HGNC Approved Gene Symbol: GSK3B
Cytogenetic location: 3q13.33 Genomic coordinates (GRCh38) : 3:119,821,321-120,094,447 (from NCBI)
Glycogen synthase kinase-3 (GSK3) is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase (see GYS1, 138570). Two isoforms, alpha (GSK3A; 606784) and beta, show a high degree of amino acid homology (Stambolic and Woodgett, 1994). GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation (Plyte et al., 1992).
Stambolic and Woodgett (1994) reported the sequence of a cDNA encoding the 420-amino acid GSK3B protein (GenBank L33801).
By Northern blot analysis, Lau et al. (1999) showed that GSK3B is predominantly expressed as 8.3- and 2.8-kb transcripts in testis, thymus, prostate, and ovary, but weakly expressed in lung and kidney. Western blot analysis revealed expression of a 46-kD protein in lung, kidney, and brain. By comparative analysis of various promoter constructs, Lau et al. (1999) observed that GSK3B expression is greater in neuronal than in kidney cell lines.
Stambolic and Woodgett (1994) demonstrated by functional analysis that the 420-amino acid GSK3B protein is inhibited by phosphorylation of serine-9. On the other hand, Wang et al. (1994) found that phosphorylation of tyrosine-216 is required for its activation.
Frame et al. (2001) demonstrated that the insulin-induced inhibition of GSK3 and its unique substrate specificity are explained by the existence of a phosphate-binding site in which arg96 is critical. Mutation of arg96 abolished the phosphorylation of 'primed' glycogen synthase as well as inhibition by protein kinase B (605213)-mediated phosphorylation of ser9. Hence, the phosphorylated N terminus acts as a pseudosubstrate, occupying the same phosphate-binding site used by primed substrates. This mutation did not affect phosphorylation of 'nonprimed' substrates in the Wnt-signaling pathway (axin, 603816 and beta-catenin, 116806), suggesting novel approaches to design more selective GSK3 inhibitors for the treatment of diabetes.
Klein and Melton (1996) proposed that GSK3B is the endogenous target of lithium in diverse systems. They observed that lithium potently and specifically inhibits GSK3B activity in vitro. Consistent with their observation, treatment duplicated the phenotype seen in Gsk3b loss-of-function mutations in Xenopus and Dictyostelium. Klein and Melton (1996) suggested that GSK3B inhibition provides a mechanism to explain how lithium can mimic insulin (176730) action. Klein and Melton (1996) hypothesized that lithium inhibition of the GSK3B pathway in the brain could explain the actions of lithium action in manic-depressive illness in addition to its effects on development and its insulinlike activity. The authors suggested that their observations could provide insights into the pathogenesis and treatment of bipolar disorder (see 125480), which is often treated with lithium.
Stambolic et al. (1996) investigated the effect of lithium on the activity of the GSK3 gene family. Using experiments in vitro as well as in intact cells, they observed that physiologic doses of lithium inhibit the activity of GSK3B. They also observed that lithium treatment of intact cells inhibits GSK3-dependent phosphorylation of the microtubule-associated protein tau (MAPT; 157140), a putative GSK3 substrate. Using lithium treatment of Drosophila and rat cells, Stambolic et al. (1996) concluded that lithium can mimic Wingless signaling in intact cells by specifically inhibiting the activity of GSK3 family members.
Khaled et al. (2002) found that GSK3B synergized with MITF (156845) in mouse melanoma cells to activate the tyrosinase (TYR; 606933) promoter. Lithium impaired the response of the tyrosinase promoter to cAMP, and cAMP increased binding of MITF to the M-box regulatory element. Khaled et al. (2002) concluded that activation of GSK3B by cAMP facilitates MITF binding to the tyrosinase promoter, stimulating melanogenesis.
In higher eukaryotes, the small GTPase Cdc42 (116952), acting through a Par6 (607484)-atypical protein kinase C (aPKC-zeta; 176982) complex, is required to establish cellular asymmetry during epithelial morphogenesis, asymmetric cell division, and directed cell migration. Etienne-Manneville and Hall (2003) used primary rat astrocytes in a cell migration assay to demonstrate that Par6-PKC-zeta interacts directly with and regulates GSK3-beta to promote polarization of the centrosome and to control the direction of cell protrusion. CDC42-dependent phosphorylation of GSK3-beta occurs specifically at the leading edge of migrating cells, and induces the interaction of APC (611731) protein with the plus ends of microtubules. The association of APC with microtubules is essential for cell polarization. Etienne-Manneville and Hall (2003) concluded that CDC42 regulates cell polarity through the spatial regulation of GSK3-beta and APC.
Juhaszova et al. (2004) used rat cardiomyocytes to study cell protection mechanisms in response to environmental stresses. They found that cell protection that exhibited a memory (so-called preconditioning) resulted from triggered mitochondrial swelling that caused enhanced substrate oxidation and reactive oxygen species production, leading to redox activation of protein kinase C, which inhibited GSK3B. Alternatively, receptor tyrosine kinase or certain G protein-coupled receptor activation elicited cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK3B via protein kinase B/Akt (164730) and mTOR (601231)/p70-s6k (608938) or protein kinase C or A pathways. Juhaszova et al. (2004) concluded that the convergence of these pathways via inhibition of GSK3B on the permeability transition pore complex, which limits mitochondrial permeability transition induction, is the general mechanism of cardiomyocyte protection.
