 SIGNOR-176609 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" "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." 0.8 SIGNOR-256239 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" ITPR1 protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" "chemical modification" 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." 0.8 SIGNOR-256238 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates "chemical activation" 10090 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." 0.8 SIGNOR-235590 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" CALM1 protein P0DP23 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR 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." 0.578 SIGNOR-252337 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 18593525 f gcesareni "Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release." 0.8 SIGNOR-179288 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "The wnt/ca2+ signaling pathway is defined by the activation of plc (phospholipase c) through wnt/fzd resulting in an increase in intracellular ca2+ levels, which activate pkcs (protein kinase c) and camkii (calcium-calmodulin-dependent kinase ii) or cn (calcineurin), a phosphatase that activates the transcription factor nfat (nuclear factor of activated t cell)." 0.8 SIGNOR-198822 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" Calcineurin complex SIGNOR-C155 SIGNOR 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" 0.827 SIGNOR-252313 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.7 SIGNOR-252344 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PRKCA protein P17252 UNIPROT NFATC1 protein O95644 UNIPROT "down-regulates activity" phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 t lperfetto "Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1. | Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines." 0.382 SIGNOR-249175 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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" 0.272 SIGNOR-244934 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LCK protein P06239 UNIPROT CD3 complex SIGNOR-C432 SIGNOR "up-regulates activity" phosphorylation 9606 8626561 t "The binding of Lck to the tyrosine-phosphorylated zeta chain of the TcR would serve to strengthen the interaction of the associated CD4 and the TcR complex, leading to increased avidity for the antigen-major histocompatibility protein complex" 0.651 SIGNOR-252305 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" AP1 complex SIGNOR-C154 SIGNOR CD3 complex SIGNOR-C432 SIGNOR "up-regulates activity" binding 9606 16473826 t scontino "When T cells encounter antigens via the T cell antigen receptor (TCR), information about the quantity and quality of antigen engagement is relayed to the intracellular signal transduction machinery. The TCR itself lacks a significant intracellular domain. Instead, it is associated with CD3 molecules that contain intracellular signaling domains that couple the TCR/CD3 complex to the downstream signaling machinery." 0.341 SIGNOR-267994 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" CD3 complex SIGNOR-C432 SIGNOR NCK1 protein P16333 UNIPROT "up-regulates activity" relocalization 9606 12110186 t "We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck." 0.336 SIGNOR-259935 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.618 SIGNOR-236321 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.892 SIGNOR-39237 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244591 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" HRAS protein P01112 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." 0.879 SIGNOR-147327 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." 0.787 SIGNOR-244843 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR 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." 0.795 SIGNOR-252353 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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" 0.7 SIGNOR-260766 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" CSK protein P41240 UNIPROT LCK protein P06239 UNIPROT down-regulates phosphorylation Tyr505 FTATEGQyQPQP 9606 BTO:0000782 1639064 t gcesareni "P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity." 0.541 SIGNOR-20371 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PIP3 smallmolecule CHEBI:16618 ChEBI mTORC2 complex SIGNOR-C2 SIGNOR "up-regulates activity" "chemical activation" 9606 26293922 t gcesareni "PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation" 0.8 SIGNOR-252430 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "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" 0.647 SIGNOR-217008 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t lperfetto "In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis" 0.789 SIGNOR-251526 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 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." 0.918 SIGNOR-235895 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.95 SIGNOR-135770 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto "Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo." 0.927 SIGNOR-101115 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT "down-regulates activity" binding 9606 23584478 t lperfetto "The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1)." 0.94 SIGNOR-167176 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser855 QRVLDTSsLTQSAPA 9606 BTO:0000007 19864431 t lperfetto "Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855))" 0.989 SIGNOR-174882 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PKA proteinfamily SIGNOR-PF17 SIGNOR DNM1L protein O00429 UNIPROT "down-regulates activity" phosphorylation Ser637 VPVARKLsAREQRDC -1 31063459 t lperfetto "For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission" 0.2 SIGNOR-262551 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" Calcineurin complex SIGNOR-C155 SIGNOR 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." 0.271 SIGNOR-252315 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MFF protein Q9GZY8 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" relocalization 9606 21149567 t gcesareni "Mff functions as an essential factor in mitochondrial recruitment of Drp1." 0.601 SIGNOR-245957 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MFN1 protein Q8IWA4 UNIPROT "up-regulates activity" phosphorylation Thr562 LPRSLASTPTAPTTP 10090 BTO:0002572 25801171 t Barakat "Finally, in Mfn1 -/- cells re-expressing the MFN1 T562A mutant, phosphorylation was undetectable even in the presence of EGF. Taken together, these data indicate that ERK phosphorylates MFN1 at T562." 0.2 SIGNOR-274134 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" FIS1 protein Q9Y3D6 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 f lperfetto "During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2)" 0.7 SIGNOR-272976 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MFN1 protein Q8IWA4 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto "OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria" 0.7 SIGNOR-272984 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MFN2 protein O95140 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto "OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria" 0.7 SIGNOR-272985 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" OPA1 protein O60313 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto "OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria" 0.7 SIGNOR-272987 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" CD274 protein Q9NZQ7 UNIPROT PDCD1 protein Q15116 UNIPROT up-regulates binding 9606 BTO:0000782 11015443 t miannu "Pd-l1, was found to bind pd-1 specifically. The functional significance of this interaction has been demonstrated in t cell assays, in which engagement of pd-1 by pd-l1 leads to the inhibition of tcr-mediated lymphocyte proliferation and cytokine secretion." 0.937 SIGNOR-82604 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MFF protein Q9GZY8 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 f lperfetto "These proteins include the classical mitochondrial fusion (MFN1, MFN2, and OPA1) and fission proteins (DRP1, MFF, FIS1, etc.) as well as several other proteins that are directly or indirectly involved in these processes (e.g. YME1L, OMA1, INF2, GDAP1, MIC13, etc." 0.7 SIGNOR-272983 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 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." 0.821 SIGNOR-216341 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" 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." 0.7 SIGNOR-216319 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" NFATC1 protein O95644 UNIPROT IL2 protein P60568 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10022916 t Barakat "Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses." 0.565 SIGNOR-275405 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PDCD1 protein Q15116 UNIPROT DNM1L protein O00429 UNIPROT "down-regulates activity" 9606 BTO:0000782 34535949 f Barakat "Mechanistically, we provided evidence that PD1 signaling downregulates Drp1 activating phosphorylation on Ser616 (and consequently mitochondrial fragmentation) via the inhibition of ERK1/2 and mTOR kinases." 0.2 SIGNOR-275406 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DNM1L protein O00429 UNIPROT "up-regulates activity" phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000007 25658205 t Barakat "Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer." 0.2 SIGNOR-275407 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PDCD1 protein Q15116 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0000782 16227604 f Barakat "Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation." 0.346 SIGNOR-275408 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" CTLA4 protein P16410 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0000782 16227604 f Barakat "Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation." 0.611 SIGNOR-275409 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PDCD1 protein Q15116 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" 9606 BTO:0000782 22740686 f Barakat "MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2" 0.265 SIGNOR-275410 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PDCD1 protein Q15116 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "down-regulates activity" 9606 BTO:0000782 22740686 f Barakat "MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2" 0.263 SIGNOR-275411 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LAG3 protein P18627 UNIPROT "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR "down-regulates activity" binding 9606 BTO:0000782 35413245 t Barakat "Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity" 0.2 SIGNOR-275412 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" PDCD1 protein Q15116 UNIPROT "T cell exhaustion" phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 28286692 f Barakat "Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity." 0.7 SIGNOR-275413 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" LAG3 protein P18627 UNIPROT "T cell exhaustion" phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 27192565 f Barakat "Lag-3, Tim-3, and TIGIT are highly expressed on dysfunctional or exhausted T cells in chronic diseases such as chronic viral infection and cancer." 