Target Information
Target General Infomation | |||||
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Target ID |
T94479
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Former ID |
TTDC00145
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Target Name |
Ribosomal protein S6 kinase
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Gene Name |
RPS6KB1
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Synonyms |
P70-S6K; S6K; RPS6KB1
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Target Type |
Clinical Trial
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Disease | Cancer [ICD9: 140-229; ICD10: C00-C96] | ||||
Ulcerative colitis [ICD9: 556; ICD10: K51] | |||||
Function |
Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the pre-initiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1complex. The free mitochondrial PPP1can then dephosphorylate RPS6KB1 at Thr-412, which is proposed to be a negative feedback mechanism for the RPS6KB1 anti- apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1- 2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin. Phosphorylates and activates the pyrimidine biosynthesis enzyme CAD, downstream of MTOR.
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BioChemical Class |
Kinase
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Target Validation |
T94479
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UniProt ID | |||||
EC Number |
EC 2.7.11.1
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Sequence |
MRRRRRRDGFYPAPDFRDREAEDMAGVFDIDLDQPEDAGSEDELEEGGQLNESMDHGGVG
PYELGMEHCEKFEISETSVNRGPEKIRPECFELLRVLGKGGYGKVFQVRKVTGANTGKIF AMKVLKKAMIVRNAKDTAHTKAERNILEEVKHPFIVDLIYAFQTGGKLYLILEYLSGGEL FMQLEREGIFMEDTACFYLAEISMALGHLHQKGIIYRDLKPENIMLNHQGHVKLTDFGLC KESIHDGTVTHTFCGTIEYMAPEILMRSGHNRAVDWWSLGALMYDMLTGAPPFTGENRKK TIDKILKCKLNLPPYLTQEARDLLKKLLKRNAASRLGAGPGDAGEVQAHPFFRHINWEEL LARKVEPPFKPLLQSEEDVSQFDSKFTRQTPVDSPDDSTLSESANQVFLGFTYVAPSVLE SVKEKFSFEPKIRSPRRFIGSPRTPVSPVKFSPGDFWGRGASASTANPQTPVEYPMETSG IEQMDVTMSGEASAPLPIRQPNSGPYKKQAFPMISKRPEHLRMNL |
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Drugs and Mode of Action | |||||
Inhibitor | 4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole | Drug Info | [527308] | ||
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol | Drug Info | [528490] | |||
ACTB-1003 | Drug Info | [543437] | |||
BISINDOLYLMALEIMIDE IX | Drug Info | [525872] | |||
CI-1040 | Drug Info | [525872] | |||
compound 1 | Drug Info | [530572] | |||
KN-62 | Drug Info | [525872] | |||
KT-5720 | Drug Info | [525872] | |||
P70S6 kinase inhibitors | Drug Info | [543437] | |||
PF-4708671 | Drug Info | [531100] | |||
RO-316233 | Drug Info | [525872] | |||
SB-415286 | Drug Info | [526012] | |||
SB-747651A | Drug Info | [527594] | |||
STAUROSPORINONE | Drug Info | [525872] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | ErbB signaling pathway | ||||
HIF-1 signaling pathway | |||||
mTOR signaling pathway | |||||
PI3K-Akt signaling pathway | |||||
AMPK signaling pathway | |||||
TGF-beta signaling pathway | |||||
Fc gamma R-mediated phagocytosis | |||||
Insulin signaling pathway | |||||
Proteoglycans in cancer | |||||
Acute myeloid leukemia | |||||
Choline metabolism in cancer | |||||
PANTHER Pathway | Insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade | ||||
PDGF signaling pathway | |||||
PI3 kinase pathway | |||||
p53 pathway by glucose deprivation | |||||
CCKR signaling map ST | |||||
Pathway Interaction Database | Insulin Pathway | ||||
IL4-mediated signaling events | |||||
CDC42 signaling events | |||||
Angiopoietin receptor Tie2-mediated signaling | |||||
Regulation of Telomerase | |||||
mTOR signaling pathway | |||||
IGF1 pathway | |||||
IL2 signaling events mediated by PI3K | |||||
Integrins in angiogenesis | |||||
RXR and RAR heterodimerization with other nuclear receptor | |||||
Signaling events mediated by Stem cell factor receptor (c-Kit) | |||||
a6b1 and a6b4 Integrin signaling | |||||
TGF-beta receptor signaling | |||||
PathWhiz Pathway | Leucine Stimulation on Insulin Signaling | ||||
Reactome | mTORC1-mediated signalling | ||||
WikiPathways | ErbB Signaling Pathway | ||||
Interferon type I signaling pathways | |||||
G13 Signaling Pathway | |||||
IL-2 Signaling Pathway | |||||
Insulin Signaling | |||||
Cytoplasmic Ribosomal Proteins | |||||
EGF/EGFR Signaling Pathway | |||||
IL-4 Signaling Pathway | |||||
IL-6 signaling pathway | |||||
Kit receptor signaling pathway | |||||
Apoptosis-related network due to altered Notch3 in ovarian cancer | |||||
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) | |||||
BDNF signaling pathway | |||||
Interleukin-11 Signaling Pathway | |||||
FSH signaling pathway | |||||
Leptin signaling pathway | |||||
TSH signaling pathway | |||||
Signaling by Insulin receptor | |||||
TOR Signaling | |||||
AMPK Signaling | |||||
IL-5 Signaling Pathway | |||||
References | |||||
Ref 521505 | ClinicalTrials.gov (NCT00033384) CI-1040 in Treating Patients With Advanced Breast, Colon, Pancreatic, or Non-Small Cell Lung Cancer. U.S. National Institutes of Health. | ||||
Ref 525872 | Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors. | ||||
Ref 526012 | Bioorg Med Chem Lett. 2001 Mar 12;11(5):635-9.3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3). | ||||
Ref 527308 | J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. | ||||
Ref 527594 | Bioorg Med Chem Lett. 2005 Jul 15;15(14):3407-11.(1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: further optimisation as highly potent and selective MSK-1-inhibitors. | ||||
Ref 528490 | J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. | ||||
Ref 530572 | 2,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles. Bioorg Med Chem Lett. 2010 Jan 15;20(2):679-83. |
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