Axon-dendrite polarity is a cardinal feature of neuronal morphology essential for information flow. Jiang et al. (2005) reported a differential distribution of GSK3-beta activity in the axon versus the dendrites. A constitutively active GSK3-beta mutant inhibited axon formation, whereas multiple axons formed from a single neuron when GSK3-beta activity was reduced by pharmacologic inhibitors, a peptide inhibitor, or small interfering RNAs. An active mechanism for maintaining neuronal polarity was revealed by the conversion of preexisting dendrites into axons upon GSK3-beta inhibition. Biochemical and functional data showed that AKT kinase and PTEN phosphatase (601728) were upstream of GSK3-beta in determining neuronal polarity. The results demonstrated that there are active mechanisms for maintaining and establishing neuronal polarity, indicated that GSK3-beta relays signaling from AKT and PTEN to play critical roles in neuronal polarity, and suggested that application of GSK3-beta inhibitors can be a novel approach to promote generation of new axons after neural injuries.
Yoshimura et al. (2005) showed that GSK3-beta phosphorylated CRMP2 (602463) at thr514 and inactivated it. Expression of the nonphosphorylated form of CRMP2 or inhibition of GSK3-beta induced the formation of multiple axon-like neurites in hippocampal neurons. Expression of constitutively active GSK3-beta impaired neuronal polarization, whereas the nonphosphorylated form of CRMP2 counteracted the inhibitory effects of GSK3-beta, indicating that GSK3-beta regulates neuronal polarity through phosphorylation of CRMP2. Treatment of hippocampal neurons with neurotrophin-3 (NT3; 162660) induced inactivation of GSK3-beta and dephosphorylation of CRMP2. Knockdown of CRMP2 inhibited NT3-induced axon outgrowth. These results suggested that NT3 decreases phosphorylated CRMP2 and increases nonphosphorylated active CRMP2, thereby promoting axon outgrowth.
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.
Lohi et al. (2005) showed that laforin (607566) is a GSK3 ser9 phosphatase, and therefore capable of inactivating glycogen synthase through GSK3. Laforin also interacted with malin (NHLRC1; 608072). 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.
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 (see 601232) 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.
Yin et al. (2006) demonstrated that GSK3-beta phosphorylates and stabilizes the orphan nuclear receptor Rev-erb-alpha (602408), a negative component of the circadian clock. Lithium treatment of cells led to rapid proteasomal degradation of Rev-erb-alpha and activation of clock gene Bmal1. A form of Rev-erb-alpha that is insensitive to lithium interfered with the expression of circadian genes. Yin et al. (2006) concluded that control of Rev-erb-alpha protein stability is thus a critical component of the peripheral clock and a biologic target of lithium therapy.
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.
Using protein pull-down and coimmunoprecipitation analyses of cotransfected HEK293 cells, Chou et al. (2006) found that GSKIP (616605) bound GSK3B in vitro and in vivo. The C-terminal 25 amino acids of GSKIP were the minimal unit required for binding to GSK3B. Kinetic analysis revealed a strong binding affinity between the GSKIP peptide and GSK3B. Site-directed mutagenesis revealed that ser109 and thr113, just upstream of the GSK3B-binding region of GSKIP, were major GSK3B phosphorylation targets. In vitro kinase assays showed that full-length GSKIP and the 25-amino acid GSKIP C-terminal peptide inhibited the kinase activity of GSK3B against axin and beta-catenin, both of which function within the Wnt signaling pathway, but they did not inhibit GSK3B-dependent phosphorylation of glycogen synthase. Western blot analysis showed that GSKIP caused nuclear accumulation of beta-catenin, and reporter gene assays revealed that GSKIP inhibited Wnt-dependent transcription. Chou et al. (2006) concluded that GSKIP has a role in negatively regulating GSK3B in Wnt signaling, possibly via binding-site overlap.
Although AKT (164730) inactivates GSK3-beta by phosphorylation at the N terminus, preventing AKT-mediated phosphorylation does not affect the cell survival pathway activated through the GSK3-beta substrate beta-catenin (116806). Thornton et al. (2008) demonstrated that p38 mitogen-activated protein kinase (MAPK) (600289) also inactivates GSK3-beta by direct phosphorylation at its C terminus, and this inactivation can lead to an accumulation of beta-catenin. p38 MAPK-mediated phosphorylation of GSK3-beta occurs primarily in the brain and thymocytes. Thornton et al. (2008) concluded that activation of beta-catenin-mediated signaling through GSK3-beta inhibition provides a potential mechanism for p38 MAPK-mediated survival in specific tissues.