0.7 SIGNOR-275414 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" CTLA4 protein P16410 UNIPROT "T cell exhaustion" phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 26086965 f Barakat "Both PD-1 and CTLA-4 inhibited the activity of Akt, a crucial molecular in regulating glucose metabolism of T cells by elevating glucose transporter 1 expression and glycolysis, suggesting that glucose metabolism may contribute to T-cell exhaustion" 0.7 SIGNOR-275415 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" EIF4E protein P06730 UNIPROT MTFP1 protein Q9UDX5 UNIPROT "up-regulates activity" "translation regulation" 10090 BTO:0002572 28918902 t Barakat "In this study, we demonstrate that mTORC1 stimulates mitochondrial fission via 4E-BP-mediated translational regulation of the mitochondrial fission factor MTFP1. Suppression of mTORC1 activity by pharmacological or genetic means causes mitochondrial hyperfusion, branching, and circularization. This is a consequence of downregulation of MTFP1 levels via the mTORC1/4E-BP pathway, thereby eliciting changes in phosphorylation and localization of the mitochondrial fission factor DRP1" 0.2 SIGNOR-275429 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MTOR protein P42345 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000661 34535949 t Barakat "Furthermore, we confirmed also in Jurkat cells that the specific silencing of both ERK1/2 and mTOR by siRNA downregulates Drp1 phosphorylation on Ser616" 0.345 SIGNOR-275430 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma "Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction" 0.7 SIGNOR-255108 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 f lperfetto "During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2)" 0.7 SIGNOR-272975 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" MTFP1 protein Q9UDX5 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" relocalization 10090 BTO:0002572 28918902 f Barakat "Regardless of the precise mechanism, our data establish MTFP1 as an essential regulator of mitochondrial fission through the modulation of DRP1 phosphorylation and recruitment to the mitochondrion." 0.398 SIGNOR-275449 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR E2F1 protein Q01094 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." 0.2 SIGNOR-233526 SIGNOR-MD "Mitochondrial dynamics in T cell exhaustion" E2F1 protein Q01094 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" "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." 0.703 SIGNOR-253864 SIGNOR-MM "Malignant Melanoma" BAX protein Q07812 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu "The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation." 0.7 SIGNOR-261494 SIGNOR-MM "Malignant Melanoma" BAK1 protein Q16611 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu "The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation." 0.7 SIGNOR-261493 SIGNOR-MM "Malignant Melanoma" "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." 0.7 SIGNOR-252376 SIGNOR-MM "Malignant Melanoma" AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto "Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins" 0.2 SIGNOR-244144 SIGNOR-MM "Malignant Melanoma" AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto "Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins" 0.2 SIGNOR-244148 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-251469 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-251470 SIGNOR-MM "Malignant Melanoma" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244156 SIGNOR-MM "Malignant Melanoma" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244160 SIGNOR-MM "Malignant Melanoma" AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni "When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner." 0.2 SIGNOR-247992 SIGNOR-MM "Malignant Melanoma" AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 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." 0.2 SIGNOR-251474 SIGNOR-MM "Malignant Melanoma" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188)" 0.2 SIGNOR-244300 SIGNOR-MM "Malignant Melanoma" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." 0.2 SIGNOR-244292 SIGNOR-MM "Malignant Melanoma" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation." 0.2 SIGNOR-244296 SIGNOR-MM "Malignant Melanoma" BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000007 15694340 t lperfetto "Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1." 0.801 SIGNOR-133756 SIGNOR-MM "Malignant Melanoma" BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 7834748 t lperfetto "Bad binds more strongly to Bcl-x, than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-x,, but not that of Bcl-2. When Bad dimerized with Bcl-x,, Bax was displaced and apoptosis was restored." 0.847 SIGNOR-249617 SIGNOR-MM "Malignant Melanoma" 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" 0.847 SIGNOR-133759 SIGNOR-MM "Malignant Melanoma" BAD protein Q92934 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 "BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203" 23725574 f irozzo "Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions." 0.7 SIGNOR-256260 SIGNOR-MM "Malignant Melanoma" BAD protein Q92934 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 BTO:0000830 15526160 f miannu "C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo." 0.7 SIGNOR-254953 SIGNOR-MM "Malignant Melanoma" BAD protein Q92934 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" binding 9606 BTO:0002552 17000778 t lperfetto "We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis" 0.329 SIGNOR-149815 SIGNOR-MM "Malignant Melanoma" BCL2 protein P10415 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto "Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis" 0.7 SIGNOR-249611 SIGNOR-MM "Malignant Melanoma" BCL2L1 protein Q07817 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" binding -1 10949026 t lperfetto "Bad dimerizes with bcl-xl at the mitochondrial membrane where it exert its killing effects. Phosphorylation of bad promotes its binding to 14-3-3 protein, which may sequester bad from bcl-xl, thus promoting cell cells survival." 0.847 SIGNOR-81125 SIGNOR-MM "Malignant Melanoma" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-MM "Malignant Melanoma" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." 0.787 SIGNOR-244827 SIGNOR-MM "Malignant Melanoma" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." 0.787 SIGNOR-244843 SIGNOR-MM "Malignant Melanoma" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation -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." 0.787 SIGNOR-244831 SIGNOR-MM "Malignant Melanoma" CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates activity" binding 9606 11154267 t lperfetto "Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity" 0.83 SIGNOR-245459 SIGNOR-MM "Malignant Melanoma" CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates activity" binding 9606 8891723 t lperfetto "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." 0.83 SIGNOR-217514 SIGNOR-MM "Malignant Melanoma" CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0001009 10753867 f lperfetto "Creb activity by akt signaling leads to increased bcl-2 promoter activity and cell survival." 0.466 SIGNOR-76558 SIGNOR-MM "Malignant Melanoma" CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776;BTO:0003076 8816467 f lperfetto "Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis" 0.466 SIGNOR-43927 SIGNOR-MM "Malignant Melanoma" CREB1 protein P16220 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16205321 f gcesareni "The results showed that the nuclear pkcalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-creb content, dna-binding activity of creb, and bcl-xl expression." 0.362 SIGNOR-140911 SIGNOR-MM "Malignant Melanoma" CREB1 protein P16220 UNIPROT MITF protein O75030 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10841026 t lperfetto "Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription." 0.641 SIGNOR-249619 SIGNOR-MM "Malignant Melanoma" CREB1 protein P16220 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni "beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state" 0.7 SIGNOR-229777 SIGNOR-MM "Malignant Melanoma" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto "We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein." 0.864 SIGNOR-216957 SIGNOR-MM "Malignant Melanoma" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." 0.864 SIGNOR-216992 SIGNOR-MM "Malignant Melanoma" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." 0.864 SIGNOR-216988 SIGNOR-MM "Malignant Melanoma" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." 0.864 SIGNOR-250762 SIGNOR-MM "Malignant Melanoma" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." 0.864 SIGNOR-250759 SIGNOR-MM "Malignant Melanoma" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." 0.864 SIGNOR-250760 SIGNOR-MM "Malignant Melanoma" E2F1 protein Q01094 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto "In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F" 0.7 SIGNOR-245477 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation -1 8929531 t lperfetto "The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL." 0.2 SIGNOR-244497 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser87 AAAGPALsPVPPVVH 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." 0.2 SIGNOR-244505 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-244494 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr56 FSSQPGHtPHPAASR 9606 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." 0.2 SIGNOR-244610 SIGNOR-MM "Malignant Melanoma" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 10090 BTO:0000669 23452850 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate." 0.914 SIGNOR-235773 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." 