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FLASH GENE
Symbol GSK3B contributors: mct - updated : 24-11-2022
HGNC name glycogen synthase kinase 3 beta
HGNC id 4617
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
conjugated PhosphoP
mono polymer monomer
HOMOLOGY
interspecies homolog to Drosophila Shaggy-Zeste-White 3
ortholog to Gsk3b, Mus musculus
ortholog to rGsk3b, Rattus norvegicus
ortholog to gsk3b, danio rerio
ortholog to GSK3B, Pan troglodytes
intraspecies homolog to GSK3A
Homologene
FAMILY
  • glycogen synthase kinase subfamily
    • CATEGORY enzyme , receptor membrane serine/threonine kinase
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • nuclear localization induced by proapoptotic signaling
  • localized at the growth cone of developing axons
    • basic FUNCTION
  • involved in energy metabolism, neuronal cell development, and body pattern formation
  • glycogen synthase kinase, dual specificity protein-kinase
  • regulating glycogen synthesis in skeletal muscle through Tyr (activating) or Ser/Thr (inactivating) phosphorylation
  • key downstream target of PI3-kinase/AKT survival signaling pathway and involved in the regulation of apoptosis
  • phosphorylating DPYSL2 and regulating neuronal polarity
  • may function as a repressor to suppress androgen receptor-mediated transactivation and cell growth
  • regulating microtubule growth and stability, phosphorylating many microtubule associated proteins such as tau, MAP1b and CRMP-2 or APC
  • playing an essential role for axon outgrowth
  • involved in the apoptotic stimulus, and thus in the process of neuronal cell death
  • involved in the regulation of the cell cycle in cerebellar granule cells
  • regulates the localization of gammaTuRC, including GCP5, to the spindle poles, thereby controlling the formation of proper mitotic spindles)
  • has a unique role in regulating death receptor-induced apoptosis, being the only enzyme known to act proximal to the four major death receptors to inhibit the initiation of apoptotic signaling by blocking CASP8 activation
  • a downstream effector of PI3K that phosphorylates proteins involved in regulating microtubule dynamics and microtubule-based transport
  • role in control neurogenesis, neuronal polarization and axon growth and guidance during brain development
  • negatively regulates the expression of the adherens junction protein CDH1, thereby influencing barrier function and inhibiting epithelial–mesenchymal transition (EMT)
  • with THRAP3, play a role in the complex network that regulates PTPRC alternative splicing
  • new role of GSK3A, GSK3B as regulators of lysosomal biogenesis which could have important consequences in neurodegenerative diseases, such as AD
  • regulates NFE2L1 expression and cell survival function in response to stress activation
  • GSK3A, GSK3B were regulated independently, but that they acted on the same physiological functions in learning and memory, in mobility and in behavior
  • GSK3B, but not GSK3A, negatively controls the neuronal differentiation of progenitor cells and GSK3B may act downstream of the mammalian target of rapamycin complex1 signaling pathway
  • both GSK3B-dependent phosphorylation and the level of CLASP2 play a role in the maintenance of CHRNA1 cluster size through the regulated capture and release of Microtubule plus-ends
  • unique cascade consisting of GSK3B, DZIP1, and RAB8A that regulates ciliogenesis after mitosis
  • cardiac myocyte GSK3A, GSK3B3 is required to maintain normal cardiac homeostasis, and its loss is incompatible with life because of cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy
    • CELLULAR PROCESS cell life, cell death/apoptosis
    nucleotide, RNA splicing
    PHYSIOLOGICAL PROCESS development , neurogenesis
    text key regulatory enzyme in glucose metabolism
    PATHWAY
    metabolism carbohydrate , energetic
    signaling signal transduction
  • key component of the wingless signaling pathway
  • autophagy-activating pathway that comprises GSK3A, GSK3B, KAT5, and ULK1
  • novel GSK3A, GSK3B/DPYSL2 pathway that connects neuronal activity to dendritic growth
  • BRD7/GSK3B/NFE2L2 axis may play a key role in mediating podocyte injury in diabetic nephropathy
    • a component
  • inhibitory components
  • part of antiapoptotic protein complex associated with death receptors that contains DDX3X and cellular inhibitor of apoptosis protein-1 (BIRC2)
  • STRAP, GSK3B and Axin form a ternary complex
  • part of functional molecular complex formed by STYK1, AKT1 and GSK3B that may relay a STYK1-directed tumourigenic cascade
