GSK3B

The protein encoded by this gene is a serine-threonine kinase belonging to the glycogen synthase kinase subfamily. It is a negative regulator of glucose homeostasis and is involved in energy metabolism, inflammation, ER-stress, mitochondrial dysfunction, and apoptotic pathways. Defects in this gene have been associated with Parkinson disease and Alzheimer disease.

Glycogen Synthase Kinase 3 Beta

Glycogen Synthase Kinase 3 Beta; EC 2.7.11.26; Serine/Threonine-Protein Kinase GSK3B; EC 2.7.11.1; GSK-3 Beta; EC 2.7.11;

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), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1 (PubMed:1846781, PubMed:9072970, PubMed:14690523, PubMed:20937854, PubMed:12554650, PubMed:11430833, PubMed:16484495).

Requires primed phosphorylation of the majority of its substrates (PubMed:11430833, PubMed:16484495).

In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:8397507).

May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:8397507).

Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase (PubMed:8397507).

In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes (PubMed:12554650).

Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA (PubMed:1846781).

Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin (PubMed:9072970).

Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules (PubMed:14690523).

MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease (PubMed:14690523).

Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854).

Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair (By similarity).

Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA) (By similarity).

Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (By similarity).

Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity).

Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin (PubMed:9819408).

Is necessary for the establishment of neuronal polarity and axon outgrowth (PubMed:20067585).

Phosphorylates MARK2, leading to inhibit its activity (By similarity).

Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity (PubMed:18348280).

Phosphorylates ZC3HAV1 which enhances its antiviral activity (PubMed:22514281).

Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation (PubMed:15448698, PubMed:15647282).

Phosphorylates SFPQ at 'Thr-687' upon T-cell activation (PubMed:20932480).

Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391).

Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (PubMed:19946213).

Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:28903391).

Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509).

Regulates the circadian rhythmicity of hippocampal long-term potentiation and ARNTL/BMLA1 and PER2 expression (By similarity).

Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, leading to activate KAT5/TIP60 acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899).

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 (PubMed:18846110).

Phosphorylates E2F1, promoting the interaction between E2F1 and USP11, leading to stabilize E2F1 and promote its activity (PubMed:17050006, PubMed:28992046).

Beta-catenin destruction complex disassembly Source: ComplexPortal
Cellular response to amyloid-beta Source: ARUK-UCL
Cellular response to interleukin-3 Source: UniProtKB
Cellular response to retinoic acid Source: ARUK-UCL
Circadian rhythm Source: UniProtKB
Dopamine receptor signaling pathway Source: ParkinsonsUK-UCL
Epithelial to mesenchymal transition Source: UniProtKB
ER overload response Source: MGI
Establishment of cell polarity Source: ARUK-UCL
Excitatory postsynaptic potential Source: ParkinsonsUK-UCL
Extrinsic apoptotic signaling pathway Source: ARUK-UCL
Extrinsic apoptotic signaling pathway in absence of ligand Source: UniProtKB
Glycogen metabolic process Source: BHF-UCL
Hippocampus development Source: BHF-UCL
Insulin receptor signaling pathway Source: GO_Central
Intracellular signal transduction Source: MGI
Maintenance of cell polarity Source: ARUK-UCL
Negative regulation of apoptotic process Source: MGI
Negative regulation of calcineurin-NFAT signaling cascade Source: UniProtKB
Negative regulation of canonical Wnt signaling pathway Source: ARUK-UCL
Negative regulation of canonical Wnt signaling pathway involved in osteoblast differentiation Source: ARUK-UCL
Negative regulation of dopaminergic neuron differentiation Source: ParkinsonsUK-UCL
Negative regulation of extrinsic apoptotic signaling pathway via death domain receptors Source: UniProtKB
Negative regulation of gene expression Source: ARUK-UCL
Negative regulation of glycogen (starch) synthase activity Source: UniProtKB
Negative regulation of glycogen biosynthetic process Source: UniProtKB
Negative regulation of mesenchymal stem cell differentiation Source: ARUK-UCL
Negative regulation of neuron death Source: UniProtKB
Negative regulation of phosphoprotein phosphatase activity Source: ARUK-UCL
Negative regulation of protein acetylation Source: ARUK-UCL
Negative regulation of protein binding Source: BHF-UCL
Negative regulation of protein-containing complex assembly Source: BHF-UCL
Negative regulation of protein localization to nucleus Source: BHF-UCL
Negative regulation of type B pancreatic cell development Source: UniProtKB
Neuron projection development Source: UniProtKB
Neuron projection organization Source: ARUK-UCL
Peptidyl-serine phosphorylation Source: ParkinsonsUK-UCL
Peptidyl-threonine phosphorylation Source: ParkinsonsUK-UCL
Positive regulation of autophagy Source: UniProtKB
Positive regulation of cell differentiation Source: ARUK-UCL
Positive regulation of cell-matrix adhesion Source: BHF-UCL
Positive regulation of cilium assembly Source: UniProtKB
Positive regulation of gene expression Source: ARUK-UCL
Positive regulation of GTPase activity Source: BHF-UCL
Positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway Source: UniProtKB
Positive regulation of mitochondrion organization Source: ParkinsonsUK-UCL
Positive regulation of neuron death Source: ParkinsonsUK-UCL
Positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: FlyBase
Positive regulation of protein binding Source: UniProtKB
Positive regulation of protein catabolic process Source: BHF-UCL
Positive regulation of protein-containing complex assembly Source: BHF-UCL
Positive regulation of protein export from nucleus Source: MGI
Positive regulation of protein localization to centrosome Source: ARUK-UCL
Positive regulation of protein localization to cilium Source: UniProtKB
Protein autophosphorylation Source: UniProtKB
Protein phosphorylation Source: UniProtKB
Regulation of axon extension Source: ARUK-UCL
Regulation of axonogenesis Source: ARUK-UCL
Regulation of cellular response to heat Source: Reactome
Regulation of circadian rhythm Source: UniProtKB
Regulation of dendrite morphogenesis Source: ARUK-UCL
Regulation of long-term synaptic potentiation Source: UniProtKB
Regulation of microtubule anchoring at centrosome Source: ARUK-UCL
Regulation of microtubule-based process Source: UniProtKB
Regulation of microtubule cytoskeleton organization Source: ARUK-UCL
Regulation of neuron projection development Source: GO_Central
Regulation of protein export from nucleus Source: ComplexPortal
Regulation of synaptic vesicle exocytosis Source: SynGO
Signal transduction Source: GO_Central
Superior temporal gyrus development Source: BHF-UCL
Viral protein processing Source: Reactome

Cytoplasm; Cell membrane; Nucleus. The phosphorylated form shows localization to cytoplasm and cell membrane (PubMed:20937854). The MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the phosphorylated form to the cell membrane (PubMed:20937854).

Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216 (PubMed:25169422). Inactivated by phosphorylation at Ser-9 (Probable). Phosphorylated in a circadian manner in the hippocampus (By similarity).
Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity.