Target General Infomation
Target ID
T94479
Former ID
TTDC00145
Target Name
Ribosomal protein S6 kinase
Gene Name
RPS6KB1
Synonyms
P70-S6K; S6K; RPS6KB1
Target Type
Clinical Trial
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.
BioChemical Class
Kinase
Target Validation
T94479
UniProt ID
EC Number
EC 2.7.11.1
Sequence
MRRRRRRDGFYPAPDFRDREAEDMAGVFDIDLDQPEDAGSEDELEEGGQLNESMDHGGVG
PYELGMEHCEKFEISETSVNRGPEKIRPECFELLRVLGKGGYGKVFQVRKVTGANTGKIF
AMKVLKKAMIVRNAKDTAHTKAERNILEEVKHPFIVDLIYAFQTGGKLYLILEYLSGGEL
FMQLEREGIFMEDTACFYLAEISMALGHLHQKGIIYRDLKPENIMLNHQGHVKLTDFGLC
KESIHDGTVTHTFCGTIEYMAPEILMRSGHNRAVDWWSLGALMYDMLTGAPPFTGENRKK
TIDKILKCKLNLPPYLTQEARDLLKKLLKRNAASRLGAGPGDAGEVQAHPFFRHINWEEL
LARKVEPPFKPLLQSEEDVSQFDSKFTRQTPVDSPDDSTLSESANQVFLGFTYVAPSVLE
SVKEKFSFEPKIRSPRRFIGSPRTPVSPVKFSPGDFWGRGASASTANPQTPVEYPMETSG
IEQMDVTMSGEASAPLPIRQPNSGPYKKQAFPMISKRPEHLRMNL
Drugs and Mode of Action
Drug(s) CI-1040 Drug Info Phase 2 Discovery agent [521505], [541019]
PF-4708671 Drug Info Clinical trial Ulcerative colitis [531100]
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 521505ClinicalTrials.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 531100Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J. 2010 Oct 15;431(2):245-55.
Ref 541019(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5676).
Ref 525872Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Ref 526012Bioorg 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 527308J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole.
Ref 527594Bioorg 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 528490J 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 5305722,3,5-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.
Ref 531100Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J. 2010 Oct 15;431(2):245-55.
Ref 543437(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1525).

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