HGNC Approved Gene Symbol: GSK3A
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:42,230,190-42,242,602 (from NCBI)
Glycogen synthase kinase 3-alpha (GSK3A; EC 2.7.1.37) is a multifunctional protein serine kinase homologous to Drosophila 'shaggy' (zeste-white3) that is implicated in the control of several regulatory proteins, including glycogen synthase (see GYS1, 138570) and transcription factors (e.g., JUN, 165160). It also plays a role in the WNT (164820) and PI3K (see PIK3CG, 601232) signaling pathways (see review by Ali et al., 2001).
Woodgett (1990) cloned rat Gsk3a and Gsk3b (605004). The deduced 483-amino acid Gsk3a protein is 93% identical overall and 99% identical in the kinase catalytic domain to the human protein (GenBank AAA62432). SDS-PAGE analysis showed expression of the 51-kD rat protein as predicted from the primary sequence. Northern blot analysis revealed wide expression of a 2.5-kb transcript in rat tissues. Western blot analysis, however, showed that expression is variable, suggesting differential modes of transcriptional and translational regulation.
Hughes et al. (1993) showed that under resting conditions GSK3A and its homologs are highly phosphorylated at tyr279 in the phosphorylation loop. Constitutive phosphorylation of this tyrosine is important for kinase activity. Dephosphorylation of tyr279 after mitogen activation is accompanied by kinase inactivation. Fang et al. (2000) found that PKA (see 188830) as well as PI3K-activated PKB (AKT1; 164730) inactivate GSK3A by phosphorylation at ser21.
Yost et al. (1998) characterized the GSK3 binding activities of FRAT1 (602503) and FRAT2 (605006), which inhibit the phosphorylation of CTNNB1 (116806) and positively regulate the WNT signaling pathway.
Fang et al. (2002) demonstrated that lysophosphatidic acid primarily utilizes a PKC (see 176960)-dependent pathway to modulate GSK3 and that certain growth factors (e.g., PDGFB, 190040), which control GSK3 mainly through PIK3-PKB, are able to regulate GSK3 through an alternative, redundant phospholipase-C-gamma (see 600220)-PKC pathway.
Alzheimer disease (AD; 104300) is associated with increased production and aggregation of amyloid-beta-40 and -42 peptides into plaques. Phiel et al. (2003) showed that GSK3A is required for maximal production of the beta-amyloid-40 and -42 peptides generated from the amyloid precursor protein (APP; 104760) by presenilin (PSEN1; 104311)-dependent gamma-secretase cleavage. In vitro, lithium, a GSK3A inhibitor, blocked the production of the beta-amyloid peptides by interfering with the gamma-secretase step. In mice expressing familial AD-associated mutations in APP and PSEN1, lithium reduced the levels of beta-amyloid peptides. Phiel et al. (2003) noted that GSK3A also phosphorylates the tau protein (MAPT; 157140), the principal component of neurofibrillary tangles in AD, and suggested that inhibition of GSK3A may offer a new therapeutic approach to AD.
Maurer et al. (2006) found that Gsk3 phosphorylated mouse Mcl1 (159552) at a conserved GSK3 phosphorylation site, and this phosphorylation led to increased ubiquitylation and degradation of Mcl1. In mouse pre-B lymphocytic cells, Il3 (147740) withdrawal or Pi3 kinase inhibition induced phosphorylation of Mcl1, and Akt or inhibition of Gsk3 activity prevented Mcl1 phosphorylation. Mcl1 with a mutation of the phosphorylation site showed enhanced stability upon Il3 withdrawal and conferred increased resistance to apoptosis compared with wildtype Mcl1. Maurer et al. (2006) concluded that control of MCL1 stability by GSK3 regulates apoptosis by growth factors, PI3 kinase, and AKT.