0.7 SIGNOR-255579 SIGNOR-MM "Malignant Melanoma" 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" 0.7 SIGNOR-254948 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244588 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244584 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" 0.2 SIGNOR-244580 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244591 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244743 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." 0.2 SIGNOR-244747 SIGNOR-MM "Malignant Melanoma" 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" 0.2 SIGNOR-249574 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-249573 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-249572 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." 0.7 SIGNOR-255580 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio "Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation." 0.7 SIGNOR-255120 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-254374 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." 0.7 SIGNOR-254354 SIGNOR-MM "Malignant Melanoma" 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" 0.7 SIGNOR-256216 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 t "The effect has been demonstrated using O75030-9" gcesareni "The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation." 0.2 SIGNOR-249575 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9534 BTO:0004055 14993270 t lperfetto "We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling." 0.758 SIGNOR-244862 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 10567369 t lperfetto "An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2" 0.758 SIGNOR-244858 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR E2F1 protein Q01094 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." 0.2 SIGNOR-233526 SIGNOR-MM "Malignant Melanoma" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto "We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities." 0.2 SIGNOR-170339 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-244501 SIGNOR-MM "Malignant Melanoma" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 8479541 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-39163 SIGNOR-MM "Malignant Melanoma" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-MM "Malignant Melanoma" KIT protein P10721 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr703 DHAEAALyKNLLHSK 10377264 t gcesareni "We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936." 0.652 SIGNOR-248283 SIGNOR-MM "Malignant Melanoma" KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" phosphorylation Tyr568 EEINGNNyVYIDPTQ 9606 BTO:0001271 12824176 t lperfetto "Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated" 0.2 SIGNOR-102633 SIGNOR-MM "Malignant Melanoma" KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" phosphorylation Tyr570 INGNNYVyIDPTQLP 9606 12824176 t lperfetto "Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated" 0.2 SIGNOR-102637 SIGNOR-MM "Malignant Melanoma" KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" phosphorylation Tyr823 DIKNDSNyVVKGNAR 9606 12824176 t lperfetto "Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. / tyr-823 is the last tyrosine residue to be autophosphorylated" 0.2 SIGNOR-102641 SIGNOR-MM "Malignant Melanoma" 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" 0.2 SIGNOR-68643 SIGNOR-MM "Malignant Melanoma" KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr936 SESTNHIySNLANCS 9606 10377264 t miannu "Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr" 0.2 SIGNOR-68647 SIGNOR-MM "Malignant Melanoma" KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" binding 9606 17259966 t miannu "The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells" 0.935 SIGNOR-254946 SIGNOR-MM "Malignant Melanoma" 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." 0.935 SIGNOR-21193 SIGNOR-MM "Malignant Melanoma" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23150757 t lperfetto "Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity" 0.968 SIGNOR-199371 SIGNOR-MM "Malignant Melanoma" 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." 0.968 SIGNOR-80528 SIGNOR-MM "Malignant Melanoma" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 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." 0.968 SIGNOR-196116 SIGNOR-MM "Malignant Melanoma" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-MM "Malignant Melanoma" MITF protein O75030 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 12086670 t lperfetto "MITF directly occupies the BCL2 promoter in vivo and this suggest that BCL2 may be a direct transcriptional target of MITF" 0.481 SIGNOR-249618 SIGNOR-MM "Malignant Melanoma" 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." 0.855 SIGNOR-175219 SIGNOR-MM "Malignant Melanoma" 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" 0.844 SIGNOR-175222 SIGNOR-MM "Malignant Melanoma" 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)," 0.746 SIGNOR-244469 SIGNOR-MM "Malignant Melanoma" PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-MM "Malignant Melanoma" 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)." 0.746 SIGNOR-134477 SIGNOR-MM "Malignant Melanoma" 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)" 0.746 SIGNOR-244480 SIGNOR-MM "Malignant Melanoma" 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." 0.746 SIGNOR-244421 SIGNOR-MM "Malignant Melanoma" 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" 0.272 SIGNOR-244934 SIGNOR-MM "Malignant Melanoma" 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." 0.272 SIGNOR-244938 SIGNOR-MM "Malignant Melanoma" 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," 0.821 SIGNOR-244429 SIGNOR-MM "Malignant Melanoma" 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" 0.821 SIGNOR-236436 SIGNOR-MM "Malignant Melanoma" PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 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" 0.8 SIGNOR-147948 SIGNOR-MM "Malignant Melanoma" PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 24647478 t "AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring" miannu "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks." 0.8 SIGNOR-65409 SIGNOR-MM "Malignant Melanoma" PTEN protein P60484 UNIPROT CREB1 protein P16220 UNIPROT "down-regulates activity" dephosphorylation Ser119 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." 0.438 SIGNOR-248543 SIGNOR-MM "Malignant Melanoma" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 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" 0.2 SIGNOR-248545 SIGNOR-MM "Malignant Melanoma" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 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" 0.2 SIGNOR-248546 SIGNOR-MM "Malignant Melanoma" PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT "up-regulates activity" dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 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" 0.2 SIGNOR-248544 SIGNOR-MM "Malignant Melanoma" PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." 0.8 SIGNOR-228145 SIGNOR-MM "Malignant Melanoma" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" 9606 19951971 t lperfetto "PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain." 0.8 SIGNOR-249628 SIGNOR-MM "Malignant Melanoma" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." 0.8 SIGNOR-175253 SIGNOR-MM "Malignant Melanoma" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9534 9637919 t lperfetto "In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation." 0.8 SIGNOR-58313 SIGNOR-MM "Malignant Melanoma" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" -1 9094314 t gcesareni "We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1)" 0.8 SIGNOR-243274 SIGNOR-MM "Malignant Melanoma" 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" 0.92 SIGNOR-37305 SIGNOR-MM "Malignant Melanoma" 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" 0.7 SIGNOR-245483 SIGNOR-MM "Malignant Melanoma" RPS6KA5 protein O75582 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 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." 0.735 SIGNOR-59458 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-131399 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-131403 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-131407 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-131387 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-131391 SIGNOR-MM "Malignant Melanoma" 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." 0.2 SIGNOR-131395 SIGNOR-MM "Malignant Melanoma" 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." 0.781 SIGNOR-175259 SIGNOR-MM "Malignant Melanoma" 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" 0.781 SIGNOR-110566 SIGNOR-MM "Malignant Melanoma" 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" 0.7 SIGNOR-255678 SIGNOR-MM "Malignant Melanoma" 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" 0.752 SIGNOR-99712 SIGNOR-MM "Malignant Melanoma" 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." 0.968 SIGNOR-34962 SIGNOR-MM "Malignant Melanoma" 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" 0.7 SIGNOR-255669 SIGNOR-MM "Malignant Melanoma" BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni "Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax bax/bak are kept in check by the pro-survival bcl-2 family members and also proposes that for apoptotic death to occur, all pro-survival bcl-2-like proteins present within a given cell need to be neutralised by bh3-only proteins, thereby derepressing bax/bak" 0.676 SIGNOR-152980 SIGNOR-MM "Malignant Melanoma" BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT "down-regulates activity" binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto "Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax." 0.637 SIGNOR-36898 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR 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 phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism." 0.742 SIGNOR-252698 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" KRAS protein P01116 UNIPROT RASSF1 protein Q9NS23 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 (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex K-Ras-RASSF1A€“MST2 complex, as reported here" 0.652 SIGNOR-249585 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" 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" 0.752 SIGNOR-99712 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" DNA_damage stimulus SIGNOR-ST1 SIGNOR TP53 protein P04637 UNIPROT "up-regulates quantity" 9606 19879762 f lperfetto "In the case of DNA-damage, phosphorylation of both p53 and Mdm2 by the checkpoint kinases ATM, ATR, Chk1 and Chk2 contributes to the dissociation of the Mdm2-p53 complex, leading to enhanced cellular p53 levels that primarily accumulate in the nucleus." 