Vincent et al. (2008) found that Gsk3b and Pten were enriched in nucleoli of oncogenic Ras (see HRAS; 190020)-transformed mouse epithelial and endothelial cells. Immunoprecipitation and chromatin immunoprecipitation assays showed that Gsk3b and Pten were part of the same complex and associated with the promoter and coding region of ribosomal DNA (rDNA; see 180450). A constitutively active Gsk3b mutant abolished nucleolar BrUTP incorporation and associated with Tafi110 (TAF1C; 604905), a member of a multisubunit complex required to recruit RNA polymerase I (see 602000). Real-time PCR showed that chemical inhibition of Gsk3b upregulated 45S, 18S, and 28S rRNA synthesis and promoted cellular proliferation. Vincent et al. (2008) concluded that GSK3B can function as a tumor suppressor through repression of rRNA biogenesis.
Using in vitro and in vivo protein interaction assays and imaging techniques, Cheng et al. (2008) found that GSK3-beta interacted directly with the spindle-associated protein astrin (SPAG5; 615562) and that the 2 proteins colocalized on the spindle apparatus in mitotic HeLa cells from prophase to anaphase. Astrin, but not GSK3-beta, also localized to the midbody. At mitosis, GSK3-beta phosphorylated astrin on thr111, thr937, and a motif from ser974 to thr978. Inhibition of GSK3-beta impaired spindle and kinetochore accumulation of astrin, in addition to impairing spindle formation at mitosis and inducing G2/M phase arrest. Depletion of astrin in HeLa cells via small interfering RNA had no effect on GSK3-beta localization. However, astrin enhanced GSK3-beta-mediated phosphorylation of other substrates. Cheng et al. (2008) concluded that association of astrin with spindle microtubules and kinetochores requires GSK3-beta kinase activity.
DISC1 (605210) plays a role in brain development and is associated with psychiatric disorders in humans. Using knockdown studies, Mao et al. (2009) found that Disc1 was required for neural progenitor cell proliferation in vitro, during embryonic mouse brain development, and in adult mouse dentate gyrus. Disc1 interacted directly with Gsk3-beta and inhibited recombinant Gsk3-beta activity in a dose-dependent manner. This inhibition of Gsk3-beta caused reduced phosphorylation and increased stabilization of beta-catenin. Knockdown of Disc1 in adult mouse dentate gyrus resulted in hyperactivity and depression-like behaviors. All effects of Disc1 knockdown were reversed by pharmacologic inhibition of Gsk3-beta. Mao et al. (2009) concluded that DISC1 regulates neural progenitor proliferation by modulating GSK3-beta activity and beta-catenin abundance.
GSK3A and GSK3B form a cytoplasmic destruction complex with APC 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.
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 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.
Varano et al. (2017) studied the effects of BCR (151410) ablation on MYC-driven mouse B-cell lymphomas and compared them with observations in human Burkitt lymphoma (113970). Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumor cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumor cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates GSK3-beta activity to support MYC-controlled gene expression. BCR- tumor cells exhibit increased GSK3-beta activity and are rescued from their competitive growth disadvantage by GSK3-beta inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3-beta activity after constitutive activation of the MAPK pathway, commonly through RAS (see 190020) mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumor cells, which usually represent a minority of the tumor bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR- tumor cells.
By mass spectrometry, immunoprecipitation, immunofluorescence, and mutation analyses in HEK293T and human glioma cells, Zhao et al. (2022) demonstrated that ZDHHC4 (621547) palmitoylated GSK3B at cys14, an evolutionarily conserved residue. ZDHHC4-mediated palmitoylation of GSK3B affected binding of GSK3B to AKT1 and p70S6K, thereby inhibiting phosphorylation of GSK3B at ser9. Palmitoylated GSK3B activated STAT3 (102582) by interacting with EZH2 (601573), thereby activating the EZH2-STAT3 axis. STAT3 also regulated transcription of ZDHHC4. Expression of ZDHHC4 was upregulated in human glioblastoma (GBM; 137800), which significantly correlated with tumor grade and poor prognosis. ZDHHC4-mediated GSK3B palmitoylation promoted development of temozolomide (TMZ) resistance in GBM by regulating the tumorigenicity of glioblastoma stem cells (GSCs) in vitro, a finding the authors validated using an in vivo mouse xenograft model. The authors concluded that GSK3B palmitoylation by ZDHHC4 affects GSK3B phosphorylation, leading to activation of the EZH2-STAT3 axis to promote GSC tumorigenicity and ultimately enhance TMZ resistance in GBM.
Dajani et al. (2001) determined the crystal structure of human GSK3B, expressed in insect cells, at 2.8-angstrom resolution. The crystal structure showed a catalytically active conformation in the absence of activation segment phosphorylation, with the sulfonate of a buffer molecule bridging the activation segment and N-terminal domain in the same way as the phosphate group of the activation segment phospho-ser/thr in other kinases. The location of this oxyanion-binding site in the substrate-binding cleft indicated direct coupling of P+4 phosphate-primed substrate binding and catalytic activation, explained the ability of GSK3B to processively hyperphosphorylate substrates with ser/thr pentad repeats, and suggested a mechanism for autoinhibition in which the phosphorylated N terminus binds as a competitive pseudosubstrate with phospho-ser9 occupying the P+4 site.
