Target Information
Target General Infomation | |||||
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Target ID |
T76910
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Former ID |
TTDS00136
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Target Name |
Glycogen synthase kinase-3
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Gene Name |
GSK3A
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Synonyms |
GSK-3; Glycogen synthase kinase 3; GSK3 alpha; Glycogen synthase kinase3 alpha; Serine/threonineprotein kinase GSK3A; GSK3A
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Target Type |
Successful
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Disease | Alcohol use disorders [ICD9: 303; ICD10: F10.2] | ||||
Acute myeloid leukemia; Acute promyelocytic leukemia [ICD9: 205.0, 208.9; ICD10: C91-C95, C92.0, C92.4] | |||||
Epilepsy [ICD10: G40] | |||||
Function |
Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase(GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1. Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal polarity and axon outgrowth. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation.
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BioChemical Class |
Kinase
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Target Validation |
T76910
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UniProt ID | |||||
EC Number |
EC 2.7.1.37
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Sequence |
MSGGGPSGGGPGGSGRARTSSFAEPGGGGGGGGGGPGGSASGPGGTGGGKASVGAMGGGV
GASSSGGGPGGSGGGGSGGPGAGTSFPPPGVKLGRDSGKVTTVVATLGQGPERSQEVAYT DIKVIGNGSFGVVYQARLAETRELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFY SSGEKKDELYLNLVLEYVPETVYRVARHFTKAKLTIPILYVKVYMYQLFRSLAYIHSQGV CHRDIKPQNLLVDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSS IDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIK AHPWTKVFKSRTPPEAIALCSSLLEYTPSSRLSPLEACAHSFFDELRCLGTQLPNNRPLP PLFNFSAGELSIQPSLNAILIPPHLRSPAGTTTLTPSSQALTETPTSSDWQSTDATPTLT NSS |
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Structure |
2DFM
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Drugs and Mode of Action | |||||
Inhibitor | 6-bromoindirubin-3'-oxime (BIO) | Drug Info | [537261] | ||
AR-534 | Drug Info | [537221] | |||
Benzofuran-3-yl-(indol-3-yl)maleimides | Drug Info | [537196] | |||
Lithium chloride | Drug Info | [535388], [536546] | |||
SB216763 | Drug Info | [537174], [537183], [537419] | |||
Valproate | Drug Info | [536096], [536880] | |||
Modulator | LY2090314 | Drug Info | [533221] | ||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
NetPath Pathway | TGF_beta_Receptor Signaling Pathway | ||||
PANTHER Pathway | Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway | ||||
Insulin/IGF pathway-protein kinase B signaling cascade | |||||
PDGF signaling pathway | |||||
Ras Pathway | |||||
Pathway Interaction Database | Degradation of beta catenin | ||||
Canonical Wnt signaling pathway | |||||
FOXM1 transcription factor network | |||||
Class I PI3K signaling events mediated by Akt | |||||
Reactome | AKT phosphorylates targets in the cytosol | ||||
XBP1(S) activates chaperone genes | |||||
Constitutive Signaling by AKT1 E17K in Cancer | |||||
References | |||||
Ref 523195 | ClinicalTrials.gov (NCT01214603) A Study in Participants With Acute Leukemia. U.S. National Institutes of Health. | ||||
Ref 536880 | Challenges and new opportunities in the investigation of new drug therapies to treat frontotemporal dementia. Expert Opin Ther Targets. 2008 Nov;12(11):1367-76. | ||||
Ref 533221 | Activating the Wnt/beta-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3. PLoS One. 2015 Apr 27;10(4):e0125028. | ||||
Ref 535388 | Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol Med. 2002 Mar;8(3):126-32. | ||||
Ref 536096 | Development of medications for alcohol use disorders: recent advances and ongoing challenges. Expert Opin Emerg Drugs. 2005 May;10(2):323-43. | ||||
Ref 536546 | Glycogen synthase kinase 3 beta (GSK-3 beta) as a therapeutic target in neuroAIDS. J Neuroimmune Pharmacol. 2007 Mar;2(1):93-6. Epub 2006 Dec 16. | ||||
Ref 536880 | Challenges and new opportunities in the investigation of new drug therapies to treat frontotemporal dementia. Expert Opin Ther Targets. 2008 Nov;12(11):1367-76. | ||||
Ref 537174 | The ceiling effect of pharmacological postconditioning with the phytoestrogen genistein is reversed by the GSK3beta inhibitor SB 216763 [3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] through mitochondrial ATP-dependent potassium channel opening. J Pharmacol Exp Ther. 2009 Jun;329(3):1134-41. Epub 2009 Mar 24. | ||||
Ref 537183 | Cocaine-induced hyperactivity and sensitization are dependent on GSK3. Neuropharmacology. 2009 Jun;56(8):1116-23. Epub 2009 Mar 27. | ||||
Ref 537196 | From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3beta inhibitors that suppress proliferation and survival of pancreatic cancer cells. J Med Chem. 2009 Apr 9;52(7):1853-63. | ||||
Ref 537221 | A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J Clin Invest. 2009 May;119(5):1382-95. doi: 10.1172/JCI37537. Epub 2009 Apr 13. | ||||
Ref 537261 | Stable generation of serum- and feeder-free embryonic stem cell-derived mice with full germline-competency by using a GSK3 specific inhibitor. Genesis. 2009 Jun;47(6):414-22. |
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