Target General Infomation
Target ID
T76910
Former ID
TTDS00136
Target Name
Glycogen synthase kinase-3
Gene Name
GSK3A
Synonyms
GSK-3; Glycogen synthase kinase 3; GSK3 alpha; Glycogen synthase kinase3 alpha; Serine/threonineprotein kinase GSK3A; GSK3A
Target Type
Successful
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.
BioChemical Class
Kinase
Target Validation
T76910
UniProt ID
EC Number
EC 2.7.1.37
Sequence
MSGGGPSGGGPGGSGRARTSSFAEPGGGGGGGGGGPGGSASGPGGTGGGKASVGAMGGGV
GASSSGGGPGGSGGGGSGGPGAGTSFPPPGVKLGRDSGKVTTVVATLGQGPERSQEVAYT
DIKVIGNGSFGVVYQARLAETRELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFY
SSGEKKDELYLNLVLEYVPETVYRVARHFTKAKLTIPILYVKVYMYQLFRSLAYIHSQGV
CHRDIKPQNLLVDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSS
IDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIK
AHPWTKVFKSRTPPEAIALCSSLLEYTPSSRLSPLEACAHSFFDELRCLGTQLPNNRPLP
PLFNFSAGELSIQPSLNAILIPPHLRSPAGTTTLTPSSQALTETPTSSDWQSTDATPTLT
NSS
Structure
2DFM
Drugs and Mode of Action
Drug(s) Valproate Drug Info Approved Epilepsy [551871]
LY2090314 Drug Info Phase 2 Acute myeloid leukemia; Acute promyelocytic leukemia [523195], [542874]
Valproate Drug Info Phase 2 Alcohol use disorders [536880]
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 523195ClinicalTrials.gov (NCT01214603) A Study in Participants With Acute Leukemia. U.S. National Institutes of Health.
Ref 536880Challenges 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 542874(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: 7958).
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 533221Activating 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 535388Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol Med. 2002 Mar;8(3):126-32.
Ref 536096Development of medications for alcohol use disorders: recent advances and ongoing challenges. Expert Opin Emerg Drugs. 2005 May;10(2):323-43.
Ref 536546Glycogen 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 536880Challenges 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 537174The 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 537183Cocaine-induced hyperactivity and sensitization are dependent on GSK3. Neuropharmacology. 2009 Jun;56(8):1116-23. Epub 2009 Mar 27.
Ref 537196From 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 537221A 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 537261Stable 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.
Ref 537419Intracellular protein phosphorylation in eosinophils and the functional relevance in cytokine production. Int Arch Allergy Immunol. 2009;149 Suppl 1:45-50. Epub 2009 Jun 3.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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