Shaw et al. (1998) mapped the GSK3B gene to chromosome 3q13.3 by FISH, confirmed by PCR amplification of somatic cell hybrids.
Stumpf (2023) mapped the GSK3B gene to chromosome 3q13.33 based on an alignment of the GSK3B sequence (GenBank BC000251) with the genomic sequence (GRCh38).
Kwok et al. (2005) identified 2 functional SNPs in the GSK3B gene: a promoter polymorphism, -50T-C (rs334558), in which the T allele has greater transcriptional activity in vitro, and an intronic polymorphism, -157T-C in intron 5 (rs6438552), in which the T allele is associated with increased levels of GSK3B lacking exons 9 and 11. Increased levels of GSK3B lacking exons 9 and 11 was correlated with enhanced phosphorylation of MAPT in vitro. In brain tissue from 12 patients with Parkinson disease (PD; 168600), there was an increased frequency of the -157T allele, a corresponding increase in GSK3B lacking exons 9 and 11, and increased phosphorylation of tau compared to 8 control brains. Conditional logistic regression analysis of the genotypes of 302 Caucasian PD patients and 184 Chinese PD patients found an association between the -50TT genotype and the H1/H2 haplotype of MAPT, as well as an association between T alleles of both GSK3B polymorphisms and risk of PD after stratification by MAPT H1/H2 haplotypes. In individuals with either the MAPT H1/H2 or H2/H2 haplotypes, the T/T genotype were increased in PD patients compared to controls (odds ratio (OR) of 1.66, p = 0.047; OR of 1.55, p = 0.091, respectively). Conversely, individuals who were homozygous for the MAPT H1 haplotype (H1/H1) showed a trend toward decreased frequency in the T/T genotypes (OR of 0.69, p = 0.082; OR of 0.59, p = 0.065, respectively). A similar result was observed in a Chinese PD cohort of 184 patients, all of whom were homozygous for H1/H1. Kwok et al. (2005) concluded that GSK3B polymorphisms interact with MAPT haplotypes to modify disease risk in PD.
Kwok et al. (2008) found that the same GSK3B and MAPT haplotypes identified in their earlier study (Kwok et al., 2005) were associated with an increased risk for Alzheimer disease (AD; 104300). In 604 AD individuals from the U.K. with at least 1 MAPT H2 haplotype, the homozygous GSK3B TT haplotype (rs334558 and rs6438552) was significantly associated with increased risk for AD (OR 1.68; p = 0.005). The H1/H1 haplotype showed a decreased risk (odds ratio of 0.47; p = 0.004). Similar results were obtained with 129 Australian AD patients. Among 179 Chinese AD patients, all of whom were homozygous for the H1 haplotype, the effect of the homozygous GSK3B TT haplotype offered a protective effect (OR of 0.33; p = 0.016). Studies of cerebellum tissue showed an association between the MAPT H1 haplotype and increased MAPT gene expression. Overexpression of either MAPT or GSK3B alone resulted in decreased levels of beta-catenin (CTNNB1; 116806), whereas cotransfection of both of these molecules increased beta-catenin signaling. Excess MAPT may sequester GSK3B and alter its effect on downstream molecules. Kwok et al. (2008) proposed a model for the epistatic interaction between GSK3B and MAPT haplotypes for discordance of beta-catenin expression and pathogenicity.
Garcia-Gorostiaga et al. (2009) replicated the associations reported by Kwok et al. (2005, 2008) in 2 Caucasian Spanish cohorts of 314 PD patients and 285 AD patients. Carriers of the GSK3B rs6438552 T/T genotype showed an increased risk for PD in the presence of 1 or 2 copies of MAPT H2 haplotype (OR, 2.95; p = 0.0003), whereas the risk for PD was decreased in the presence of 2 copies of the MAPT H1 haplotype (OR, 0.34; p = 0.009); similarly, the interaction between GSK3B rs334558 T/T genotype and MAPT H1/H1 haplotype was associated with a decreased risk for PD (OR, 0.42; p = 0.03). The estimated frequency of the GSK3B T/T haplotype was significantly greater in PD patients who carried at least 1 copy of the MAPT H2 haplotype (p = 0.01) and also in AD patients who were homozygous for the MAPT H2 haplotype (p = 0.02). The data confirmed the biologic mechanism proposed for this genetic interaction: discordant changes with high levels of GSK3 (GSK3 T/T haplotype) and low levels of tau (MAPT H2 haplotype) may increase both AD and PD risk; conversely, concordant changes with high levels of GSK3 and high levels of tau (MAPT H1 haplotype) may decrease PD risk.