  • GSK3B-SKAP-KIF2B signaling axis constitutes a dynamic link between spindle microtubule plus-ends and mitotic chromosomes to achieve faithful cell division
    • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
    • protein
  • APC-beta-catenin complex
  • facilitating NFKB activation
  • PTK2B protein tyrosine kinase 2 beta (PTK2B)
  • v-akt murine thymoma viral oncogene homolog 1 (AKT1) (AKT1/GSK3B signaling required for axons elongation and branching )
  • phosphorylates tau protein
  • tubulin polymerization promoting protein (TPPP)
  • phosphorylated by AKT1 and ILK1
  • ninein (NIN) (phosphorylating NIN)
  • calcium binding tyrosine-(Y)-phosphorylation regulated (CABYR)
  • mucin 1, cell surface associated (MUC1)
  • prune homolog (Drosophila) (PRUNE)
  • NF-kappaB
  • A kinase (PRKA) anchor protein 11 (AKAP11)
  • human dynamin-like protein IV (HdynIV)
  • Axin and requently rearranged in advanced T-cell lymphomas 1 and 2 (Frat1, Frat2)
  • DF3/MUC1 carcinoma-associated antigen and beta-catenin
  • modulates Notch1 signaling
  • binds and phosphorylates Notch2
  • p53 after DNA damage
  • E2F transcription factor 1 (E2F1)
  • SMAD family member 3 (SMAD3)
  • FRAT2 significantly increased GSK3B-mediated phosphorylation of MAPT at a primed epitope while not significantly affecting the phosphorylation of unprimed sites
  • snail homolog 1 (Drosophila), SNAI1
  • Bicaudal-D, BICD
  • interacting with HK2 (mitochondrial HK2 is a promoter of neuronal survival under the regulation of GSK3B)
  • interacting with MAP3K11 (cell death induced by GSK3B was mediated by MAP3K11 in a manner dependent on its phosphorylation of the specific residues within the C-terminal domain by GSK3B)
  • interacting with HSPH1 and HSPA5, a key component of the unfolded protein response (promotes ER stress-induced caspase-3 activation)
  • interacts with and phosphorylates the spindle-associated protein SPAG5, resulting in targeting SPAG5 to the spindle microtubules and kinetochores
  • Disrupted in Schizophrenia 1, DISC1
  • interacting with TJP2 (TJP2 overexpression results in changes in GSK3B phosphorylation and apoptosis-related gene expression and these changes increase the susceptibility of inner ear cells to apoptosis)
  • controlling expression of the AJC (Apical Junctional Complex) proteins OCLN, CLDN1 and CDH1 as well as regulation of downstream signaling events essential for maintaining epithelial barrier and homeostatic functions
  • is a key physiological substrate of GSK3B in regulating chromosomal alignment and mitotic progression through its effect on spindle microtubule
  • important role of PGRN in neurite outgrowth and involvement of GSK3B in mediating PGRN activity
  • GSK3B is a crucial regulator of RELB degradation, stressing the relevant linkage between the NFKB system and GSK3B
  • binding of GSK3B with a novel scaffold protein, STRAP, through its WD40 domains
  • KITLG and TLR4 ligand cooperated to induce phosphorylation of GSK3B at Tyr216 by simultaneous activation of ERK and MAPK14 pathways
  • LMTK2 regulates a known pathway that controls phosphorylation of kinesin-1 light chain-2 (KLC2) by glycogen synthase kinase-3&
    • 946; (GSK3B)
  • GSK3B activity regulates mitochondrial axonal trafficking largely in a MAPT-dependent manner
  • DNAJB6 binds HSPA8 and causes dephosphorylation of GSK3B at Ser 9 by recruiting protein phosphatase, PPP2CA
  • EIF2AK2 positively regulates the differentiation of osteoblasts by mediating GSK3B activity through a CTNNB1-independent pathway
  • redundant functions of GSK3A and GSK3B through phosphorylation of RELA at Thr-254 play a crucial role in early stages of chondrocyte differentiation
  • GSK3B regulates NR3C1 response by genomic and nongenomic mechanisms
  • GSK3B can inhibit PPP2CA by increasing the inhibitory L309-demethylation involving upregulation of PPME1 and inhibition of LCMT1
  • NUB1 interacted with both MAPT and GSK3B to disrupt their interaction, and abolished recruitment of GSK3B to MAPT inclusions
  • directly phosphorylates KLF6, which augments its induction of CDKN1A and resultant growth suppression)
  • PRKCA and AKT1 modulate platelet function by phosphorylating and inhibiting GSK3A/GSK3B, thereby relieving the negative effect of GSK3A/GSK3B on thrombin-mediated platelet activation
  • GSK3B interacts with NFE2L1 and phosphorylates the CDC4 phosphodegron domain (CPD) in NFE2L1
  • FBXW7 together with GSK3B negatively regulates CSF3R expression and its downstream signaling
  • interaction of GSK3B and its priming kinase DYRK2 regulate the activity of EIF2B in cardiac myocytes
