Glycogen synthase kinase-3 alpha

UniProt P49840 Organism Homo sapiens Gene GSK3A EC 2.7.11.26, 2.7.11.1

Also known as: GSK3A

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 (By similarity). 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 (By similarity). Is necessary for the establishment of neuronal polarity and axon outgrowth (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions which activates KAT5/TIP60 acetyltransferase activity and promotes acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR.

Classification

Family (Pfam): PF00069 Pkinase
InterPro: GSK-3, Kinase-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser/Thr_kinase_AS, STKc_GSK3
Functional cluster: Serine/Threonine Protein Kinases

Experimental structures · PDB · 2

7SXF X-ray 1.94A
7SXG X-ray 2.40A

A predicted model is available from AlphaFold.

Gene Ontology · 58

Drugs targeting this protein · 4

LITHIUM CARBONATE inhibitor
AZD-1080 inhibitor
LITHIUM CITRATE inhibitor
LY-2090314 inhibitor

Related proteins · sequence + function similarity

Glycogen synthase kinase-3 alpha 0.99
Glycogen synthase kinase-3 alpha 0.97
Protein kinase shaggy 0.86
Glycogen synthase kinase-3 beta 0.84
Glycogen synthase kinase-3 beta 0.82
Glycogen synthase kinase-3 beta 0.82
Glycogen synthase kinase-3 beta 0.82
Glycogen synthase kinase-3 beta 0.82
Shaggy-related protein kinase GSK1 0.81
Shaggy-related protein kinase kappa 0.80
Shaggy-related protein kinase zeta 0.80
Shaggy-related protein kinase GSK4 0.80

Co-cited proteins · studied together in the literature

Glycogen synthase kinase-3 beta 10 shared papers
Low molecular weight protein-tyrosine phosphatase A 1 shared papers
Protein associated with UVRAG as autophagy enhancer 1 shared papers
Catenin delta-2 1 shared papers
Catenin delta-2 1 shared papers
Protein associated with UVRAG as autophagy enhancer 1 shared papers
Glycogen synthase kinase-3 alpha 1 shared papers
F-box/WD repeat-containing protein 7 1 shared papers
Rapamycin-insensitive companion of mTOR 1 shared papers
Serine/threonine-protein kinase ULK1 1 shared papers
Protein LMBR1L 1 shared papers
Ubiquitin-associated domain-containing protein 2 1 shared papers

Literature · 24 cited papers

LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling. Science · 2019
Pacer is a mediator of mTORC1 and GSK3-TIP60 signaling in regulation of autophagosome maturation and lipid metabolism. Mol. Cell · 2019
Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation. J. Biol. Chem. · 2015
Mycobacterium tuberculosis promotes anti-apoptotic activity of the macrophage by PtpA protein-dependent dephosphorylation of host GSK3alpha. J. Biol. Chem. · 2014
An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science · 2012
Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
GSK-3 phosphorylates delta-catenin and negatively regulates its stability via ubiquitination/proteosome-mediated proteolysis. J. Biol. Chem. · 2009
Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci. Signal. · 2009
Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal. Chem. · 2009
Large-scale proteomics analysis of the human kinome. Mol. Cell. Proteomics · 2009
… and 12 more in the literature graph

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