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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" "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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-AML1-ETO "AML1-ETO in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-ASXL1 "ASXL1 in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-BCRABL "BCR-ABL in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-DNMT3A "DNMT3A in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" "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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" "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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FLT3 "FLT3 in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" "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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" "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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" "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-FusionProteins "Onco-fusion proteins in AML" "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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-FusionProteins "Onco-fusion proteins in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-IDH_TET "IDH-TET in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-AML-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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-KIT "KIT in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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_miRNA "miRNA in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" "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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" "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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" "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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" "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-MLL "MLL fusion protein in AML" "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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" "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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-MLL "MLL fusion protein in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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-NP1 "NPM1 in AML" 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_TF HaematopoiesisTranscriptionalControl GATA1 protein P15976 UNIPROT TAL1 protein P17542 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 7632958 f irozzo "Moreover, GATA-1 but not GATA-2 or GATA-3 was able to transactivate SCL promoter 1a in a T-cell environment. These results suggest that inactivity of SCL promoter 1a in T cells reflected the absence of GATA-1 rather than the presence of trans-dominant negative regulators." 0.789 SIGNOR-256047 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA2 protein P23769 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12432220 f irozzo "Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression." 0.448 SIGNOR-256056 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 protein P15976 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12432220 f irozzo "Furthermore, GATA-1 has been shown to auto-regulate its own gene expression." 0.2 SIGNOR-256057 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl 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_TF HaematopoiesisTranscriptionalControl GATA1 protein P15976 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 9606 BTO:0004826 10753833 t irozzo "GATA-1 represses PU.1 activity.We have in this report found that the GATA-1 transcription factor is capable of functionally interfering with the PU.1 protein and have provided evidence that this interference is mediated through interaction between the PU.1 ETS domain and the GATA-1 C-finger region." 0.619 SIGNOR-256050 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 protein P17947 UNIPROT GATA1 protein P15976 UNIPROT "down-regulates activity" binding 10090 10364157 t irozzo "We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation." 0.619 SIGNOR-256049 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl NAB2 protein Q15742 UNIPROT EGR2 protein P11161 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000414 20506119 f miannu "Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop." 0.575 SIGNOR-253888 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl EGR2 protein P11161 UNIPROT NAB2 protein Q15742 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782 20506119 f miannu "In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression." 0.575 SIGNOR-253885 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl EGR2 protein P11161 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000848 20506119 f miannu "In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2." 0.575 SIGNOR-253883 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GFI1 protein Q99684 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 10090 BTO:0000725 17197705 t miannu "Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line." 0.593 SIGNOR-256043 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl NAB2 protein Q15742 UNIPROT GFI1 protein Q99684 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 16923394 f miannu "Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene." 0.393 SIGNOR-256042 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl EGR2 protein P11161 UNIPROT GFI1 protein Q99684 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 16923394 f miannu "Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene." 0.309 SIGNOR-256041 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA2 protein P23769 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27545880 f irozzo "GATA-2 phosphorylation facilitates GATA-2 chromatin occupancy at GATA-2 target genes. GATA-2 stimulates GATA2 transcription through positive autoregulation" 0.2 SIGNOR-256090 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GFI1 protein Q99684 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates 9606 20861919 f irozzo "In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation." 0.7 SIGNOR-256084 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KLF1 protein Q13351 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0000725 28026072 f irozzo "Activation of KLF1 at day 10 of the differentiation process when hematopoietic progenitor cells were present, enhanced erythroid commitment and differentiation." 0.7 SIGNOR-256086 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl FLI1 protein Q01543 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates 9606 BTO:0000565 28052010 f irozzo "The ETS-related transcription factor Fli-1 affects many developmental programs including erythroid and megakaryocytic differentiation, and is frequently de-regulated in cancer." 0.7 SIGNOR-256087 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl EGR2 protein P11161 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 BTO:0001412 1864967 f irozzo "Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes." 0.7 SIGNOR-256089 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 protein P17947 UNIPROT EGR2 protein P11161 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16923394 f miannu "PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation" 0.372 SIGNOR-256040 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 protein P17947 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16923394 f miannu "PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation" 0.307 SIGNOR-256039 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 17671233 f irozzo "C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment.Transcriptional induction of PU.1 by C/EBPα may play a role in myeloid lineage specification." 0.528 SIGNOR-256055 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl HRAS protein P01112 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates activity" phosphorylation Ser192 PSTTGAAsPASSSAG 9606 25056917 f "Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity" 0.357 SIGNOR-259945 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl MAPK14 protein Q16539 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 25056917 t "P38α promotes multi‐site GATA‐2 phosphorylation, increasing its localization in nuclear foci enriched in an active form of RNA polymerase II and its capacity to regulate endogenous target genes." 0.269 SIGNOR-259946 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 protein P17947 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15767686 f irozzo "These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU.1 gene expression.These data demonstrate that PU.1 protein is in a complex binding to a site within the kb −14 URE, suggesting that autoregulation through this region might be important for expression of PU.1." 0.2 SIGNOR-256070 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 protein P15976 UNIPROT KLF1 protein Q13351 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 8195185 f irozzo "Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3." 0.504 SIGNOR-256051 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 protein P15976 UNIPROT ZFPM1 protein Q8IX07 UNIPROT "up-regulates activity" binding 9606 21853041 t miannu "GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1." 0.802 SIGNOR-256059 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl 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_TF HaematopoiesisTranscriptionalControl SPI1 protein P17947 UNIPROT JUN protein P05412 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 17041602 f miannu "Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets." 0.554 SIGNOR-256065 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GFI1 protein Q99684 UNIPROT EGR2 protein P11161 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 16923394 f irozzo "Importantly, overexpression of Gfi-1 in these cells resulted in the attenuation of both Egr-1 and Egr-2 expression, but not Nab-2." 