  • phosphorylation and activation of SRF by GSK3B is critical for SRF-dependent axon growth in mammalian central neurons)
  • TARDBP leads to activation of GSK3B and GSK3B regulates the VAPB-RMDN3 interaction
  • ALDOC, ALDOA and ALDOB activate Wnt signaling in a GSK3B-dependent mechanism
  • PCDH9 is a novel regulator of EMT by increasing the activity of GSK3B and inhibiting SNAI1
  • MACF1 interacts with and mediates GSK3B signaling in developing neurons
  • GSK3B is important for stabilizing and/or controlling the expression of functional SLC6A5, SLC6A9 on the neural cell surface
  • transport system, organized by AGRN through PI3 kinase, GSK3B, CLASP2, and PHLDB2, for precise delivery of CHRNA1 vesicles from the subsynaptic nuclei to the overlying synaptic membrane
  • molecular mechanism by which glucose deprivation can induce the GSK3B-independent protein degradation of CTNNB1, leading to autophagy
  • GSK3B regulates the sorting of GPHN and NLGN2 complexes in a KIF5A-dependent manner
  • ZNRF1 promotes Wallerian degeneration by degrading AKT1 to induce GSK3B activation
  • GIMAP5 is essential for the inactivation of GSK3B following T cell activation
  • STIP1 acts as a scaffold promoting the interaction between KDM1A and GSK3B
  • BCL2L14, PIEZO2,HOXB8, KIF18A, DLK1, TNFSF14, CASQ2 genes may play an important role in the GSK3B-mediated osteoblast apoptosis process
  • PIWIL2 suppressed GSK3B induced phosphorylation and ubiquitination of CTNNB1, and thus increased CTNNB1 accumulation in the nucleus
  • MCL1 stability is regulated by the kinase GSK3B and the E3 ubiquitin ligase HUWE1 in regulating AMBRA1-mediated mitophagy
  • phosphorylation of USP27X by GSK3B maintains the stability and oncogenic functions of CBX2
    • cell & other
    REGULATION
    activated by tyrosine phosphorylation
    inhibited by NTF3
    AKT1 phosphorylation
    P24
    lithium
    repressed by protein kinase A
    Other regulated by wnt signaling pathway and by insulin
    may be regulated by multiple mechanisms and its basal activity subjected to activation or inhibition
    regulated by focal adhesion kinase (FAK)
    regulated by tyrosine and serine/threonine phosphorylation
    phosphorylated by serum and glucocorticoid-inducible kinase-like kinase (SGKL)
    NUB1 regulation of GSK3B could modulate numerous signalling pathways in which GSK3B is a centrally important effector
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in Alzeihmer's disease and might be a useful diagnostic marker
    constitutional       loss of function
    enhances the differentiation and reduces the proliferation of adult olfactory epithelium neural precursors
    Susceptibility
    Variant & Polymorphism SNP
  • single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression and influences onset of illness in patients affected by bipolar disorder
  • association between Glycogen Synthase Kinase-3beta genetic polymorphism and Late-Onset Alzheimer's Disease
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerative 
    modulating GSK3B or similar signaling events may provide therapeutic benefits for FTDU17 (with GRN mutations)
    miscelleaneousurinarychronic kidney disease
    GSK3B−SNAI1 axis may be a suitable target for the treatment of chronic kidney diseases
    cancer  
    targeting GSK3B and DDX3X may be a useful strategy for promoting death receptor-induced apoptosis
    neurologyneurodegenerativealzheimer
    use of inhibitors of this kinase for therapies in AD and related dementias are already available
    ANIMAL & CELL MODELS
  • overexpression of Gsk3b in conditional transgenic mice results in hyperphosphorylation of tau and neurodegeneration
  • Gsk3b-deficient mice embryos show severe liver degeneration, a phenotype consistent with excessive tummor nercrosis factor
  • Xenopus dominant negative mutants induced dorsal differentiation
  • alterations of GSK3 profoundly affect neuronal morphology in culture
  • knockdown of both GSK3B markedly reduced axon growth in dissociated cultures
  • Homozygous null mice display cleft palate, incomplete fusion of the ribs at the midline and bifid sternum as well as delayed sternal ossification
  • Gsk3b knockin mice (Tph2) show a markedly reduced brain serotonin (5-HT) neurotransmission production and behavioral abnormalities in tests assessing 5-HT-mediated emotional states
  • Gsk3b-/- mice exhibit hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation
  • concomitant loss of Gsk3a and Gsk3b in the oocyte significantly increased neonatal death rate due to congestive heart failur