Hoeflich et al. (2000) generated mice deficient in Gsk3b by targeted disruption. Although Gsk3b +/- male and female mice were healthy and fertile, they did not give rise to live Gsk3b -/- progeny. Embryonic lethality occurred between embryonic days 13.5 and 14.5 due to severe liver degeneration, a phenotype consistent with excessive tumor necrosis factor (TNF; 191160) toxicity, as observed in mice lacking genes involved in the activation of transcription factor NFKB (see 164011). Gsk3b-deficient embryos were rescued by inhibition of TNF using anti-TNF-alpha antibody. Fibroblasts from Gsk3b-deficient embryos were hypersensitive to TNF-alpha and showed reduced NFKB function. Lithium treatment, which inhibits GSK3, sensitized wildtype fibroblasts to TNF and inhibited transactivation of NFKB. The early steps leading to NFKB activation were unaffected by the loss of Gsk3b, indicating that NFKB is regulated by GSK3B at the level of the transcriptional complex. Thus, GSK3B facilitates NFKB function. Ali et al. (2001) noted that loss of Gsk3b is not compensated by Gsk3a (606784) and that NFKB activation is the only known differentiator between the 2 enzymes.
Lucas et al. (2001) generated mice overexpressing GSK3B in the brain during adulthood. These mice showed decreased levels of nuclear beta-catenin (116806) and hyperphosphorylation of tau in hippocampal neurons, the latter resulting in pretangle-like somatodendritic localization of tau. Reactive astrocytosis and microgliosis were also indicative of neuronal stress and cell death, which was confirmed by TUNEL assay. Lucas et al. (2001) concluded that in vivo overexpression of GSK3B results in neurodegeneration and suggested that these mice can be used as an animal model to study the relevance of GSK3B deregulation to the pathogenesis of Alzheimer disease.
Fuster-Matanzo et al. (2013) confirmed that overexpression of Gsk3b was detrimental to neurogenesis in mice. Expression of exogenous Gsk3b first appeared in immature neurons. Overexpression of Gsk3b depleted the pool of neuronal precursors and led to an increased percentage of immature neurons. Moreover, Gsk3b blocked neuronal maturation and caused neuronal mislocalization. Overexpression of Gsk3b also increased the neuroinflammatory response and reduced neuron density in adults, likely due to Gsk3b-induced apoptosis.
Trivedi et al. (2007) generated Hdac2 (605164) -/- mice and observed that Hdac2 deficiency or chemical histone deacetylase inhibition prevented the reexpression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the Inpp5f gene (609389), resulting in constitutive activation of the Gsk3b gene via inactivation of Akt and Pdpk1 (605213). Transgenic mice overexpressing Hdac2 had augmented hypertrophy associated with inactivated Gsk3b; chemical inhibition of activated Gsk3b caused Hdac2-deficient adults to become sensitive to hypertrophic stimulation. Trivedi et al. (2007) suggested that HDAC2 and GSK3B are components of a regulatory pathway involved in the cardiac hypertrophic response.
Liu et al. (2007) discovered a genetic requirement for GSK3B in midline development. Homozygous null mice displayed cleft palate, incomplete fusion of ribs at the midline, and bifid sternum, as well as delayed sternal ossification. Using a chemically regulated allele of GSK3B developed by Stankunas et al. (2003), Liu et al. (2007) defined requirements for GSK3B activity during discrete temporal windows in palatogenesis and skeletogenesis. The rapamycin-dependent allele of GSK3B produces GSK3B fused to a tag, FRB* (FKBP/rapamycin binding), resulting in a rapidly destabilized chimeric protein. In the absence of drug, GSK3B(FRB*/FRB*) mutants appeared phenotypically identical to GSK3B-null mutants. In the presence of drug, GSK3BFRB* is rapidly stabilized, restoring protein levels and activity. Using this system, mutant phenotypes were rescued by restoring endogenous GSK3B activity during 2 distinct periods in gestation.
Beaulieu et al. (2008) generated knockin mice with a variant of Tph2 (607478) resulting in markedly decreased brain 5HT production and behavioral abnormalities related to depression and anxiety. The reduction of 5HT was associated with activation of Gsk3b in the frontal cortex. Inactivation of Gsk3b in Tph2 knockin mice alleviated the aberrant behaviors induced by 5HT deficiency. Beaulieu et al. (2008) concluded that Tph2 plays a role in serotonin homeostasis and identified GSK3B-mediated signaling as an important pathway involved in serotonin-related behaviors.
Using GSK3-deficient mouse embryonic stem cells, Kerkela et al. (2008) found markedly impaired cardiomyocyte differentiation in Gsk3b-deficient cells compared to Gsk3a-deficient cells, which had less severe impairment. They generated Gsk3a- and Gsk3b-null mice and observed that, while Gsk3a-null mice were born without a cardiac phenotype, no liveborn Gsk3b-null mice were recovered, and Gsk3b-null embryos had double-outlet right ventricle, ventricular septal defects, and hypertrophic myopathy, with near obliteration of the ventricular cavities. Hypertrophic myopathy was caused by cardiomyocyte hyperproliferation without hypertrophy and was associated with increased expression and nuclear localization of 3 regulators of proliferation, GATA4 (600576), cyclin D1 (168461), and cMyc (190080). Kerkela et al. (2008) concluded that GSK3B is a central regulator of embryonic cardiomyocyte proliferation and differentiation as well as of outflow tract development.