0.309 SIGNOR-256133 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl JUN protein P05412 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 10090 BTO:0000725 17041602 f miannu "These results show that restoration of c-Jun expression rescues the myelomonocytic differentiation block in preleukemic PU.1-knockdown bone marrow cells, suggesting that c-Jun is a critical downstream target in PU.1-knockdown HSCs." 0.7 SIGNOR-256066 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KMT2A protein Q03164 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" methylation 10090 BTO:0002884 22012064 t irozzo "Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression." 0.447 SIGNOR-255874 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 9606 23817177 t irozzo "RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity." 0.57 SIGNOR-255708 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0002181 22012064 t irozzo "Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels" 0.57 SIGNOR-255707 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl 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_TF HaematopoiesisTranscriptionalControl CBFB protein Q13951 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 10090 BTO:0002883 11179217 t "The RUNX genes encode the α subunit of the transcription factor PEBP2/CBF. The β subunit consists of the non-RUNX protein PEBP2β. We found that RUNX1/AML1, which is essential for hematopoiesis, is continuously subjected to proteolytic degradation mediated by the ubiquitin–proteasome pathway. When PEBP2β is present, however, the ubiquitylation of RUNX1 is abrogated and this causes a dramatic inhibition of RUNX1 proteolysis." 0.847 SIGNOR-255742 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl CBFB protein Q13951 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 10090 11179217 t irozzo "We observed previously that the RUNX proteins are susceptible to proteolytic degradation (Ogawa et al., 1993b). In this study, we show that the ubiquitin‚proteasome system is largely responsible for this degradation. We also show that when PEBP2Œ≤ dimerizes with RUNX it inhibits the ubiquitylation of RUNX, which is necessary for the protein to be targeted for proteolysis by the proteasome." 0.847 SIGNOR-255712 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 protein P15976 UNIPROT CBFB protein Q13951 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004475 19825991 f miannu "Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors." 0.517 SIGNOR-254190 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 protein P17947 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12433372 f irozzo "Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene.The above experiments suggested that PU.1 may physiologically downregulate the expression of the GATA-2 gene during the differentiation of myeloid progenitors into macrophages." 0.576 SIGNOR-256069 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 9606 BTO:0000664 10411939 t irozzo "Here we demonstrate that a region of the PU.1 Ets domain (the winged helix–turn–helix wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid target genes." 0.576 SIGNOR-256071 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl CEBPA protein P49715 UNIPROT GFI1 protein Q99684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20924107 f irozzo "We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1." 0.375 SIGNOR-256068 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl ZFPM1 protein Q8IX07 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21853041 t miannu "GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1." 0.75 SIGNOR-256061 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl FLI1 protein Q01543 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 12556498 t irozzo "On the other hand, our data demonstrate that FLI-1 also interacts with GATA-1. However, FLI-1 does not repress but enhances GATA-1 activity." 0.517 SIGNOR-256045 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl FLI1 protein Q01543 UNIPROT KLF1 protein Q13351 UNIPROT "down-regulates activity" binding 10090 BTO:0004475 12556498 t irozzo "FLI-1 represses the transcriptional activity of EKLF.Our data indicate that the ETS domain of FLI-1 is absolutely required to inhibit EKLF activity. Since the FLI-1 ETS domain interacts with the DNA binding domain of EKLF, one possibility could be that FLI-1 inhibits the binding of EKLF to its DNA targets" 0.368 SIGNOR-256044 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 protein P15976 UNIPROT FLI1 protein Q01543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10523830 f irozzo "Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression." 0.517 SIGNOR-256053 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KLF1 protein Q13351 UNIPROT FLI1 protein Q01543 UNIPROT "down-regulates activity" binding 10090 BTO:0004475 12556498 t irozzo "The present study also shows that EKLF itself inhibits FLI-1 activity. As suggested above for the inhibition of EKLF activity, the inhibition of FLI-1 activity most probably involves the indirect recruitment of EKLF to FLI-1 target promoters by protein-protein interaction." 0.368 SIGNOR-256046 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 protein P17947 UNIPROT TAL1 protein P17542 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 16298389 t irozzo "PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity" 0.441 SIGNOR-256048 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 protein P15976 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12432220 f irozzo "Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression." 0.448 SIGNOR-256058 SIGNOR-AML_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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_TRIPLETS AML_TRIPLETS 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-DD "DNA repair in cancer" ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." 0.802 SIGNOR-106440 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT RIF1 protein Q5UIP0 UNIPROT "up-regulates activity" binding 9606 15342490 t miannu "Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. After induction of double-strand breaks (DSBs), Rif1 formed foci that colocalized with other DNA-damage-response factors. This response was strictly dependent on ATM (ataxia telangiectasia mutated) and 53BP1, but not affected by diminished function of ATR (ATM- and Rad3-related kinase), BRCA1, Chk2, Nbs1, and Mre11." 0.504 SIGNOR-259059 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser28 PHGSVTQsQGSSSQS 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to irser28 was also found to be phosphorylated in an atm-dependent manner" 0.839 SIGNOR-81395 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser35 SQGSSSQsQGISSSS 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir" 0.839 SIGNOR-81403 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1330 QMRHQSEsQGVGLSD 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks" 0.823 SIGNOR-72048 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 12024016 t gcesareni "Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner." 0.823 SIGNOR-87845 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser317 ENVKYSSsQPEPRTG 9606 20068082 t gcesareni "Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation." 0.849 SIGNOR-163106 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 20068082 t gcesareni "Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation." 0.849 SIGNOR-163110 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Thr302 PEPEVLStQEDLFDQ 9606 22621922 t gcesareni "Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm." 0.876 SIGNOR-197619 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT MRE11 protein P49959 UNIPROT up-regulates phosphorylation Ser264 EQQLFYIsQPGSSVV 9606 10608806 t lperfetto "In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage." 0.2 SIGNOR-73366 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks" 0.823 SIGNOR-72056 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Atm resides in a complex with brca1 and phosphorylated brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a brca1-deficient cell line.Atm-dependent phosphorylation of ser1423 or ser1524 also occurred in vivo," 0.823 SIGNOR-72079 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1466 KSSEYPIsQNPEGLS 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks" 0.823 SIGNOR-72060 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." 0.823 SIGNOR-72064 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10550055 t gcesareni "Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner." 0.823 SIGNOR-72075 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000150 12183412 t gcesareni "Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint." 0.823 SIGNOR-91482 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser831 EPVEQDSsQPSLPLV 9606 22621922 t gcesareni "Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm." 0.876 SIGNOR-197615 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser1219 DDTESLHsQGEEEFD 9606 22621922 t gcesareni "Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm." 0.876 SIGNOR-197611 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser29 IEDSQPEsQVLEDDS 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" 0.876 SIGNOR-100645 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser6 sQLDSDFS 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" 0.876 SIGNOR-100649 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT RAD50 protein Q92878 UNIPROT unknown phosphorylation Ser635 KLFDVCGsQDFESDL 9606 17570479 t llicata "The ms/ms fragmentation spectra (figure s7) confirmed the phosphorylation of rad50 at the predicted atm substrate site, s635, in agreement with published data" 0.815 SIGNOR-156077 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." 