0.7 SIGNOR-209690 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" 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" 0.694 SIGNOR-124122 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" 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)" 0.676 SIGNOR-55546 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto "Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes." 0.879 SIGNOR-235478 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 14967450 t miannu "All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor" 0.2 SIGNOR-256162 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio "Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation." 0.7 SIGNOR-255120 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" 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." 0.892 SIGNOR-39237 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." 0.787 SIGNOR-244827 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 17306385 t miannu "Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase" 0.784 SIGNOR-256168 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." 0.7 SIGNOR-254354 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." 0.7 SIGNOR-251550 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" relocalization 9606 BTO:0001130 23633519 t lperfetto "Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring." 0.8 SIGNOR-236490 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 24647478 t lperfetto "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478" 0.8 SIGNOR-252712 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9534 9637919 t lperfetto "In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation." 0.8 SIGNOR-58313 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-254374 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" 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)." 0.746 SIGNOR-134477 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" 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)," 0.746 SIGNOR-244469 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" 9606 19951971 t lperfetto "PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain." 0.8 SIGNOR-249628 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." 0.8 SIGNOR-175253 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto "BRAF kinase is a downstream target of KRAS and activates the MAPK pathway." 0.879 SIGNOR-160043 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" 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." 0.9 SIGNOR-93199 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto "P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation." 0.784 SIGNOR-252671 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto "The egf-r coimmunoprecipitated with p85 alpha" 0.784 SIGNOR-252672 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" binding 9606 12297050 t lperfetto "Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase." 0.95 SIGNOR-186159 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 7518560 t lperfetto "Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc)." 0.924 SIGNOR-235721 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding -1 BTO:0000567 16729043 t lperfetto "We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K." 0.924 SIGNOR-236327 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" IGF1R protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni "Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively)" 0.702 SIGNOR-252690 SIGNOR-NSCLCN "Non-small-cell lung cancer (NSCLC)" KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." 0.878 SIGNOR-156906 SIGNOR-PC "Prostate Cancer" 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" 0.633 SIGNOR-244439 SIGNOR-PC "Prostate Cancer" ERG protein P11308 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25277175 f miannu "Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3." 0.283 SIGNOR-251554 SIGNOR-PC "Prostate Cancer" ERG protein P11308 UNIPROT EZH2 protein Q15910 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25277175 f miannu "Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3." 0.342 SIGNOR-251555 SIGNOR-PC "Prostate Cancer" AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24505269 t miannu "Recurrent gene fusion between the androgen-regulated gene TMPRSS2 and members of the ETS transcription factor family, most commonly ERG, are present in about 50% of prostate cancer cases. Presence of this fusion gene is a critical event in the development of prostate cancer. the more aggressive phenotype that arises with the presence of TMPRSS2-ERG at least in part is caused by changes in the tumor stroma." 0.576 SIGNOR-251545 SIGNOR-PC "Prostate Cancer" HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni "Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene." 0.929 SIGNOR-38429 SIGNOR-PC "Prostate Cancer" TMPRSS2 protein O15393 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25122198 t miannu "we identified pro-hepatocyte growth factor (HGF) as a TMPRSS2 substrate and confirmed that HGF and it’s cognate receptor c-Met are activated in prostate cancers expressing TMPRSS2, a finding that also associated with the acquisition of a pro-invasive mesenchymal gene expression program." 0.2 SIGNOR-263657 SIGNOR-PC "Prostate Cancer" MET protein P08581 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001033 22035268 f miannu "C-Met expression and activation appears to be one of the common mechanisms of resistance to other targeted therapies. Given these multiple roles of c-Met in prostate cancer, several c-Met inhibitors have been developed. Evidence to date suggests that aberrant activation of the HGF/c-Met axis in prostate cancer epithelial cells appears to be a relatively late event in tumor progression. C-Met expression increases in advanced stages of the disease, with the highest expression observed in bone metastases." 0.7 SIGNOR-263658 SIGNOR-PC "Prostate Cancer" PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." 0.8 SIGNOR-228145 SIGNOR-PC "Prostate Cancer" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9534 9637919 t lperfetto "In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation." 0.8 SIGNOR-58313 SIGNOR-PC "Prostate Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f miannu "c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo." 0.7 SIGNOR-254952 SIGNOR-PC "Prostate Cancer" AR protein P10275 UNIPROT Differentiation phenotype SIGNOR-PH37 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" 0.7 SIGNOR-251538 SIGNOR-PC "Prostate Cancer" AR protein P10275 UNIPROT NKX3-1 protein Q99801 UNIPROT "up-regulates quantity by expression" "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." 0.504 SIGNOR-251546 SIGNOR-PC "Prostate Cancer" AR protein P10275 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 15861399 f miannu "AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation" 0.7 SIGNOR-251540 SIGNOR-PC "Prostate Cancer" AR protein P10275 UNIPROT UBE2C protein O00762 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19632176 t 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." 0.398 SIGNOR-251543 SIGNOR-PC "Prostate Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." 0.7 SIGNOR-251550 SIGNOR-PC "Prostate Cancer" 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." 0.504 SIGNOR-251547 SIGNOR-PC "Prostate Cancer" 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." 0.968 SIGNOR-34962 SIGNOR-PC "Prostate Cancer" 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" 0.7 SIGNOR-255669 SIGNOR-PC "Prostate Cancer" FOXA1 protein P55317 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24875621 t miannu "FOXA1 directly inhibits AR expression and thus the transcription of its target genes. FOXA1 inhibits AR gene expression in prostate cancer. oss of FOXA1 may lead to androgen-independent AR signaling and thus castration-resistant prostate cancer progression. Indeed, we have recently reported that FOXA1 is downregulated in CRPC" 0.77 SIGNOR-251541 SIGNOR-PC "Prostate Cancer" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23150757 t lperfetto "Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity" 0.968 SIGNOR-199371 SIGNOR-PC "Prostate Cancer" MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo "These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation." 0.7 SIGNOR-259110 SIGNOR-PC "Prostate Cancer" MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni "C-myc has emerged as one of the central regulators of mammalian cell proliferation." 0.7 SIGNOR-56572 SIGNOR-PC "Prostate Cancer" MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 f "andrea cerquone perpetuini" "We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation" 0.7 SIGNOR-255414 SIGNOR-PC "Prostate Cancer" 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" 0.901 SIGNOR-251531 SIGNOR-PC "Prostate Cancer" 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." 0.768 SIGNOR-179175 SIGNOR-PC "Prostate Cancer" 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" 0.901 SIGNOR-251530 SIGNOR-PC "Prostate Cancer" 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" 0.524 SIGNOR-251552 SIGNOR-PC "Prostate Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT "down-regulates activity" phosphorylation Ser792 CVRMRHLsQEFGWLQ 9534 BTO:0001538 11404460 t lperfetto "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790" 0.2 SIGNOR-244136 SIGNOR-PC "Prostate Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser215 SGRAREAsGAPTSSK 9606 BTO:0000938 17470458 t lperfetto "The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor" 0.2 SIGNOR-244140 SIGNOR-PC "Prostate Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation." 0.2 SIGNOR-244296 SIGNOR-PC "Prostate Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." 0.2 SIGNOR-244292 SIGNOR-PC "Prostate Cancer" 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." 0.367 SIGNOR-251549 SIGNOR-PC "Prostate Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188)" 0.2 SIGNOR-244300 SIGNOR-PC "Prostate Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 f "Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation" 0.7 SIGNOR-254353 SIGNOR-PC "Prostate Cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-257606 SIGNOR-PC "Prostate Cancer" 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" 0.357 SIGNOR-251548 SIGNOR-PC "Prostate Cancer" 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)," 0.746 SIGNOR-244469 SIGNOR-PC "Prostate Cancer" 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)." 0.746 SIGNOR-134477 SIGNOR-PC "Prostate Cancer" 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." 