Zeng et al. (2005) provided biochemical and genetic evidence for a dual kinase mechanism for LRP6 (603507) phosphorylation and activation. GSK3, which is known for its inhibitory role in Wnt signaling through the promotion of beta-catenin (116806) phosphorylation and degradation, mediates the phosphorylation and activation of LRP6. Zeng et al. (2005) showed that Wnt induces sequential phosphorylation of LRP6 by GSK3 and casein kinase-1 (see 600505), and this dual phosphorylation promotes the engagement of LRP6 with the scaffolding protein Axin (603816). Zeng et al. (2005) further showed that a membrane-associated form of GSK3, in contrast to the cytosolic GSK3, stimulates Wnt signaling and Xenopus axis duplication. Zeng et al. (2005) concluded that their results identified 2 key kinases mediating Wnt coreceptor activation, revealed an unexpected and intricate logic of Wnt/beta-catenin signaling, and illustrated GSK3 as a genuine switch that dictates both on and off states of this pivotal regulatory pathway.
Natural killer (NK) cells from individuals with X-linked lymphoproliferative syndrome (XLP; 308240) exhibit functional defects when stimulated through the NK cell receptor, 2B4 (CD244; 605554), most likely due to aberrant intracellular signaling initiated by mutations in the gene encoding the adaptor molecule SAP (SH2D1A; 300490). Aoukaty and Tan (2005) found that NK cells from individuals with XLP failed to phosphorylate GSK3A and GSK3B after stimulation of 2B4. Lack of GSK3 phosphorylation inactivated GSK3 and prevented accumulation of the transcriptional coactivator beta-catenin in the cytoplasm and its subsequent translocation to the nucleus. Aoukaty and Tan (2005) identified VAV1 (164875), RAC1 (602048), RAF1 (164760), MEK2 (MAP2K2; 601263), ERK1 (MAPK3; 601795), and ERK3 (MAPK6; 602904) as proteins potentially involved in mediating the signaling pathway between 2B4 and GSK3/CTNNB and found that some of these elements were aberrant in XLP NK cells. Aoukaty and Tan (2005) concluded that GSK3 and beta-catenin mediate signaling of 2B4 in NK cells and that dysfunction of some of the elements in the transduction pathway between 2B4 and GSK3/beta-catenin may result in diminished IFNG (147570) secretion and cytotoxic function of NK cells in XLP patients.
Lohi et al. (2005) showed that laforin is a GSK3 ser9 phosphatase, and therefore capable of inactivating GYS1. Laforin also interacted with malin (NHLRC1; 608072), which acts as an E3 ubiquitin ligase binding GYS1. The authors proposed that laforin, in response to appearance of polyglucosans, directs 2 negative feedback pathways: polyglucosan-laforin-GSK3-GYS1 to inhibit GYS1 activity and polyglucosan-laforin-malin-GYS1 to remove GYS1 through proteasomal degradation.
Wang et al. (2008) reported pharmacologic, physiologic, and genetic studies that demonstrated an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukemia, genetically defined by mutations of the MLL (159555) protooncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signaling pathways, GSK3 paradoxically supports MLL leukemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27(KIP1) (600778). Inhibition of GSK3 in a preclinical murine model of MLL leukemia provided promising evidence of efficacy and earmarked GSK3 as a candidate cancer drug target.
GSK3A and GSK3B form a cytoplasmic destruction complex with APC (611731) and AXIN that mediates the phosphorylation of a wide range of proteins, leading to their ubiquitination and subsequent degradation in proteasomes. The activity of the destruction complex is inhibited by the WNT signaling pathway. Using human and mouse cells and Xenopus oocytes, Taelman et al. (2010) showed that WNT signaling triggered sequestration of GSK3 from the cytosol into multivesicular bodies and thereby inhibited protein degradation by sequestering GSK3 from cytosolic substrates. Addition of WNT3A (606359) reduced endogenous cytosolic GSK3 activity, and endocytosed WNT3A colocalized with GSK3 in acidic endosomal vesicles. Depletion of GSK3A and GSK3B in HEK293 cells protected the same range of proteins as WNT3A treatment. Depletion of the endosomal sorting proteins HRS (HGS; 604375) or VPS4 (see 609982) also reduced GSK3 endocytosis and inhibited WNT signaling. The GSK3 substrate beta-catenin was required for endocytosis of the GSK3-containing complex, as was the kinase activity of GSK3. Taelman et al. (2010) concluded that rising beta-catenin levels during WNT signaling function in a positive-feedback loop by facilitating GSK3 sequestration, allowing newly translated beta-catenin to accumulate in the nucleus.