0.823 SIGNOR-187591 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t gcesareni "The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells." 0.876 SIGNOR-197622 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser25 PCLIIEDsQPESQVL 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" 0.876 SIGNOR-100641 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser50 TSTMPNSsQSSHSSS 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to iratm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro." 0.839 SIGNOR-81407 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser19 SHGSSACsQPHGSVT 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir" 0.839 SIGNOR-81391 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser33 TQSQGSSsQSQGISS 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir" 0.839 SIGNOR-81399 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr26 SQPHGSVtQSQGSSS 9606 BTO:0000007 12024051 t gcesareni "We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr" 0.839 SIGNOR-87850 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t gcesareni "Here we show that in vitro, atm phosphorylates the ser-gln/thr-gln (sq/tq) cluster domain (scd) on chk2, which contains seven sq/tq motifs, and thr68 is the major in vitro phosphorylation site by atm. Atm predominantly phosphorylates chk2 at thr68, promoting homodimerization and activation via intramolecular trans-autophosphorylation at thr383/387." 0.839 SIGNOR-81438 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000150 10550055 t lperfetto "Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint." 0.823 SIGNOR-72052 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm" 0.823 SIGNOR-72068 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1542 EEQQLEEsGPHDLTE 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm" 0.823 SIGNOR-72072 SIGNOR-DD "DNA repair in cancer" ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser784 GVEKCSDsQSWEDIA 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" 0.876 SIGNOR-100653 SIGNOR-DD "DNA repair in cancer" ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1280 QVILAKAsQEHHLSE 9606 BTO:0002181 11114888 t llicata "Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication." 0.802 SIGNOR-250582 SIGNOR-DD "DNA repair in cancer" ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 23422745 t gcesareni "The phosphorylation of atr and atm substrates, chk1, chk2, h2ax, and brca1 was significantly reduced or abrogated in mutant cells." 0.802 SIGNOR-201050 SIGNOR-DD "DNA repair in cancer" ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." 0.802 SIGNOR-106436 SIGNOR-DD "DNA repair in cancer" ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." 0.802 SIGNOR-106432 SIGNOR-DD "DNA repair in cancer" ATR protein Q13535 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates phosphorylation Ser601 EMDLAHNsQSMHASS 9606 21242293 t lperfetto "Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair" 0.414 SIGNOR-171290 SIGNOR-DD "DNA repair in cancer" ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1143 PMGSSHAsQVCSETP 9606 BTO:0002181 11114888 t llicata "Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication." 0.802 SIGNOR-250581 SIGNOR-DD "DNA repair in cancer" ATR protein Q13535 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 17124492 t lperfetto "Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment" 0.747 SIGNOR-150870 SIGNOR-DD "DNA repair in cancer" ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Thr1394 SQSDILTtQQRDTMQ 9606 BTO:0002181 11114888 t llicata "Although no single mutation eliminated the GST–BRCA1 (1314–1863) electrophoretic mobility shift, a quadruple mutant (GST–BRCA14A) containing Ala substitutions at Ser 1387, Thr 1394, Ser 1423, and Ser 1457 showed no alteration in electrophoretic mobility after phosphorylation by ATR-containing immune complexes (Fig.2D). The total incorporation of 32Pi into the GST–BRCA14Asubstrate was reduced by 70% relative to that obtained with wild-type GST–BRCA1 (1314–1863), suggesting that these four residues account for most, but not all of the phosphorylation sites in this fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication." 0.802 SIGNOR-250583 SIGNOR-DD "DNA repair in cancer" BRCA1 protein P38398 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 15549093 f lperfetto "The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination" 0.7 SIGNOR-251500 SIGNOR-DD "DNA repair in cancer" BRCA1 protein P38398 UNIPROT ATM protein Q13315 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001130 22832221 f gcesareni "Brca1/e2f1/ctipbinding to atm promoter activates atm transcription." 0.823 SIGNOR-198467 SIGNOR-DD "DNA repair in cancer" BRCA2 protein P51587 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu "Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates" 0.556 SIGNOR-204538 SIGNOR-DD "DNA repair in cancer" CHEK1 protein O14757 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation Thr309 LRKGRGEtRICKIYD 9606 15665856 t gcesareni "We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner" 0.846 SIGNOR-133375 SIGNOR-DD "DNA repair in cancer" CHEK2 protein O96017 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser988 PPLFPIKsFVKTKCK 9606 BTO:0000150 14701743 t gcesareni "In this study, we tested the hypothesis that the brca1-mediated regulation of recombination requires the chk2- and atm-dependent phosphorylation sites." 0.791 SIGNOR-120575 SIGNOR-DD "DNA repair in cancer" DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates 9606 26527132 f lperfetto "Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair." 0.7 SIGNOR-242616 SIGNOR-DD "DNA repair in cancer" DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT "up-regulates activity" 9606 19151762 f lperfetto "Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68" 0.7 SIGNOR-242605 SIGNOR-DD "DNA repair in cancer" DNA_damage stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 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-242609 SIGNOR-DD "DNA repair in cancer" MLH1/PMS2 complex SIGNOR-C59 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 29175432 f "MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans" 0.7 SIGNOR-257600 SIGNOR-DD "DNA repair in cancer" RAD50 protein Q92878 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 10426999 t amattioni "Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex." 0.788 SIGNOR-69701 SIGNOR-DD "DNA repair in cancer" RAD50 protein Q92878 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 17713585 t fstefani "To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50." 0.2 SIGNOR-157478 SIGNOR-DD "DNA repair in cancer" 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-DD "DNA repair in cancer" RIF1 protein Q5UIP0 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 15342490 f miannu "This result would suggest that Rif1 acts in an intra-S-phase checkpoint pathway that is separate from the Nbs1 pathway. Although a role for human Rif1 at telomeres is not excluded, our data show that the primary function of Rif1 is in the DNA-damage response. Rif1 localizes to DSBs in an ATM- and 53BP1-dependent manner and functions in the intra-S-phase checkpoint that serves to slow down DNA synthesis when DNA damage has occurred." 0.7 SIGNOR-259060 SIGNOR-DD "DNA repair in cancer" SLX4 protein Q8IY92 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR up-regulates binding 9606 24726326 t lperfetto "Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair." 0.822 SIGNOR-217652 SIGNOR-DD "DNA repair in cancer" TP53BP1 protein Q12888 UNIPROT RIF1 protein Q5UIP0 UNIPROT "up-regulates activity" binding 10090 23333305 t miannu "RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination." 0.688 SIGNOR-259058 SIGNOR-DD "DNA repair in cancer" PALB2 protein Q86YC2 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates binding 9606 19423707 t miannu "We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage." 0.758 SIGNOR-185656 SIGNOR-DD "DNA repair in cancer" PALB2 protein Q86YC2 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu "Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates" 0.541 SIGNOR-204541 SIGNOR-DD "DNA repair in cancer" PALB2 protein Q86YC2 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates binding 9606 BTO:0000150 16793542 t miannu "Palb2 colocalizes with brca2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions." 0.942 SIGNOR-147217 SIGNOR-DD "DNA repair in cancer" DNA_damage stimulus SIGNOR-ST1 SIGNOR PALB2 protein Q86YC2 UNIPROT "up-regulates activity" 9606 BTO:0001938 19369211 f lperfetto "Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations." 0.7 SIGNOR-244490 SIGNOR-DD "DNA repair in cancer" PALB2 protein Q86YC2 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 19369211 t lperfetto "The BRCA1-PALB2 interaction is required for homologous recombination repair.Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex." 0.853 SIGNOR-244487 SIGNOR-DD "DNA repair in cancer" POLH protein Q9Y253 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 21242293 f miannu "In this study we show that, in human cells, polη becomes phosphorylated by ATR at Ser601 after UV irradiation. Phosphorylation requires physical interaction of polη with Rad18 but is independent of PCNA monoubiquitination. We show that UV-induced phosphorylation of polη is required for normal survival and postreplication repair and is involved in checkpoint control." 0.7 SIGNOR-259061 SIGNOR-DD "DNA repair in cancer" DNA_damage stimulus SIGNOR-ST1 SIGNOR MLH1/PMS2 complex SIGNOR-C59 SIGNOR up-regulates -1 10542278 f miannu "HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay." 0.7 SIGNOR-259062 SIGNOR-DD "DNA repair in cancer" DNA_damage stimulus SIGNOR-ST1 SIGNOR SLX4 protein Q8IY92 UNIPROT up-regulates -1 10542278 f miannu "HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay." 0.7 SIGNOR-259063 SIGNOR-DD "DNA repair in cancer" ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates -1 10542278 f miannu "HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay." 0.7 SIGNOR-259064 SIGNOR-DD "DNA repair in cancer" MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 17713585 f lperfetto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB." 0.7 SIGNOR-251502 SIGNOR-DD "DNA repair in cancer" MRE11 protein P49959 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR "form complex" binding 17713585 t lperfetto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50." 