0.746 SIGNOR-244421 SIGNOR-PC "Prostate Cancer" PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-PC "Prostate Cancer" 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)" 0.746 SIGNOR-244480 SIGNOR-PC "Prostate Cancer" 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." 0.746 SIGNOR-244396 SIGNOR-PC "Prostate Cancer" 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" 0.821 SIGNOR-236436 SIGNOR-PC "Prostate Cancer" 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," 0.821 SIGNOR-244429 SIGNOR-PC "Prostate Cancer" 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" 0.7 SIGNOR-242649 SIGNOR-PC "Prostate Cancer" 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" 0.619 SIGNOR-143961 SIGNOR-PC "Prostate Cancer" 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." 0.458 SIGNOR-251997 SIGNOR-PC "Prostate Cancer" 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." 0.633 SIGNOR-166478 SIGNOR-PC "Prostate Cancer" PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT "down-regulates activity" 9606 18794881 f lperfetto "The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3))." 0.738 SIGNOR-209856 SIGNOR-PC "Prostate Cancer" 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." 0.478 SIGNOR-251529 SIGNOR-PC "Prostate Cancer" 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." 0.7 SIGNOR-251544 SIGNOR-PC "Prostate Cancer" 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" 0.2 SIGNOR-244259 SIGNOR-PC "Prostate Cancer" 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" 0.7 SIGNOR-251539 SIGNOR-PC "Prostate Cancer" 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)." 0.54 SIGNOR-251542 SIGNOR-PC "Prostate Cancer" 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." 0.968 SIGNOR-80528 SIGNOR-PC "Prostate Cancer" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 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." 0.968 SIGNOR-196116 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser45 GATTTAPsLSGKGNP -1 17208333 t llicata "We showed that CCND1-CDK6 phosphorylates beta-catenin on serine 45 (S45). This phosphorylation creates a priming site for glycogen synthase kinase 3beta (GSK3beta) and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade." 0.639 SIGNOR-250647 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CDK4 protein P11802 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "form complex" binding 9606 7736585 t gcesareni "D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb," 0.964 SIGNOR-32301 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f "Simone Vumbaca" "we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells." 0.7 SIGNOR-255654 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CDKN2A protein P42771 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR down-regulates binding 9606 8891723 t luana "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." 0.813 SIGNOR-259810 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.881 SIGNOR-121965 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" EGFR protein P00533 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" 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." 0.881 SIGNOR-235692 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" STAT3 protein P40763 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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. " 0.79 SIGNOR-259456 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.7 SIGNOR-252275 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto "The egf-r coimmunoprecipitated with p85 alpha" 0.784 SIGNOR-252672 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." 0.7 SIGNOR-251550 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" relocalization 9606 BTO:0001130 23633519 t lperfetto "Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring." 0.8 SIGNOR-236490 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.7 SIGNOR-255693 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.814 SIGNOR-217394 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" binding 9606 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." 0.814 SIGNOR-64092 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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)." 0.7 SIGNOR-255489 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.7 SIGNOR-245039 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.796 SIGNOR-252703 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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," 0.796 SIGNOR-252715 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.7 SIGNOR-252292 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CDKN2B protein P42772 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 BTO:0000763 9042862 t gcesareni "We present evidence that the different subcellular location of p15 and p27 ensures the prior access of p15 to cdk4. In the cell, p15 is localized mostly in the cytoplasm, whereas p27 is nuclear. p15 prevails over p27 or a p27 construct consisting of the cdk inhibitory domain tagged with a nuclear localization signal. However, when p15 and p27 are forced to reside in the same subcellular location, either the cytoplasm or the nucleus, p15 no longer prevents p27 from binding to cdk4. These properties allow p15 and p27 to coordinately inhibit cdk4 and cdk2." 0.88 SIGNOR-46758 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" FHIT protein P49789 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates 9606 BTO:0000551 15313915 f miannu "We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein." 0.427 SIGNOR-127610 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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." 0.609 SIGNOR-256286 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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." 0.609 SIGNOR-256287 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates activity" binding 9606 8891723 t lperfetto "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." 0.83 SIGNOR-217514 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates activity" binding 9606 11154267 t lperfetto "Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity" 0.83 SIGNOR-245459 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR 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 phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism." 0.742 SIGNOR-252698 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." 0.7 SIGNOR-254354 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.7 SIGNOR-256216 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." 0.878 SIGNOR-156906 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.828 SIGNOR-236107 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.719 SIGNOR-235178 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.72 SIGNOR-32748 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.71 SIGNOR-229560 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.71 SIGNOR-229557 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.719 SIGNOR-235183 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.649 SIGNOR-253332 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.71 SIGNOR-235168 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.719 SIGNOR-235188 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.649 SIGNOR-256181 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.531 SIGNOR-256180 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" AP1 complex SIGNOR-C154 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto "AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation." 0.7 SIGNOR-252356 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.72 SIGNOR-246732 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto "Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals." 0.828 SIGNOR-235995 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.816 SIGNOR-235380 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.816 SIGNOR-235385 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.72 SIGNOR-246728 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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)." 0.72 SIGNOR-255962 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.72 SIGNOR-32744 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.2 SIGNOR-256179 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.2 SIGNOR-256178 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation -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." 0.787 SIGNOR-244831 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." 0.787 SIGNOR-244843 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 t lperfetto "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." 0.2 SIGNOR-244361 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t lperfetto "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." 0.2 SIGNOR-244357 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation." 0.2 SIGNOR-244296 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." 0.2 SIGNOR-244292 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188)" 0.2 SIGNOR-244300 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.7 SIGNOR-245483 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 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." 0.968 SIGNOR-196116 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23150757 t lperfetto "Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity" 0.968 SIGNOR-199371 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.968 SIGNOR-80528 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." 0.864 SIGNOR-250760 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." 0.864 SIGNOR-250759 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." 0.864 SIGNOR-250762 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 24647478 t lperfetto "Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478" 0.8 SIGNOR-252712 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 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]." 0.8 SIGNOR-252713 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 17306385 t miannu "Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase" 0.784 SIGNOR-256168 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" E2F1 protein Q01094 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto "In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F" 0.7 SIGNOR-245477 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.92 SIGNOR-37305 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.7 SIGNOR-255678 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." 0.864 SIGNOR-216988 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." 