Konig et al. (2010) used an integrative systems approach, based on genomewide RNA interference screening, to identify 295 cellular cofactors required for early-stage influenza virus replication. Within this group, those involved in kinase-regulated signaling, ubiquitination, and phosphatase activity are the most highly enriched, and 181 factors assemble into a highly significant host-pathogen interaction network. Moreover, 219 of the 295 factors were confirmed to be required for efficient wildtype influenza virus growth, and further analysis of a subset of genes showed 23 factors essential for viral entry, including members of the vacuolar ATPase (see 192132) and COPI (see 601924) protein families, fibroblast growth factor receptor (FGFR) proteins, and GSK3-beta. Furthermore, 10 proteins were confirmed to be involved in post-entry steps of influenza virus replication. These include nuclear import components, proteases, and the calcium/calmodulin-dependent protein kinase (CaM kinase) II-beta (CAMK2B; 607707). Notably, growth of swine-origin H1N1 influenza virus is also dependent on the identified host factors, and Konig et al. (2010) showed that small molecule inhibitors of several factors, including vATPase and CAMK2B, antagonize influenza virus replication.
Ali, A., Hoeflich, K. P., Woodgett, J. R. Glycogen synthase kinase-3 : properties, functions, and regulation. Chem. Rev. 101: 2527-2540, 2001. [PubMed: 11749387] [Full Text: https://doi.org/10.1021/cr000110o]
Aoukaty, A., Tan, R. Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease. J. Immun. 174: 4551-4558, 2005. [PubMed: 15814676] [Full Text: https://doi.org/10.4049/jimmunol.174.8.4551]
Beaulieu, J.-M., Zhang, X., Rodriguiz, R. M., Sotnikova, T. D., Cools, M. J., Wetsel, W. C., Gainetdinov, R. R., Caron, M. G. Role of GSK3-beta in behavioral abnormalities induced by serotonin deficiency. Proc. Nat. Acad. Sci. 105: 1333-1338, 2008. [PubMed: 18212115] [Full Text: https://doi.org/10.1073/pnas.0711496105]
Cheng, T.-S., Hsiao, Y.-L., Lin, C.-C., Yu, C.-T. R, Hsu, C.-M., Chang, M.-S., Lee, C.-I., Huang, C.-Y. F., Howng, S.-L., Hong, Y.-R. Glycogen synthase kinase 3-beta interacts with and phosphorylates the spindle-associated protein astrin. J. Biol. Chem. 283: 2454-2464, 2008. [PubMed: 18055457] [Full Text: https://doi.org/10.1074/jbc.M706794200]
Chou, H.-Y., Howng, S.-L., Cheng, T.-S., Hsiao, Y.-L., Lieu, A.-S., Loh, J.-K., Hwang, S.-L., Lin, C.-C., Hsu, C.-M., Wang, C., Lee, C.-I, Lu, P.-J., Chou, C.-K., Huang, C.-Y., Hong, Y.-R. GSKIP is homologous to the Axin GSK3-beta interaction domain and functions as a negative regulator of GSK3-beta. Biochemistry 45: 11379-11389, 2006. [PubMed: 16981698] [Full Text: https://doi.org/10.1021/bi061147r]
Dajani, R., Fraser, E., Roe, S. M., Young, N., Good, V., Dale, T. C., Pearl, L. H. Crystal structure of glycogen synthase kinase 3-beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105: 721-732, 2001. [PubMed: 11440715] [Full Text: https://doi.org/10.1016/s0092-8674(01)00374-9]
Etienne-Manneville, S., Hall, A. Cdc42 regulates GSK-3-beta and adenomatous polyposis coli to control cell polarity. Nature 421: 753-756, 2003. [PubMed: 12610628] [Full Text: https://doi.org/10.1038/nature01423]
Frame, S., Cohen, P., Biondi, R. M. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Molec. Cell 7: 1321-1327, 2001. [PubMed: 11430833] [Full Text: https://doi.org/10.1016/s1097-2765(01)00253-2]
Fuster-Matanzo, A., Llorens-Martin, M., Sirerol-Piquer, M. S., Garcia-Verdugo, J. M., Avila, J., Hernandez, F. Dual effects of increased glycogen synthase kinase-3-beta activity on adult neurogenesis. Hum. Molec. Genet. 22: 1300-1315, 2013. [PubMed: 23257288] [Full Text: https://doi.org/10.1093/hmg/dds533]
Garcia-Gorostiaga, I., Sanchez-Juan, P., Mateo, I., Rodriguez-Rodriguez, E., Sanchez-Quintana, C., Curiel del Olmo, S., Vazquez-Higuera, J. L., Berciano, J., Combarros, O., Infante, J. Glycogen synthase kinase-3 and tau genes interact in Parkinson's and Alzheimer's diseases. (Letter) Ann. Neurol. 65: 759-760, 2009. [PubMed: 19557862] [Full Text: https://doi.org/10.1002/ana.21687]