0.2 SIGNOR-251504 SIGNOR-ES "ErbB receptors in 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-ES "ErbB receptors in 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-ES "ErbB receptors in 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-ES "ErbB receptors in 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-ES "ErbB receptors in 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-ES "ErbB receptors in 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-ES "ErbB receptors in 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-ES "ErbB receptors in cancer" 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-ES "ErbB receptors in cancer" 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-ES "ErbB receptors in cancer" 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-ES "ErbB receptors in 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-ES "ErbB receptors in cancer" "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-ES "ErbB receptors in 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-ES "ErbB receptors in 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-ES "ErbB receptors in 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-ES "ErbB receptors in cancer" 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-ES "ErbB receptors in cancer" 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-ES "ErbB receptors in cancer" 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-ES "ErbB receptors in cancer" "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-ES "ErbB receptors in cancer" Neuregulin proteinfamily SIGNOR-PF37 SIGNOR "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "up-regulates activity" binding 9606 18415007 t miannu "The neuregulin family consists of four genes, NRG1-4 which can each encode products containing a domain related to the epidermal growth factor family of ligands. they may be released by regulated proteolysis to act as soluble proteins which can interact and activate members of the EGF receptor family of receptor tyrosine kinases" 0.91 SIGNOR-256161 SIGNOR-ES "ErbB receptors in 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-ES "ErbB receptors in 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIIA "FLT3-ITD in AML" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 17726008 t gcesareni "However p38alfa also inactivates gsk3b by direct phosphorilation of the c-terminal residue ser389. this non-canonicl p38 mapk-dependent phosphorilation of gsk3b seems to occur primarily in the brain and thymocytes." 0.29 SIGNOR-157548 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT "down-regulates activity" phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 t lperfetto "Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain" 0.2 SIGNOR-137255 SIGNOR-FIS "FLT3-ITD signaling" MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser394 TRQTPVDsPDDSTLS 9823 BTO:0004712 23486913 t lperfetto "Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway" 0.96 SIGNOR-201530 SIGNOR-FIS "FLT3-ITD signaling" PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 9445476 t gcesareni "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." 0.726 SIGNOR-55306 SIGNOR-FIS "FLT3-ITD signaling" DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates 9606 26527132 f lperfetto "Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair." 0.7 SIGNOR-242616 SIGNOR-FIS "FLT3-ITD signaling" PARP1 protein P09874 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" relocalization 9606 17891139 t miannu "We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus." 0.558 SIGNOR-261321 SIGNOR-FIS "FLT3-ITD signaling" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 t lperfetto "Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation." 0.2 SIGNOR-244673 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" XPO1 protein O14980 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" relocalization 9606 17891139 t miannu "We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus." 0.549 SIGNOR-260067 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" CREB1 protein P16220 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f gcesareni "In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1" 0.25 SIGNOR-142103 SIGNOR-FIS "FLT3-ITD signaling" PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 t llicata "Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3" 0.446 SIGNOR-195766 SIGNOR-FIS "FLT3-ITD signaling" MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." 0.627 SIGNOR-154783 SIGNOR-FIS "FLT3-ITD signaling" AMPK complex SIGNOR-C15 SIGNOR MAPK14 protein Q16539 UNIPROT "up-regulates activity" 10090 20660302 f "P38 MAPK mediates the effect of AMPK on Gr induced transcriptional activity" 0.279 SIGNOR-255951 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" PDPK1 protein O15530 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 t miannu "Full-length RSK1, RSK2, and RSK3 Are Activated when Coexpressed with PDK1 in COS7 Cells. Ser221 phosphorylation is increased 2–3-fold during ERK-mediated activation of RSK1 in COS1 cells" 0.631 SIGNOR-250270 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 14593102 f lperfetto "Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required" 0.56 SIGNOR-250573 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR "up-regulates activity" "chemical activation" 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" 0.8 SIGNOR-258763 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" PKA proteinfamily SIGNOR-PF17 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 8386317 t miannu "CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes." 0.2 SIGNOR-263653 SIGNOR-FIS "FLT3-ITD signaling" TLR4 protein O00206 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." 0.417 SIGNOR-263652 SIGNOR-FIS "FLT3-ITD signaling" JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 24315690 t miannu "In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity" 0.821 SIGNOR-253340 SIGNOR-FIS "FLT3-ITD signaling" JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates activity" phosphorylation Ser70 RDPVARTsPLQTPAA -1 11323415 t Luana "JNK1 directly phosphorylates Bcl2 at Ser70 in vitro and co-localizes with Bcl2 in mitochondrial membranes in vivo." 0.2 SIGNOR-261133 SIGNOR-FIS "FLT3-ITD signaling" MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t lperfetto "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2." 0.695 SIGNOR-153944 SIGNOR-FIS "FLT3-ITD signaling" RPS6KA1 protein Q15418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto "S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity." 0.357 SIGNOR-110917 SIGNOR-FIS "FLT3-ITD signaling" RPS6KA1 protein Q15418 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto "Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK." 0.289 SIGNOR-209871 SIGNOR-FIS "FLT3-ITD signaling" RPS6KA1 protein Q15418 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 10558990 t lperfetto "The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival." 0.752 SIGNOR-72117 SIGNOR-FIS "FLT3-ITD signaling" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." 0.2 SIGNOR-250553 SIGNOR-FIS "FLT3-ITD signaling" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto "Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK." 0.2 SIGNOR-244595 SIGNOR-FIS "FLT3-ITD signaling" STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "up-regulates activity" phosphorylation -1 14976552 t lperfetto "We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP_activated protein kinase (AMPK)." 0.614 SIGNOR-242602 SIGNOR-FIS "FLT3-ITD signaling" CyclinE/CDK2 complex SIGNOR-C16 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21524151 f miannu "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-262532 SIGNOR-FIS "FLT3-ITD signaling" MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Thr206 PNAILKLtDFGFAKE -1 7592979 t miannu "In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction" 0.768 SIGNOR-250101 SIGNOR-FIS "FLT3-ITD signaling" CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser608 TAADMYLsPVRSPKK BTO:0001968 10207050 t llicata "In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule." 0.752 SIGNOR-250747 SIGNOR-FIS "FLT3-ITD signaling" CHEK1 protein O14757 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" phosphorylation Ser612 MYLSPVRsPKKKGST 9606 17380128 t llicata "These results suggest that ser612 is phosphorylated by chk1/2 after dna damage, leading to the formation of prb-e2f-1. phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1" 0.42 SIGNOR-153904 SIGNOR-FIS "FLT3-ITD signaling" CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "down-regulates activity" binding 9606 BTO:0000093 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" 0.891 SIGNOR-245462 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 t gcesareni "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" 0.756 SIGNOR-121895 SIGNOR-FIS "FLT3-ITD signaling" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 14963330 t lperfetto "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" 0.756 SIGNOR-178690 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto "These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination" 0.76 SIGNOR-188412 SIGNOR-FIS "FLT3-ITD signaling" TLR4 protein O00206 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." 0.488 SIGNOR-261929 SIGNOR-FIS "FLT3-ITD signaling" TLR4 protein O00206 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." 0.429 SIGNOR-261930 SIGNOR-FIS "FLT3-ITD signaling" S100A9 protein P06702 UNIPROT TLR4 protein O00206 UNIPROT "up-regulates activity" binding 9606 28137827 t miannu "RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells. S100A9 binds to TLR4 and induces signaling pathways,promoting leukemic cell differentiation and proliferation arrest. Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-kB." 0.552 SIGNOR-261918 SIGNOR-FIS "FLT3-ITD signaling" CEBPB protein P17676 UNIPROT S100A9 protein P06702 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001370 9706399 t "Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells." 0.2 SIGNOR-254044 SIGNOR-FIS "FLT3-ITD signaling" GSK3B protein P49841 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation 9606 33081032 t miannu "GSK3β regulates S6K1 activity positively through modulating phosphorylation of S6K1 at p.Ser371." 