0.864 SIGNOR-216992 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto "We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein." 0.864 SIGNOR-216957 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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" 0.7 SIGNOR-255669 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto "We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation" 0.889 SIGNOR-216389 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto "We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation" 0.889 SIGNOR-216385 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto "Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta." 0.821 SIGNOR-216365 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" 0.66 SIGNOR-244281 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" binding 9606 12297050 t lperfetto "Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase." 0.95 SIGNOR-186159 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" 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." 0.9 SIGNOR-93199 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f "The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size." 0.7 SIGNOR-256063 SIGNOR-PDAP "Pancreatic ductal adenocarcinoma (PDA)" AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto "Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1." 0.735 SIGNOR-217586 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -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." 0.2 SIGNOR-246252 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." 0.2 SIGNOR-246260 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 t lperfetto "Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor." 0.2 SIGNOR-26590 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." 0.2 SIGNOR-246244 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 t lperfetto "Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor." 0.2 SIGNOR-26582 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." 0.2 SIGNOR-246248 SIGNOR-RMS Rhabdomyosarcoma 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." 0.956 SIGNOR-182484 SIGNOR-RMS Rhabdomyosarcoma 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." 0.956 SIGNOR-175662 SIGNOR-RMS Rhabdomyosarcoma HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni "Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene." 0.929 SIGNOR-38429 SIGNOR-RMS Rhabdomyosarcoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001412 10570290 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-236792 SIGNOR-RMS Rhabdomyosarcoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 8479541 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-39163 SIGNOR-RMS Rhabdomyosarcoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 10090 BTO:0000669 23452850 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate." 0.914 SIGNOR-235773 SIGNOR-RMS Rhabdomyosarcoma GRB2 protein P62993 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates binding 9606 12766170 t "Grb2-associated binding (Gab) scaffolding/adapter proteins are a family of three members including mammalian Gab1, Gab2, and Gab3 that are highly conserved." lperfetto "The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2" 0.874 SIGNOR-235917 SIGNOR-RMS Rhabdomyosarcoma GAB1 protein Q13480 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 11043767 t lperfetto "We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1." 0.456 SIGNOR-83343 SIGNOR-RMS Rhabdomyosarcoma FOXO1 protein Q12778 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 25510553 t miannu "FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription." 0.603 SIGNOR-263496 SIGNOR-RMS Rhabdomyosarcoma FGFR4 protein P22455 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 10918587 t "Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3." 0.4 SIGNOR-251142 SIGNOR-RMS Rhabdomyosarcoma FGF1 protein P05230 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." 0.828 SIGNOR-18454 SIGNOR-RMS Rhabdomyosarcoma 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" 0.7 SIGNOR-254948 SIGNOR-RMS Rhabdomyosarcoma 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" 0.7 SIGNOR-256216 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." 0.7 SIGNOR-255579 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma "The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding." 0.7 SIGNOR-255580 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-254374 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." 0.7 SIGNOR-254354 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio "Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation." 0.7 SIGNOR-255120 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t "Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK." 0.2 SIGNOR-252079 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto "We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities." 0.2 SIGNOR-170339 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr57 NFDFVTEtPLEGDFA 9606 19364816 t lperfetto "We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation." 0.2 SIGNOR-244513 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t "We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction" 0.2 SIGNOR-259919 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser597 VPMNPNLsSEDPNLF 9606 15379552 t lperfetto "Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)" 0.2 SIGNOR-129192 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr476 EANYVPMtPGTFDFS 9606 15379552 t lperfetto "Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)" 0.2 SIGNOR-129200 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr312 ISYDIPPtPGNTYQI 9606 15379552 t lperfetto "Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)" 0.2 SIGNOR-129196 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser454 YVPMNPNsPPRQHSS 9606 15379552 t lperfetto "Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)" 0.2 SIGNOR-129188 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 t gcesareni "Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130." 0.2 SIGNOR-244618 SIGNOR-RMS Rhabdomyosarcoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MYOG protein P15173 UNIPROT down-regulates binding 9606 21902831 t lperfetto "In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms." 0.339 SIGNOR-216972 SIGNOR-RMS Rhabdomyosarcoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates binding 9606 21902831 t lperfetto "In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms." 0.433 SIGNOR-216969 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma "For example, 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" 0.7 SIGNOR-255695 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f "Simone Vumbaca" "we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells." 0.7 SIGNOR-255654 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 18316399 t "Simone Vumbaca" "Together, these results suggest that B-Cat increases MyoD binding to E box elements" 0.408 SIGNOR-255653 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 BTO:0000887 18316399 t gcesareni "We showed that beta-catenin interacts directly with myod, a basic helix-loop-helix transcription factor essential for muscle differentiation and enhances its binding to e box elements and transcriptional activity." 0.408 SIGNOR-161113 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16510874 f gcesareni "Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp." 0.75 SIGNOR-19153 SIGNOR-RMS Rhabdomyosarcoma CDKN2A protein P42771 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f "Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation." 0.7 SIGNOR-259406 SIGNOR-RMS Rhabdomyosarcoma CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates activity" binding 9606 8891723 t lperfetto "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." 0.83 SIGNOR-217514 SIGNOR-RMS Rhabdomyosarcoma CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates activity" binding 9606 11154267 t lperfetto "Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity" 0.83 SIGNOR-245459 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." 0.787 SIGNOR-244843 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation -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." 0.787 SIGNOR-244831 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." 0.787 SIGNOR-244827 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 21900390 f miannu "RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK)." 0.661 SIGNOR-260082 SIGNOR-RMS Rhabdomyosarcoma 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" 0.2 SIGNOR-244187 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." 0.7 SIGNOR-251550 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f miannu "c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo." 0.7 SIGNOR-254952 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." 0.7 SIGNOR-257606 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 f "Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation" 0.7 SIGNOR-254353 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation" 0.2 SIGNOR-252351 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto "Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export." 0.2 SIGNOR-252347 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" 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" 0.2 SIGNOR-252349 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" 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. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus." 0.2 SIGNOR-252346 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" 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)." 0.2 SIGNOR-252352 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation 9606 21440011 t lperfetto "Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs" 0.2 SIGNOR-252348 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation" 0.2 SIGNOR-252350 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT "up-regulates activity" 9606 16293724 f lperfetto "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway." 0.2 SIGNOR-244225 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244156 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244160 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244152 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto "Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo." 0.2 SIGNOR-244222 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni "Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt." 0.2 SIGNOR-244184 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni "Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, 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." 0.2 SIGNOR-244180 SIGNOR-RMS Rhabdomyosarcoma 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." 0.679 SIGNOR-246377 SIGNOR-RMS Rhabdomyosarcoma 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." 