Lin et al. (2012) reported that GSK3, when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 (601409) through phosphorylating TIP60 serine at codon 86. This directly acetylates and stimulates the protein kinase ULK1 (603168), which is required for autophagy. Cells engineered to express TIP60(S86A) that cannot be phosphorylated by GSK3 could not undergo serum deprivation-induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in Ulk-null mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. Lin et al. (2012) concluded that their findings uncovered an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy.
Kim et al. (2013) reported that WNT signaling is governed by phosphorylation regulation of the axin (603816) scaffolding function. Phosphorylation by GSK3 kept axin activated (open) for beta-catenin (116806) interaction and poised for engagement of LRP6 (603507). Formation of the WNT-induced LRP6-axin signaling complex promoted axin dephosphorylation by protein phosphatase-1 (see 176875) and inactivated (closed) axin through an intramolecular interaction. Inactivation of axin diminished its association with beta-catenin and LRP6, thereby inhibiting beta-catenin phosphorylation and enabling activated LRP6 to selectively recruit active axin for inactivation reiteratively.
Using somatic cell hybrid and FISH analysis, Hansen et al. (1997) mapped the GSK3A gene to chromosome 19q13.1-q13.2, a locus distinct from that for GSK3B at 3q13.3-q21.
By RT-PCR and SSCP analysis, Hansen et al. (1997) detected only silent polymorphisms in the 2 GSK3 isoforms in diabetes mellitus type II (NIDDM; 125853) patients and their first-degree relatives. Based on this finding and mapping data, the authors concluded that GSK3 is unlikely to be involved in the pathogenesis of NIDDM.
By expressing GSK3A and GSK3B and kinase-dead mutants, generated by altering 2 consecutive lysine residues, in frog eggs, He et al. (1995) showed that the dominant-negative mutants induced dorsal differentiation whereas the wildtype forms caused ventral differentiation. The authors suggested that dorsal differentiation involves the suppression of GSK3 activity by a Wnt-related signal.
Jia et al. (2002) reported that in addition to the role of Gsk3 proteins as inhibitory components of the Wnt pathway, they also inhibit the 'hedgehog' (Hh) pathway (see SHH, 600725) in Drosophila. Gsk3 phosphorylates 'cubitus interruptus' (Ci; see GLI3, 165240) after a primed phosphorylation by PKA, causing hyperphosphorylation of Ci and thus targeting it for proteolytic processing. In contrast, Hh opposes Ci proteolysis by promoting its dephosphorylation.
Trowbridge et al. (2006) showed that hematopoietic repopulation by hematopoietic stem cells (HSC) can be augmented by administration of a GSK3 inhibitor to recipient mice transplanted with mouse or human HSCs. The results suggested that the use of GSK3 inhibitors may provide a potent and unique clinical approach to directly enhance HSC repopulation in vivo.
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Kim, S.-E., Huang, H., Zhao, M., Zhang, X., Zhang, A., Semonov, M. V., MacDonald, B. T., Zhang, X., Abreu, J. G., Peng, L., He, X. Wnt stabilization of beta-catenin reveals principles for morphogen receptor-scaffold assemblies. Science 340: 867-870, 2013. [PubMed: 23579495] [Full Text: https://doi.org/10.1126/science.1232389]
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Maurer, U., Charvet, C., Wagman, A. S., Dejardin, E., Green, D. R. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Molec. Cell 21: 749-760, 2006. [PubMed: 16543145] [Full Text: https://doi.org/10.1016/j.molcel.2006.02.009]
Phiel, C. J., Wilson, C. A., Lee, V. M.-Y., Klein, P. S. GSK-3-alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 423: 435-439, 2003. [PubMed: 12761548] [Full Text: https://doi.org/10.1038/nature01640]
Taelman, V. F., Dobrowolski, R., Plouhinec, J.-L., Fuentealba, L. C., Vorwald, P. P., Gumper, I., Sabatini, D. D., De Robertis, E. M. Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell 143: 1136-1148, 2010. [PubMed: 21183076] [Full Text: https://doi.org/10.1016/j.cell.2010.11.034]
Trowbridge, J. J., Xenocostas, A., Moon, R. T., Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nature Med. 12: 89-98, 2006. [PubMed: 16341242] [Full Text: https://doi.org/10.1038/nm1339]
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