0.357 SIGNOR-263513 SIGNOR-FIS "FLT3-ITD signaling" MAPK14 protein Q16539 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" 9606 BTO:0001255 12839928 f miannu "Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes." 0.674 SIGNOR-263511 SIGNOR-FIS "FLT3-ITD signaling" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CHEK1 protein O14757 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 28138032 f miannu "Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Ras–MEK signaling transcriptionally activates Chk1, which appears to sustain cancer cell growth by maintaining DNA damage levels below a threshold that would otherwise drive apoptosis." 0.2 SIGNOR-263069 SIGNOR-FIS "FLT3-ITD signaling" GSK3B protein P49841 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" 10090 24260231 f miannu "Involvement of GSK3 Inhibition by the PI3K/Akt Pathway in Regulation of Etoposide-induced Chk1 Activation. GSK3ß regulates etoposide-induced Chk1 activation. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. Thus, proteasomal degradation of Chk1 as well as GSK3 activation may be involved in negative regulation of etoposide-induced Chk1 by imatinib in these cells." 0.297 SIGNOR-263050 SIGNOR-FIS "FLT3-ITD signaling" MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000527 16740698 t miannu "Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor" 0.752 SIGNOR-146915 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" GSK3B protein P49841 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser129 QKRREILsRRPSYRK 10116 12162494 t "GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant" 0.694 SIGNOR-251233 SIGNOR-FIS "FLT3-ITD signaling" ATR protein Q13535 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto "Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potentialit is, therefore, likely that atm and atr regulate creb phosphorylation collectively in response to stress stimuli." 0.345 SIGNOR-124060 SIGNOR-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Thr100 LKRLFSGtQISTIAE 9606 15073328 t lperfetto "Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp)" 0.521 SIGNOR-124051 SIGNOR-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto "Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potential," 0.521 SIGNOR-124047 SIGNOR-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT "down-regulates activity" phosphorylation Ser97 TIAESEDsQESVDSV 9606 15073328 t lperfetto "Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivophosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp)" 0.521 SIGNOR-124043 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" CREB1 protein P16220 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 8355 10775268 f lperfetto "Here we demonstrate that the closely related acetyltransferases p300 and cbp potentiate beta-catenin-mediated activation of the siamois promoter" 0.454 SIGNOR-76984 SIGNOR-FIS "FLT3-ITD signaling" CREB1 protein P16220 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" binding 9606 15126506 t lperfetto "We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity" 0.515 SIGNOR-252894 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9122197 f gcesareni "P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis" 0.756 SIGNOR-47541 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7834749 t "Nuclear p53" amattioni "Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis" 0.756 SIGNOR-33922 SIGNOR-FIS "FLT3-ITD signaling" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 16151013 t "Cytosolic p53" amattioni "P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization." 0.756 SIGNOR-140242 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" DNA_damage stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 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-242609 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT "up-regulates activity" 9606 19151762 f lperfetto "Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68" 0.7 SIGNOR-242605 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-153483 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75025 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75645 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-74839 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75017 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites" 0.796 SIGNOR-153475 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75637 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-74831 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." 0.796 SIGNOR-74835 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 17339337 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-153479 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75641 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." 0.796 SIGNOR-75633 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75013 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10801407 t gcesareni "The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20" 0.796 SIGNOR-77144 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17339337 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-153463 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75009 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75629 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-74823 SIGNOR-FIS "FLT3-ITD signaling" CHEK2 protein O96017 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" phosphorylation Ser612 MYLSPVRsPKKKGST 9606 BTO:0000093 17380128 t lperfetto "Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1" 0.421 SIGNOR-153908 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" olaparib chemical CHEBI:83766 ChEBI PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni 0.8 SIGNOR-195016 SIGNOR-FIS "FLT3-ITD signaling" U0126 chemical CHEBI:90693 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 9873633 t lperfetto "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2." 0.8 SIGNOR-244958 SIGNOR-FIS "FLT3-ITD signaling" pimozide chemical CHEBI:8212 ChEBI STAT5A protein P42229 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001545 23264850 t miannu "We have identified the psychotropic drug pimozide as an effective inhibitor of STAT5 function. Pimozide inhibits the tyrosine phosphorylation of STAT5, leading to the death of AML cells through the induction of apoptosis." 0.8 SIGNOR-260125 SIGNOR-FIS "FLT3-ITD signaling" sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT "down-regulates activity" "chemical inhibition" 9606 7566123 t Monia "Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin." 0.8 SIGNOR-261074 SIGNOR-FIS "FLT3-ITD signaling" "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000567 10702313 t gcesareni "Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme." 0.8 SIGNOR-75389 SIGNOR-FIS "FLT3-ITD signaling" wortmannin chemical CHEBI:52289 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 8162590 t gcesareni "The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase." 0.8 SIGNOR-252666 SIGNOR-FIS "FLT3-ITD signaling" quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 19754199 t "Compound 7 (AC220) (quizartinib) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models." 0.8 SIGNOR-255666 SIGNOR-FIS "FLT3-ITD signaling" Selinexor chemical CID:71481097 PUBCHEM XPO1 protein O14980 UNIPROT "down-regulates activity" "chemical inhibition" 9606 30510142 t miannu "Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (C17H11F6N7O; see ref. 4; for its chemical structure). The drug binds and inhibits exportin XPO-1 that mediates nuclear export of proteins and mRNAs." 0.8 SIGNOR-262537 SIGNOR-FIS "FLT3-ITD signaling" KU-55933 chemical CID:5278396 PUBCHEM ATM protein Q13315 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000793 28341201 t miannu "KU-55933 blocked phosphorylation of ATM in H2O2 and Dox models of cell damage. the neuroprotective efficacy of KU-55933, a potent inhibitor of ATM, against cell damage evoked by oxidative stress (hydrogen peroxide, H2O2) has been studied in human neuroblastoma SH-SY5Y cells and compared with the efficacy of this agent in models of doxorubicin (Dox)- and staurosporine (St)-evoked cell death." 0.8 SIGNOR-262536 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" FLT3 protein P36888 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15498859 f "Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells." 0.422 SIGNOR-261519 SIGNOR-FIS "FLT3-ITD signaling" STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15498859 t "Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells." 0.377 SIGNOR-261517 SIGNOR-FIS "FLT3-ITD signaling" PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 18467333 t gcesareni "Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt." 0.386 SIGNOR-178615 SIGNOR-FIS "FLT3-ITD signaling" PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou "Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene." 0.386 SIGNOR-252966 SIGNOR-FIS "FLT3-ITD signaling" PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto "Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo" 0.479 SIGNOR-164642 SIGNOR-FIS "FLT3-ITD signaling" FLT3 protein P36888 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. 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." 0.289 SIGNOR-261520 SIGNOR-FIS "FLT3-ITD signaling" mTORC2 complex SIGNOR-C2 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu "MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity" 0.354 SIGNOR-256171 SIGNOR-FIS "FLT3-ITD signaling" IKBKB protein O14920 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C14 23332762 t gcesareni "Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation." 