Hoeflich, K. P., Luo, J., Rubie, E. A., Tsao, M.-S., Jin, O., Woodgett, J. R. Requirement for glycogen synthase kinase-3-beta in cell survival and NF-kappa-B activation. Nature 406: 86-90, 2000. [PubMed: 10894547] [Full Text: https://doi.org/10.1038/35017574]
Jiang, H., Guo, W., Liang, X., Rao, Y. Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3-beta and its upstream regulators. Cell 120: 123-135, 2005. [PubMed: 15652487] [Full Text: https://doi.org/10.1016/j.cell.2004.12.033]
Juhaszova, M., Zorov, D. B., Kim, S.-H., Pepe, S., Fu, Q., Fishbein, K. W., Ziman, B. D., Wang, S., Ytrehus, K., Antos, C. L., Olson, E. N., Sollott, S. J. Glycogen synthase kinase-3-beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J. Clin. Invest. 113: 1535-1549, 2004. [PubMed: 15173880] [Full Text: https://doi.org/10.1172/JCI19906]
Kerkela, R., Kockeritz, L., MacAulay, K., Zhou, J., Doble, B. W., Beahm, C., Greytak, S., Woulfe, K., Trivedi, C. M., Woodgett, J. R., Epstein, J. A., Force, T., Huggins, G. S. Deletion of GSK-3-beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. J. Clin. Invest. 118: 3609-3618, 2008. [PubMed: 18830417] [Full Text: https://doi.org/10.1172/JCI36245]
Khaled, M., Larribere, L., Bille, K., Aberdam, E., Ortonne, J.-P., Ballotti, R., Bertolotto, C. Glycogen synthase kinase 3-beta is activated by cAMP and plays an active role in the regulation of melanogenesis. J. Biol. Chem. 277: 33690-33697, 2002. [PubMed: 12093801] [Full Text: https://doi.org/10.1074/jbc.M202939200]
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]
Klein, S. P., Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Nat. Acad. Sci. 93: 8455-8459, 1996. [PubMed: 8710892] [Full Text: https://doi.org/10.1073/pnas.93.16.8455]
Konig, R., Stertz, S., Zhou, Y., Inoue, A., Hoffmann, H.-H., Bhattacharyya, S., Alamares, J. G., Tscherne, D. M., Ortigoza, M. B., Liang, Y., Gao, Q., Andrews, S. E., and 14 others. Human host factors required for influenza virus replication. Nature 463: 813-817, 2010. [PubMed: 20027183] [Full Text: https://doi.org/10.1038/nature08699]
Kwok, J. B. J., Hallupp, M., Loy, C. T., Chan, D. K. Y., Woo, J., Mellick, G. D., Buchanan, D. D., Silburn, P. A., Halliday, G. M., Schofield, P. R. GSK3B polymorphisms alter transcription and splicing in Parkinson's disease. Ann. Neurol. 58: 829-839, 2005. [PubMed: 16315267] [Full Text: https://doi.org/10.1002/ana.20691]
Kwok, J. B. J., Loy, C. T., Hamilton, G., Lau, E., Hallupp, M., Williams, J., Owen, M. J., Broe, G. A., Tang, N., Lam, L., Powell, J. F., Lovestone, S., Schofield, P. R. Glycogen synthase kinase-3 and tau genes interact in Alzheimer's disease. Ann. Neurol. 64: 446-454, 2008. [PubMed: 18991351] [Full Text: https://doi.org/10.1002/ana.21476]
Lau, K. F., Miller, C. C., Anderton, B. H., Shaw, P. C. Expression analysis of glycogen synthase kinase-3 in human tissues. J. Pept. Res. 54: 85-91, 1999. [PubMed: 10448973] [Full Text: https://doi.org/10.1034/j.1399-3011.1999.00083.x]
Lau, K. F., Miller, C. C., Anderton, B. H., Shaw, P. C. Molecular cloning and characterization of the human glycogen synthase kinase-3-beta promoter. Genomics 60: 121-128, 1999. [PubMed: 10486203] [Full Text: https://doi.org/10.1006/geno.1999.5875]
Liu, K. J., Arron, J. R., Stankunas, K., Crabtree, G. R., Longaker, M. T. Chemical rescue of cleft palate and midline defects in conditional GSK-3-beta mice. Nature 446: 79-82, 2007. [PubMed: 17293880] [Full Text: https://doi.org/10.1038/nature05557]
Lohi, H., Ianzano, L., Zhao, X.-C., Chan, E. M., Turnbull, J., Scherer, S. W., Ackerley, C. A., Minassian, B. A. Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum. Molec. Genet. 14: 2727-2736, 2005. [PubMed: 16115820] [Full Text: https://doi.org/10.1093/hmg/ddi306]
Lucas, J. J., Hernandez, F., Gomez-Ramos, P., Moran, M. A., Hen, R., Avila, J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3-beta conditional transgenic mice. EMBO J. 20: 27-39, 2001. [PubMed: 11226152] [Full Text: https://doi.org/10.1093/emboj/20.1.27]