0.679 SIGNOR-246373 SIGNOR-RMS Rhabdomyosarcoma 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." 0.679 SIGNOR-246368 SIGNOR-RMS Rhabdomyosarcoma 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" 0.829 SIGNOR-201703 SIGNOR-RMS Rhabdomyosarcoma 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" 0.829 SIGNOR-175256 SIGNOR-RMS Rhabdomyosarcoma 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" 0.829 SIGNOR-141647 SIGNOR-RMS Rhabdomyosarcoma 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" 0.829 SIGNOR-122075 SIGNOR-RMS Rhabdomyosarcoma 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" 0.7 SIGNOR-242649 SIGNOR-RMS Rhabdomyosarcoma 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," 0.821 SIGNOR-244429 SIGNOR-RMS Rhabdomyosarcoma 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" 0.821 SIGNOR-236436 SIGNOR-RMS Rhabdomyosarcoma 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." 0.272 SIGNOR-244938 SIGNOR-RMS Rhabdomyosarcoma 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" 0.272 SIGNOR-244934 SIGNOR-RMS Rhabdomyosarcoma 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." 0.746 SIGNOR-244396 SIGNOR-RMS Rhabdomyosarcoma 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)" 0.746 SIGNOR-244480 SIGNOR-RMS Rhabdomyosarcoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 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." 0.746 SIGNOR-243203 SIGNOR-RMS Rhabdomyosarcoma 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." 0.746 SIGNOR-244421 SIGNOR-RMS Rhabdomyosarcoma 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)." 0.746 SIGNOR-134477 SIGNOR-RMS Rhabdomyosarcoma 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)," 0.746 SIGNOR-244469 SIGNOR-RMS Rhabdomyosarcoma PDGFRA protein P16234 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 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." 0.495 SIGNOR-247984 SIGNOR-RMS Rhabdomyosarcoma 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." 0.323 SIGNOR-254377 SIGNOR-RMS Rhabdomyosarcoma PDGFB protein P01127 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" binding 9606 11331882 t miannu "Pdgf-b activates both pdgfr-alpha and pdgfr-beta" 0.721 SIGNOR-107397 SIGNOR-RMS Rhabdomyosarcoma 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." 0.776 SIGNOR-114268 SIGNOR-RMS Rhabdomyosarcoma 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" 0.7 SIGNOR-219371 SIGNOR-RMS Rhabdomyosarcoma PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18854138 f lperfetto "Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts." 0.598 SIGNOR-181624 SIGNOR-RMS Rhabdomyosarcoma PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by destabilization" 10090 17548510 f "Simone Vumbaca" "Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability" 0.598 SIGNOR-255637 SIGNOR-RMS Rhabdomyosarcoma 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" 0.347 SIGNOR-249596 SIGNOR-RMS Rhabdomyosarcoma 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." 0.482 SIGNOR-181621 SIGNOR-RMS Rhabdomyosarcoma 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." 0.366 SIGNOR-251572 SIGNOR-RMS Rhabdomyosarcoma MYOG protein P15173 UNIPROT PAX7 protein P23759 UNIPROT "down-regulates quantity by destabilization" 10090 BTO:0004058 17548510 f "Simone Vumbaca" "Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions" 0.493 SIGNOR-255638 SIGNOR-RMS Rhabdomyosarcoma MYOG protein P15173 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25211658 t "P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells" 0.333 SIGNOR-251575 SIGNOR-RMS Rhabdomyosarcoma MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 10090 7791789 f lperfetto "The upregulation of p21 occurred at the levels of mrna and protein," 0.402 SIGNOR-235831 SIGNOR-RMS Rhabdomyosarcoma MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f lperfetto "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." 0.7 SIGNOR-37458 SIGNOR-RMS Rhabdomyosarcoma MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001103 15870273 t "Simone Vumbaca" "We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter" 0.466 SIGNOR-255639 SIGNOR-RMS Rhabdomyosarcoma MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001103 12694204 t "Simone Vumbaca" "We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation." 0.466 SIGNOR-255640 SIGNOR-RMS Rhabdomyosarcoma MYOD1 protein P15172 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 indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by myod and other regulatory proteins." 0.466 SIGNOR-135984 SIGNOR-RMS Rhabdomyosarcoma MYOD1 protein P15172 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." 0.466 SIGNOR-235009 SIGNOR-RMS Rhabdomyosarcoma MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 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." 0.402 SIGNOR-238529 SIGNOR-RMS Rhabdomyosarcoma MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates "transcriptional regulation" 9606 25211658 t "P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells" 0.402 SIGNOR-251574 SIGNOR-RMS Rhabdomyosarcoma MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 f "andrea cerquone perpetuini" "We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation" 0.7 SIGNOR-255414 SIGNOR-RMS Rhabdomyosarcoma MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni "C-myc has emerged as one of the central regulators of mammalian cell proliferation." 0.7 SIGNOR-56572 SIGNOR-RMS Rhabdomyosarcoma MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo "These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation." 0.7 SIGNOR-259110 SIGNOR-RMS Rhabdomyosarcoma MYC protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12835716 t gcesareni "C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a" 0.771 SIGNOR-102743 SIGNOR-RMS Rhabdomyosarcoma MYC protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12835716 t gcesareni "C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a" 0.784 SIGNOR-102740 SIGNOR-RMS Rhabdomyosarcoma MET protein P08581 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 22128289 t irozzo "For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS." 0.698 SIGNOR-256261 SIGNOR-RMS Rhabdomyosarcoma MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250290 SIGNOR-RMS Rhabdomyosarcoma MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250289 SIGNOR-RMS Rhabdomyosarcoma MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250288 SIGNOR-RMS Rhabdomyosarcoma MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." 0.677 SIGNOR-250552 SIGNOR-RMS Rhabdomyosarcoma MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-RMS Rhabdomyosarcoma MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "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" 0.758 SIGNOR-258989 SIGNOR-RMS Rhabdomyosarcoma KRAS protein P01116 UNIPROT PIK3CA protein P42336 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 phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism." 0.911 SIGNOR-175204 SIGNOR-RMS Rhabdomyosarcoma KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." 0.878 SIGNOR-156906 SIGNOR-RMS Rhabdomyosarcoma IGF2 protein P01344 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" binding 9606 22810696 t lperfetto "These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients." 0.825 SIGNOR-251495 SIGNOR-RMS Rhabdomyosarcoma 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." 0.2 SIGNOR-246256 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20044479 t lperfetto "We have described that upon ligand binding, igf-1r directly interacts with and phosphorylates pdk1 at tyr373/376" 0.34 SIGNOR-236544 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t lperfetto "Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376, and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376" 0.34 SIGNOR-166714 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 t lperfetto "Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376 (11, 12, 14, 17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376" 0.34 SIGNOR-166710 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL -1 20044479 t lperfetto "IGF-1R Directly Interacts with and Phosphorylates PDK1 in Vitro" 0.34 SIGNOR-236548 SIGNOR-RMS Rhabdomyosarcoma IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 t lperfetto "Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor." 0.2 SIGNOR-26586 SIGNOR-RMS Rhabdomyosarcoma RB1 protein P06400 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21524151 f miannu "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." 0.7 SIGNOR-262533 SIGNOR-RMS Rhabdomyosarcoma CDKN1A protein P38936 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" 9606 10439039 f gcesareni "P21 may inhibit cell cycle progression by preventing the phosphorylation of prb." 0.719 SIGNOR-69925 SIGNOR-RMS Rhabdomyosarcoma 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" 0.7 SIGNOR-251563 SIGNOR-RMS Rhabdomyosarcoma TBX2 protein Q13207 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24470334 f "TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells" 0.7 SIGNOR-251562 SIGNOR-RMS Rhabdomyosarcoma 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." 0.25 SIGNOR-251561 SIGNOR-RMS Rhabdomyosarcoma 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." 0.311 SIGNOR-251560 SIGNOR-RMS Rhabdomyosarcoma 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" 0.347 SIGNOR-249593 SIGNOR-RMS Rhabdomyosarcoma STAT3 protein P40763 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11278729 t lperfetto "Coexpression of activated c-Src and Stat3 synergistically induced strong HGF promoter activity in SP1 cells" 0.629 SIGNOR-251742 SIGNOR-RMS Rhabdomyosarcoma 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." 0.7 SIGNOR-256256 SIGNOR-RMS Rhabdomyosarcoma 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" 0.7 SIGNOR-245048 SIGNOR-RMS Rhabdomyosarcoma 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." 0.7 SIGNOR-255632 SIGNOR-RMS Rhabdomyosarcoma 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." 0.519 SIGNOR-255416 SIGNOR-RMS Rhabdomyosarcoma 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." 0.758 SIGNOR-255413 SIGNOR-RMS Rhabdomyosarcoma 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" 0.584 SIGNOR-45122 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr242 FFQQQMIyDSPPSRA 9606 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" 0.709 SIGNOR-236314 SIGNOR-RMS Rhabdomyosarcoma 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." 0.793 SIGNOR-247341 SIGNOR-RMS Rhabdomyosarcoma 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." 