0.262 SIGNOR-192614 SIGNOR-FIS "FLT3-ITD signaling" IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway" 0.692 SIGNOR-252947 SIGNOR-FIS "FLT3-ITD signaling" IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 11815618 t lperfetto "Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator." 0.922 SIGNOR-249365 SIGNOR-FIS "FLT3-ITD signaling" AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT "up-regulates activity" phosphorylation Ser1261 PMKKLHVsTINLQKA 10090 BTO:0002572 31186373 t miannu "AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. AMPK associates with and phosphorylates mTOR within mTORC2., these data indicate that AMPK phosphorylates mTOR on Ser1261 within mTORC2, an event that correlates with increased mTORC2 autophosphorylation and downstream signaling." 0.572 SIGNOR-262535 SIGNOR-FIS "FLT3-ITD signaling" MTOR protein P42345 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR "form complex" binding 9606 25628925 t lperfetto "Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)" 0.732 SIGNOR-262534 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 21690091 t gcesareni "Upon dna damage, h2ax is phosphorylated by ataxia telangiectasia mutated (atm) and atm-related kinases at serine 139, known as ?_?_?_-H2ax, which serves as a docking site to recruit the mediator of dna damage checkpoint protein 1 (mdc1) to sites of dna damage, named dna damage foci" 0.2 SIGNOR-174442 SIGNOR-FIS "FLT3-ITD signaling" MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR GSK3B protein P49841 UNIPROT "up-regulates activity" phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0001253 15020233 t lperfetto "In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta." 0.2 SIGNOR-244780 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" CHEK1 protein O14757 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation Thr309 LRKGRGEtRICKIYD 9606 15665856 t gcesareni "We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner" 0.846 SIGNOR-133375 SIGNOR-FIS "FLT3-ITD signaling" FLT3 protein P36888 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 f "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" 0.252 SIGNOR-261550 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 23151663 t gcesareni "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." 0.863 SIGNOR-199504 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 11158290 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." 0.871 SIGNOR-217403 SIGNOR-FIS "FLT3-ITD signaling" NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 f gcesareni "The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types." 0.7 SIGNOR-245043 SIGNOR-FIS "FLT3-ITD signaling" NOTCH1 protein P46531 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782;BTO:0001271;BTO:0000785 16847353 f gcesareni "We identified c-myc as a direct target of notch1" 0.676 SIGNOR-147944 SIGNOR-FIS "FLT3-ITD signaling" ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni "We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels" 0.2 SIGNOR-262522 SIGNOR-FIS "FLT3-ITD signaling" MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 18451303 t gcesareni "Here, we show that p38 mitogen-activated protein kinase (mapk) also inactivates gsk3beta by direct phosphorylation at its c terminus, and this inactivation can lead to an accumulation of beta-catenin." 0.29 SIGNOR-178603 SIGNOR-FIS "FLT3-ITD signaling" GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 16407239 t lperfetto "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) ." 0.37 SIGNOR-217430 SIGNOR-FIS "FLT3-ITD signaling" GSK3B protein P49841 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates phosphorylation 9606 12123574 t gcesareni "Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling." 0.461 SIGNOR-90608 SIGNOR-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 20068082 t gcesareni "Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation." 0.849 SIGNOR-163110 SIGNOR-FIS "FLT3-ITD signaling" BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 8358790 t lperfetto "Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered." 0.637 SIGNOR-249612 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" ATR protein Q13535 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11865061 t gcesareni "Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation." 0.744 SIGNOR-115134 SIGNOR-FIS "FLT3-ITD signaling" ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto "We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm." 0.528 SIGNOR-119546 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" AKT1 protein P31749 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 t gcesareni "The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1." 0.428 SIGNOR-124365 SIGNOR-FIS "FLT3-ITD signaling" 3-(9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione chemical CID:10029385 PUBCHEM GSK3B protein P49841 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000183 31562256 t miannu "Indeed, we demonstrated that the selective GSK3 inhibitor LY2090314 significantly reduced cell proliferation in control pancreatic cancer cell lines" 0.8 SIGNOR-262539 SIGNOR-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0002552 11331603 t lperfetto "Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear." 0.76 SIGNOR-107256 SIGNOR-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0000971 17936559 t gcesareni "Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation." 0.76 SIGNOR-158324 SIGNOR-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 t gcesareni "Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation." 0.76 SIGNOR-94268 SIGNOR-FIS "FLT3-ITD signaling" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser386 DDKITQAsQSQESED 9606 BTO:0000007 19816404 t lperfetto "These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination" 0.76 SIGNOR-188408 SIGNOR-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" 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-FIS "FLT3-ITD signaling" LY2603618 chemical CID:11955855 PUBCHEM CHEK1 protein O14757 UNIPROT "down-regulates activity" "chemical inhibition" 9606 33261142 t miannu "Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance." 0.8 SIGNOR-262538 SIGNOR-FIS "FLT3-ITD signaling" 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-HC "Hippo in cancer" WWTR1 protein Q9GZV5 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni "Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis." 0.7 SIGNOR-199208 SIGNOR-HC "Hippo in 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-HC "Hippo in cancer" YAP1 protein P46937 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni "Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis." 0.7 SIGNOR-199214 SIGNOR-HC "Hippo in cancer" WWTR1 protein Q9GZV5 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni "Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis." 0.7 SIGNOR-199211 SIGNOR-HC "Hippo in cancer" STK3/4 proteinfamily SIGNOR-PF41 SIGNOR Mob1 proteinfamily SIGNOR-PF42 SIGNOR "up-regulates activity" phosphorylation 9606 23431053 t miannu "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" 0.9 SIGNOR-256185 SIGNOR-HC "Hippo in cancer" TEAD proteinfamily SIGNOR-PF22 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 26258633 t miannu "YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis." 0.351 SIGNOR-277658 SIGNOR-HC "Hippo in cancer" "Caspase 7 complex" complex SIGNOR-C232 SIGNOR PARP1 protein P09874 UNIPROT down-regulates cleavage 9606 11058599 t amattioni "Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis." 0.723 SIGNOR-256470 SIGNOR-HC "Hippo in cancer" Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "up-regulates activity" binding 9606 21084559 t miannu "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1." 0.943 SIGNOR-256186 SIGNOR-HC "Hippo in cancer" TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR "up-regulates activity" phosphorylation 9606 23431053 t miannu "The thousand-and-one (TAO) amino acids kinase or TAOK1 – 3 has been shown to directly phosphorylate and activate Hpo or MST1/2." 0.368 SIGNOR-256182 SIGNOR-HC "Hippo in cancer" YAP1 protein P46937 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni "Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis." 0.7 SIGNOR-199217 SIGNOR-HC "Hippo in cancer" YAP1 protein P46937 UNIPROT TEAD proteinfamily SIGNOR-PF22 SIGNOR "up-regulates activity" binding 9606 23431053 t miannu "YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death" 0.942 SIGNOR-230719 SIGNOR-HC "Hippo in cancer" WWTR1 protein Q9GZV5 UNIPROT TEAD proteinfamily SIGNOR-PF22 SIGNOR "up-regulates activity" binding 9606 23431053 t miannu "YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death" 0.898 SIGNOR-230722 SIGNOR-HC "Hippo in cancer" LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "down-regulates activity" phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t miannu "In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus." 0.2 SIGNOR-256187 SIGNOR-HC "Hippo in cancer" LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 protein P46937 UNIPROT "down-regulates activity" phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t miannu "In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus." 0.2 SIGNOR-256188 SIGNOR-MC "mTOR in cancer" mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000132 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." 