Mao, Y., Ge, X., Frank, C. L., Madison, J. M., Koehler, A. N., Doud, M. K., Tassa, C., Berry, E. M., Soda, T., Singh, K. K., Biechele, T., Petryshen, T. L., Moon, R. T., Haggarty, S. J., Tsai, L.-H. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3-beta/beta-catenin signaling. Cell 136: 1017-1031, 2009. [PubMed: 19303846] [Full Text: https://doi.org/10.1016/j.cell.2008.12.044]
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]
Plyte, S. E., Hughes, K., Nikolakaki, E., Pulverer, B. J., Woodgett, J. R. Glycogen synthase kinase-3: functions in oncogenesis and development. Biochim. Biophys. Acta 1114: 147-162, 1992. [PubMed: 1333807] [Full Text: https://doi.org/10.1016/0304-419x(92)90012-n]
Shaw, P. C., Davies, A. F., Lau, K. F., Garcia-Barcelo, M., Waye, M. M., Lovestone, S., Miller, C. C., Anderton, B. H. Isolation and chromosomal mapping of human glycogen synthase kinase-3 alpha and 3 beta encoding genes. Genome 41: 720-727, 1998. [PubMed: 9809441]
Stambolic, V., Ruel, L., Woodgett, J. R. Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cells. Curr. Biol. 6: 1664-1668, 1996. Note: Erratum: Curr. Biol. 7: 196 only, 1997. [PubMed: 8994831] [Full Text: https://doi.org/10.1016/s0960-9822(02)70790-2]
Stambolic, V., Woodgett, J. R. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem. J. 303: 701-704, 1994. [PubMed: 7980435] [Full Text: https://doi.org/10.1042/bj3030701]
Stankunas, K., Bayle, J. H., Gestwicki, J. E., Lin, Y.-M., Wandless, T. J., Crabtree, G. R. Conditional protein alleles using knockin mice and a chemical inducer of dimerization. Molec. Cell 12: 1615-1624, 2003. [PubMed: 14690613] [Full Text: https://doi.org/10.1016/s1097-2765(03)00491-x]
Stumpf, A. M. Personal Communication. Baltimore, Md. 10/12/2023.
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]
Thornton, T. M., Pedraza-Alva, G., Deng, B., Wood, C. D., Aronshtam, A., Clements, J. L., Sabio, G., Davis, R. J., Matthews, D. E., Doble, B., Rincon, M. Phosphorylation by p38 MAPK as an alternative pathway for GSK3-beta inactivation. Science 320: 667-670, 2008. [PubMed: 18451303] [Full Text: https://doi.org/10.1126/science.1156037]
Trivedi, C. M., Luo, Y., Yin, Z., Zhang, M., Zhu, W., Wang, T., Floss, T., Goettlicher, M., Ruiz Noppinger, P., Wurst, W., Ferrari, V. A., Abrams, C. S., Gruber, P. J., Epstein, J. A. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3-beta activity. Nature Med. 13: 324-331, 2007. [PubMed: 17322895] [Full Text: https://doi.org/10.1038/nm1552]
Varano, G., Raffel, S., Sormani, M., Zanardi, F., Lonardi, S., Zasada, C., Perucho, L., Patrocelli, V., Haake, A., Lee, A. K., Bugatti, M., Paul, U., and 9 others. The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3-beta inhibition. Nature 546: 302-306, 2017. [PubMed: 28562582] [Full Text: https://doi.org/10.1038/nature22353]
Vincent, T., Kukalev, A., Andang, M., Pettersson, R., Percipalle, P. The glycogen synthase kinase (GSK) 3-beta represses RNA polymerase I transcription. Oncogene 27: 5254-5259, 2008. [PubMed: 18490923] [Full Text: https://doi.org/10.1038/onc.2008.152]
Wang, Q. M., Fiol, C. J., DePaoli-Roach, A. A., Roach, P. J. Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation. J. Biol. Chem. 269: 14566-14574, 1994. [PubMed: 7514173]
Yin, L., Wang, J., Klein, P. S., Lazar, M. A. Nuclear receptor Rev-erb-alpha is a critical lithium-sensitive component of the circadian clock. Science 311: 1002-1005, 2006. [PubMed: 16484495] [Full Text: https://doi.org/10.1126/science.1121613]
Yoshimura, T., Kawano, Y., Arimura, N., Kawabata, S., Kikuchi, A., Kaibuchi, K. GSK-3-beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120: 137-149, 2005. [PubMed: 15652488] [Full Text: https://doi.org/10.1016/j.cell.2004.11.012]
Zeng, X., Tamai, K., Doble, B., Li, S., Huang, H., Habas, R., Okamura, H., Woodgett, J., He, X. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438: 873-877, 2005. [PubMed: 16341017] [Full Text: https://doi.org/10.1038/nature04185]
Zhao, C., Yu, H., Fan, X., Niu, W., Fan, J., Sun, S., Gong, M., Zhao, B., Fang, Z., Chen, X. GSK3-beta palmitoylation mediated by ZDHHC4 promotes tumorigenicity of glioblastoma stem cells in temozolomide-resistant glioblastoma through the EZH2-STAT3 axis. Oncogenesis 11: 28, 2022. [PubMed: 35606353] [Full Text: https://doi.org/10.1038/s41389-022-00402-w]