0.793 SIGNOR-235445 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t miannu "Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376" 0.586 SIGNOR-166722 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 t miannu "Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376" 0.586 SIGNOR-166718 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Tyr9 ARTTSQLyDAVPIQS 9606 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." 0.586 SIGNOR-109533 SIGNOR-RMS Rhabdomyosarcoma 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." 0.663 SIGNOR-47152 SIGNOR-RMS Rhabdomyosarcoma 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" 0.584 SIGNOR-45130 SIGNOR-RMS Rhabdomyosarcoma 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" 0.584 SIGNOR-45126 SIGNOR-RMS Rhabdomyosarcoma 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." 0.584 SIGNOR-246264 SIGNOR-RMS Rhabdomyosarcoma 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." 0.584 SIGNOR-247197 SIGNOR-RMS Rhabdomyosarcoma 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." 0.584 SIGNOR-247193 SIGNOR-RMS Rhabdomyosarcoma 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." 0.584 SIGNOR-246276 SIGNOR-RMS Rhabdomyosarcoma 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." 0.584 SIGNOR-246268 SIGNOR-RMS Rhabdomyosarcoma 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." 0.584 SIGNOR-246272 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000007 19881549 t lperfetto "Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis" 0.709 SIGNOR-236302 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 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" 0.709 SIGNOR-236318 SIGNOR-RMS Rhabdomyosarcoma 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" 0.709 SIGNOR-236306 SIGNOR-RMS Rhabdomyosarcoma 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" 0.709 SIGNOR-236310 SIGNOR-TC "Thyroid cancer" 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" 0.8 SIGNOR-251996 SIGNOR-TC "Thyroid cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244152 SIGNOR-TC "Thyroid cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244156 SIGNOR-TC "Thyroid cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" 0.2 SIGNOR-244160 SIGNOR-TC "Thyroid cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT "up-regulates activity" 9606 16293724 f lperfetto "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway." 0.2 SIGNOR-244225 SIGNOR-TC "Thyroid cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto "Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo." 0.2 SIGNOR-244222 SIGNOR-TC "Thyroid cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." 0.2 SIGNOR-249645 SIGNOR-TC "Thyroid cancer" 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." 0.2 SIGNOR-249646 SIGNOR-TC "Thyroid cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser315 DFRSRTNsNASTVSG 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." 0.2 SIGNOR-249647 SIGNOR-TC "Thyroid cancer" AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." 0.7 SIGNOR-251550 SIGNOR-TC "Thyroid cancer" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 10090 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." 0.787 SIGNOR-244827 SIGNOR-TC "Thyroid cancer" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." 0.787 SIGNOR-244843 SIGNOR-TC "Thyroid cancer" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation -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." 0.787 SIGNOR-244831 SIGNOR-TC "Thyroid cancer" BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." 0.787 SIGNOR-251988 SIGNOR-TC "Thyroid cancer" BRAF protein P15056 UNIPROT SLC5A5 protein Q92911 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19861538 t miannu "The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression." 0.2 SIGNOR-251989 SIGNOR-TC "Thyroid cancer" BRAF protein P15056 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity" relocalization 9606 19861538 f miannu "The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression." 0.249 SIGNOR-251987 SIGNOR-TC "Thyroid cancer" CCDC6-RET "fusion protein" SIGNOR-FP9 SIGNOR SHC1 protein P29353 UNIPROT "up-regulates activity" binding 9606 16946010 t miannu "RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade" 0.2 SIGNOR-251986 SIGNOR-TC "Thyroid cancer" CTNNB1 protein P35222 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16510874 f gcesareni "Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp." 0.75 SIGNOR-19153 SIGNOR-TC "Thyroid cancer" CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada "Wnt-10b, is a molecular switch that governs adipogenesis. 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)." 0.537 SIGNOR-80592 SIGNOR-TC "Thyroid cancer" ELE1-RET "fusion protein" SIGNOR-FP10 SIGNOR SHC1 protein P29353 UNIPROT "up-regulates activity" binding 9606 16946010 t miannu "RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade" 0.2 SIGNOR-251985 SIGNOR-TC "Thyroid cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto "We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities." 0.2 SIGNOR-170339 SIGNOR-TC "Thyroid cancer" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG protein P37231 UNIPROT "up-regulates quantity by expression" phosphorylation 10090 BTO:0000011 12270934 t lperfetto "Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression." 0.2 SIGNOR-235334 SIGNOR-TC "Thyroid cancer" FOXO3 protein O43524 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." 0.7 SIGNOR-217887 SIGNOR-TC "Thyroid cancer" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 10090 BTO:0000669 23452850 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate." 0.914 SIGNOR-235773 SIGNOR-TC "Thyroid cancer" GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates activity" relocalization 9606 8479541 t "GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP" lperfetto "Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." 0.914 SIGNOR-39163 SIGNOR-TC "Thyroid cancer" "Ionizing radiation" stimulus SIGNOR-ST16 SIGNOR CCDC6-RET "fusion protein" SIGNOR-FP9 SIGNOR up-regulates 9606 23128507 f miannu "In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents" 0.7 SIGNOR-251999 SIGNOR-TC "Thyroid cancer" "Ionizing radiation" stimulus SIGNOR-ST16 SIGNOR ELE1-RET "fusion protein" SIGNOR-FP10 SIGNOR up-regulates 9606 23128507 f miannu "In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents" 0.7 SIGNOR-251984 SIGNOR-TC "Thyroid cancer" KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t miannu "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." 0.878 SIGNOR-156906 SIGNOR-TC "Thyroid cancer" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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." 0.758 SIGNOR-244776 SIGNOR-TC "Thyroid cancer" MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni "C-myc has emerged as one of the central regulators of mammalian cell proliferation." 0.7 SIGNOR-56572 SIGNOR-TC "Thyroid cancer" 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)" 0.746 SIGNOR-244480 SIGNOR-TC "Thyroid cancer" 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." 0.746 SIGNOR-244421 SIGNOR-TC "Thyroid cancer" 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)," 0.746 SIGNOR-244469 SIGNOR-TC "Thyroid cancer" 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" 0.272 SIGNOR-244934 SIGNOR-TC "Thyroid cancer" 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." 0.272 SIGNOR-244938 SIGNOR-TC "Thyroid cancer" 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." 0.537 SIGNOR-164516 SIGNOR-TC "Thyroid cancer" 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." 0.458 SIGNOR-251997 SIGNOR-TC "Thyroid cancer" PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." 0.8 SIGNOR-228145 SIGNOR-TC "Thyroid cancer" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." 0.8 SIGNOR-175253 SIGNOR-TC "Thyroid cancer" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9534 9637919 t lperfetto "In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation." 0.8 SIGNOR-58313 SIGNOR-TC "Thyroid cancer" PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" -1 9094314 t gcesareni "We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1)" 0.8 SIGNOR-243274 SIGNOR-TC "Thyroid cancer" RET protein P07949 UNIPROT PDPK1 protein O15530 UNIPROT "up-regulates activity" phosphorylation Tyr9 ARTTSQLyDAVPIQS 10029 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." 0.2 SIGNOR-235863 SIGNOR-TC "Thyroid cancer" 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." 0.659 SIGNOR-36902 SIGNOR-TC "Thyroid cancer" 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." 0.965 SIGNOR-236366 SIGNOR-TC "Thyroid cancer" 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." 0.965 SIGNOR-235881 SIGNOR-TC "Thyroid cancer" 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" 0.965 SIGNOR-236236 SIGNOR-TC "Thyroid cancer" 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." 0.774 SIGNOR-236363 SIGNOR-TC "Thyroid cancer" 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" 0.382 SIGNOR-251994 SIGNOR-TC "Thyroid cancer" 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" 0.382 SIGNOR-251995 SIGNOR-TC "Thyroid cancer" TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 9606 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." 0.846 SIGNOR-249548 SIGNOR-TC "Thyroid cancer" 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." 0.552 SIGNOR-227503 SIGNOR-TC "Thyroid cancer" TGFB1 protein P01137 UNIPROT SLC5A5 protein Q92911 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14623893 f miannu "The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression" 0.2 SIGNOR-259912 SIGNOR-TC "Thyroid cancer" iodide smallmolecule CHEBI:16382 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI "up-regulates quantity" "precursor of" 9606 23349248 t miannu "After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO)." 0.8 SIGNOR-259913 SIGNOR-TC "Thyroid cancer" TPO protein P07202 UNIPROT TG protein P01266 UNIPROT "up-regulates activity" "catalytic activity" 9606 23349248 t miannu "After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO)." 0.507 SIGNOR-259914 SIGNOR-TC "Thyroid cancer" 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." 0.7 SIGNOR-259915 SIGNOR-TC "Thyroid cancer" 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" 0.829 SIGNOR-122075 SIGNOR-TC "Thyroid cancer" 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" 0.829 SIGNOR-141647 SIGNOR-TC "Thyroid cancer" 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" 0.829 SIGNOR-175256 SIGNOR-TC "Thyroid cancer" iodide smallmolecule CHEBI:16382 ChEBI TPO protein P07202 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0004708 23349248 t miannu "After transport through the apical membrane, Iodide is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO)." 0.8 SIGNOR-268139