0.647 SIGNOR-251983 SIGNOR-MC "mTOR in cancer" mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" 0.647 SIGNOR-252454 SIGNOR-MC "mTOR in cancer" mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni "MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt" 0.647 SIGNOR-252448 SIGNOR-MC "mTOR in cancer" mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" 0.647 SIGNOR-252451 SIGNOR-MC "mTOR in cancer" 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-MC "mTOR in 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-MC "mTOR in cancer" IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 BTO:0000551 20966354 t lperfetto "Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin." 0.77 SIGNOR-256170 SIGNOR-MC "mTOR in cancer" 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-MC "mTOR in cancer" 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-MC "mTOR in 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-MC "mTOR in 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-MC "mTOR in 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-MC "mTOR in 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-MC "mTOR in 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-MC "mTOR in cancer" RAGAC complex SIGNOR-C113 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" relocalization 9606 20381137 t gcesareni "The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb" 0.693 SIGNOR-228158 SIGNOR-MC "mTOR in cancer" AminoAcids stimulus SIGNOR-ST5 SIGNOR LAMTOR complex SIGNOR-C26 SIGNOR up-regulates 9606 BTO:0000007 SIGNOR-C3 20381137 f lperfetto "The trimeric Ragulator complex, which comprises the p18, p14, and MP1 proteins, anchors the Rag GTPases to the lysosome, and, like the Rags, is necessary for mTORC1 activation by amino acids" 0.7 SIGNOR-228152 SIGNOR-MC "mTOR in 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-MC "mTOR in 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-MC "mTOR in cancer" LAMTOR complex SIGNOR-C26 SIGNOR RAGAC complex SIGNOR-C113 SIGNOR "up-regulates activity" relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto "We identify the trimeric Ragulator protein complex as a new component of the mTORC1 pathway that interacts with the Rag GTPases, is essential for localizing them and mTORC1 to the lysosomal surface, and is necessary for the activation of the mTORC1 pathway by amino acids." 0.878 SIGNOR-228155 SIGNOR-MC "mTOR in 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-MC "mTOR in 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-MC "mTOR in 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-MC "mTOR in 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-MC "mTOR in 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-MC "mTOR in cancer" mTORC2 complex SIGNOR-C2 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu "MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity" 0.354 SIGNOR-256171 SIGNOR-MC "mTOR in cancer" mTORC1 complex SIGNOR-C3 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu "MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity" 0.343 SIGNOR-256172 SIGNOR-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1-FLT3-DNMT3A "Triple mutant AML" 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-NPM1_new NPM1_new 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-PCP "p53 in cancer" 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-PCP "p53 in cancer" 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-PCP "p53 in cancer" 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-PCP "p53 in cancer" 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-PCP "p53 in cancer" 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-PCP "p53 in cancer" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0000971 17936559 t gcesareni "Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation." 0.76 SIGNOR-158324 SIGNOR-PCP "p53 in cancer" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0002552 11331603 t lperfetto "Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear." 0.76 SIGNOR-107256 SIGNOR-PCP "p53 in cancer" 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-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." 0.796 SIGNOR-74835 SIGNOR-PCP "p53 in cancer" 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-PCP "p53 in cancer" BAX protein Q07812 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 10629050 t "Following Bid-induced conformational change" lperfetto "Following bid-induced conformational change, bax oligomerizes and inserts tightly within the outer mitochondrial membrane. The integration of bax in the outer mitochondrial membrane is followed by cytochrome crelease" 0.2 SIGNOR-73895 SIGNOR-PCP "p53 in cancer" BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 8358790 t lperfetto "Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered." 0.637 SIGNOR-249612 SIGNOR-PCP "p53 in cancer" ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto "We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm." 0.528 SIGNOR-119546 SIGNOR-PCP "p53 in cancer" ATR protein Q13535 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11865061 t gcesareni "Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation." 0.744 SIGNOR-115134 SIGNOR-PCP "p53 in cancer" 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-PCP "p53 in cancer" 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-PCP "p53 in cancer" 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-PCP "p53 in cancer" TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 8242752 t lperfetto "The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents." 0.879 SIGNOR-37145 SIGNOR-PCP "p53 in cancer" CyclinE/CDK2 complex SIGNOR-C16 SIGNOR G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto "In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F" 0.7 SIGNOR-245480 SIGNOR-PCP "p53 in cancer" CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "down-regulates activity" binding 9606 BTO:0000093 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" 0.891 SIGNOR-245462 SIGNOR-PCP "p53 in cancer" TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21524151 t lperfetto "P53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting G1/S entry." 0.879 SIGNOR-173425 SIGNOR-PCP "p53 in cancer" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 16151013 t "Cytosolic p53" amattioni "P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization." 0.756 SIGNOR-140242 SIGNOR-PCP "p53 in cancer" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9122197 f gcesareni "P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis" 0.756 SIGNOR-47541 SIGNOR-PCP "p53 in 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-PCP "p53 in cancer" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 t gcesareni "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" 0.756 SIGNOR-121895 SIGNOR-PCP "p53 in cancer" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 14963330 t lperfetto "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" 0.756 SIGNOR-178690 SIGNOR-PCP "p53 in cancer" TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7834749 t "Nuclear p53" amattioni "Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis" 0.756 SIGNOR-33922 SIGNOR-PCP "p53 in cancer" RB1 protein P06400 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 21524151 f lperfetto "Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time." 0.7 SIGNOR-245486 SIGNOR-PCP "p53 in 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-PCP "p53 in 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-PCP "p53 in 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-PCP "p53 in cancer" 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-PCP "p53 in cancer" DNA_damage stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 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-242609 SIGNOR-PCP "p53 in cancer" DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT "up-regulates activity" 9606 19151762 f lperfetto "Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68" 0.7 SIGNOR-242605 SIGNOR-PCP "p53 in cancer" 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-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." 0.796 SIGNOR-75633 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17339337 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-153463 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75025 SIGNOR-PCP "p53 in cancer" TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7566157 t gcesareni "The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting g1/s entry." 0.879 SIGNOR-29248 SIGNOR-PCP "p53 in cancer" 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-PCP "p53 in cancer" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto "These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination" 0.76 SIGNOR-188412 SIGNOR-PCP "p53 in cancer" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 t gcesareni "Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation." 0.76 SIGNOR-94268 SIGNOR-PCP "p53 in cancer" ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser386 DDKITQAsQSQESED 9606 BTO:0000007 19816404 t lperfetto "These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination" 0.76 SIGNOR-188408 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-74839 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites" 0.796 SIGNOR-153475 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75013 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" phosphorylation Ser612 MYLSPVRsPKKKGST 9606 BTO:0000093 17380128 t lperfetto "Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1" 0.421 SIGNOR-153908 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75017 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75645 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75629 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-74823 SIGNOR-PCP "p53 in cancer" 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-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75009 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-153483 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-74831 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75637 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10801407 t gcesareni "The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20" 0.796 SIGNOR-77144 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 17339337 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-153479 SIGNOR-PCP "p53 in cancer" CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." 0.796 SIGNOR-75641 SIGNOR-PGC "PPARgamma in cancer" RAR proteinfamily SIGNOR-PF45 SIGNOR RXR proteinfamily SIGNOR-PF44 SIGNOR "up-regulates activity" binding 9606 1310351 t miannu "Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins." 0.723 SIGNOR-256198 SIGNOR-PGC "PPARgamma in cancer" PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 f lperfetto "Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor" 0.7 SIGNOR-228622 SIGNOR-PGC "PPARgamma in cancer" PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 f lperfetto "Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor" 0.7 SIGNOR-256229 SIGNOR-PGC "PPARgamma in cancer" RXR proteinfamily SIGNOR-PF44 SIGNOR PPARG protein P37231 UNIPROT "up-regulates activity" binding 9606 11237216 t miannu "Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology" 0.2 SIGNOR-259057 SIGNOR-PGC "PPARgamma in cancer" RXR proteinfamily SIGNOR-PF44 SIGNOR RAR proteinfamily SIGNOR-PF45 SIGNOR "up-regulates activity" binding 9606 1310351 t miannu "Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins." 0.723 SIGNOR-256199 SIGNOR-PGC "PPARgamma in cancer" "Fatty acid" stimulus SIGNOR-ST19 SIGNOR PPARG protein P37231 UNIPROT up-regulates 9606 29369787 t miannu "Omega 3 fatty acids and fibrates are considered as natural and pharmacological ligands of PPARα, respectively, that reduce inflammation and arteriosclerosis in cardiovascular system" 0.7 SIGNOR-256189 SIGNOR-PGC "PPARgamma in cancer" 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-PGC "PPARgamma in cancer" CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" binding 10090 BTO:0003346 16847334 t "Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain" 0.537 SIGNOR-256072 SIGNOR-PGC "PPARgamma in cancer" "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." 0.8 SIGNOR-256197 SIGNOR-PGC "PPARgamma in cancer" 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-PGC "PPARgamma in 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-PGC "PPARgamma in 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-PGC "PPARgamma in cancer" "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." 0.8 SIGNOR-256190 SIGNOR-RS "RTKs in 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-RS "RTKs in 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-RS "RTKs in cancer" 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-RS "RTKs in cancer" RTKs proteinfamily SIGNOR-PF38 SIGNOR PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 17306385 t miannu "Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase" 0.2 SIGNOR-256166 SIGNOR-RS "RTKs in cancer" GF proteinfamily SIGNOR-PF39 SIGNOR RTKs proteinfamily SIGNOR-PF38 SIGNOR "up-regulates activity" binding 9606 17306385 t miannu "Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate." 0.2 SIGNOR-256163 SIGNOR-RS "RTKs in 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-RS "RTKs in 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-RS "RTKs in 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-RS "RTKs in cancer" 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-RS "RTKs in 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-RS "RTKs in cancer" 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-RS "RTKs in 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-RS "RTKs in cancer" 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-RS "RTKs in cancer" RTKs proteinfamily SIGNOR-PF38 SIGNOR GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 17306385 t miannu "The adaptor protein Grb2 can bind with activated RTKs through an SH2 domain-phosphotyrosine interaction, while through the SH3 domain (a binding domain specific to proline-rich sequences) Grb2 interacts with the guanine nucleotide exchange factor, Sos." 0.2 SIGNOR-256167 SIGNOR-RS "RTKs in 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-RS "RTKs in cancer" 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-RS "RTKs in 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-RS "RTKs in 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-RS "RTKs in 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-RS "RTKs in 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-RS "RTKs in 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-RS "RTKs in cancer" 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-TSC "TGFb in cancer" CDKN2B protein P42772 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0001056 14681685 f "The Ink4b gene (Cdkn2b) encodes p15Ink4b, a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice." 0.7 SIGNOR-259407 SIGNOR-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-TSC "TGFb in 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-TSC "TGFb in cancer" 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-TSC "TGFb in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 t lperfetto "Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome" 0.794 SIGNOR-165022 SIGNOR-WC "Wnt in cancer" RNF146 protein Q9NTX7 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates quantity" ubiquitination 9606 BTO:0000007 21799911 t "By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins." 0.52 SIGNOR-259998 SIGNOR-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in cancer" 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-WC "Wnt in 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni "We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels" 0.2 SIGNOR-262522 SIGNOR-WNT/FLT3 WNT/FLT3 DVL1 protein O14640 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" binding 9606 SIGNOR-C110 20837657 t gcesareni "In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization." 0.627 SIGNOR-167957 SIGNOR-WNT/FLT3 WNT/FLT3 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 23151663 t gcesareni "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." 0.863 SIGNOR-199504 SIGNOR-WNT/FLT3 WNT/FLT3 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 11955436 t gcesareni "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." 0.863 SIGNOR-116520 SIGNOR-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni "Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9" 0.2 SIGNOR-242578 SIGNOR-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 t lperfetto "Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome" 0.794 SIGNOR-165022 SIGNOR-WNT/FLT3 WNT/FLT3 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 22944199 t amattioni "When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp." 0.2 SIGNOR-253124 SIGNOR-WNT/FLT3 WNT/FLT3 Frizzled proteinfamily SIGNOR-PF11 SIGNOR GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism." 0.2 SIGNOR-253125 SIGNOR-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" binding 9606 19365405 t gcesareni "B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1." 0.824 SIGNOR-185268 SIGNOR-WNT/FLT3 WNT/FLT3 DAAM1 protein Q9Y4D1 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 9606 23151663 f gcesareni "In pcp, dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58." 0.406 SIGNOR-199381 SIGNOR-WNT/FLT3 WNT/FLT3 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 9606 23151663 f gcesareni "In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58." 0.586 SIGNOR-199384 SIGNOR-WNT/FLT3 WNT/FLT3 DVL1 protein O14640 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT "up-regulates activity" binding 9606 19365405 t gcesareni "B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1." 0.738 SIGNOR-185271 SIGNOR-WNT/FLT3 WNT/FLT3 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 9606 19365405 t gcesareni "B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1." 0.586 SIGNOR-185274 SIGNOR-WNT/FLT3 WNT/FLT3 GNAS protein P63092 UNIPROT ADCY1 protein Q08828 UNIPROT "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" 0.633 SIGNOR-156958 SIGNOR-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto "The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity." 0.909 SIGNOR-235766 SIGNOR-WNT/FLT3 WNT/FLT3 MAPK8 protein P45983 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation Ser71 SRRSGLCsPSYVAVT 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-236384 SIGNOR-WNT/FLT3 WNT/FLT3 MAPK8 protein P45983 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 20974802 t gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription." 0.383 SIGNOR-169007 SIGNOR-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 MYC protein P01106 UNIPROT DKK1 protein O94907 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17485441 f gcesareni "C-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity" 0.388 SIGNOR-245355 SIGNOR-WNT/FLT3 WNT/FLT3 MYC protein P01106 UNIPROT SFRP1 protein Q8N474 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 "BTO:0004896; BTO:0004300" 17485441 f gcesareni "c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity" 0.358 SIGNOR-245360 SIGNOR-WNT/FLT3 WNT/FLT3 PRKACA protein P17612 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" phosphorylation Ser188 ARRGKKKsGCLVL 10090 12654918 t miannu "PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell." 0.519 SIGNOR-250047 SIGNOR-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0000007 16476742 t lperfetto "In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin" 0.48 SIGNOR-144482 SIGNOR-WNT/FLT3 WNT/FLT3 DKK1 protein O94907 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 11448771 t gcesareni "We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6." 0.905 SIGNOR-109247 SIGNOR-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 LRP6 protein O75581 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 23209147 t Gianni "The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization." 0.713 SIGNOR-262526 SIGNOR-WNT/FLT3 WNT/FLT3 Wnt proteinfamily SIGNOR-PF40 SIGNOR LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 15578921 t Gianni "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." 0.2 SIGNOR-131577 SIGNOR-WNT/FLT3 WNT/FLT3 SFRP1 protein Q8N474 UNIPROT Wnt proteinfamily SIGNOR-PF40 SIGNOR down-regulates binding 9606 BTO:0000782 10347172 t gcesareni "Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling." 0.797 SIGNOR-262527 SIGNOR-WNT/FLT3 WNT/FLT3 ADCY1 protein Q08828 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" 9606 27065076 f Gianni "Adenylate cyclases (AC) produce cAMP from adenosin-tri-phosphate (ATP). High levels of cytosolic cAMP lead to activation of protein kinase A (PKA)" 0.518 SIGNOR-262528 SIGNOR-WNT/FLT3 WNT/FLT3 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-WNT/FLT3 WNT/FLT3 FOXO1 protein Q12778 UNIPROT TCF4 protein P15884 UNIPROT "down-regulates activity" binding 9606 BTO:0000797 18250171 t Gianni "Here we show that the beta-catenin binding to FOXO serves a dual effect. beta-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with beta-catenin, thereby inhibiting TCF transcriptional activity." 0.267 SIGNOR-262529