GSK3B

Description

The GSK3B (glycogen synthase kinase 3 beta) is a protein-coding gene located on chromosome 3.

Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the GSK3B gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased susceptibility towards bipolar disorder.

== Function == Glycogen synthase kinase-3 (GSK-3) is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and an inactivating agent of glycogen synthase. Two isoforms, alpha (GSK3A) and beta, show a high degree of amino acid homology. GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation. It might be a new therapeutic target for ischemic stroke.

== Disease relevance == Homozygous disruption of the Gsk3b locus in mice results in embryonic lethality during mid-gestation. This lethality phenotype could be rescued by inhibition of tumor necrosis factor. Two SNPs at this gene, rs334558 (-50T/C) and rs3755557 (-1727A/T), are associated with efficacy of lithium treatment in bipolar disorder.

GSK3B is a constitutively active protein kinase that acts as a negative regulator in various cellular processes, including glucose homeostasis, Wnt signaling, and regulation of transcription factors and microtubules. It achieves this by phosphorylating and inactivating a wide range of substrates, including glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU, and MACF1. The majority of its substrates require primed phosphorylation for GSK3B to act upon them. In skeletal muscle, GSK3B plays a role in insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity, thereby reducing glycogen synthesis. It may also contribute to the development of insulin resistance by regulating the activation of transcription factors. GSK3B regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in a similar manner to glycogen synthase. In Wnt signaling, GSK3B forms a complex with APC, AXIN1, and CTNNB1/beta-catenin, phosphorylating the N-terminus of CTNNB1, which leads to its degradation via the ubiquitin/proteasome system. GSK3B also phosphorylates JUN near its DNA-binding domain, decreasing its affinity for DNA. It phosphorylates NFATC1/NFATC on conserved serine residues, promoting NFATC1/NFATC nuclear export and inhibiting its gene regulation, effectively opposing the action of calcineurin. GSK3B phosphorylates MAPT/TAU on 'Thr-548', significantly reducing its ability to bind and stabilize microtubules. MAPT/TAU is a key component of neurofibrillary tangles found in Alzheimer's disease. GSK3B plays a crucial role in ERBB2-dependent stabilization of microtubules at the cell cortex. It phosphorylates MACF1, inhibiting its binding to microtubules, which is vital for its function in bulge stem cell migration and skin wound repair. GSK3B likely 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). GSK3B negatively regulates replication in pancreatic beta-cells, leading to apoptosis, loss of beta-cells, and diabetes. By phosphorylating the anti-apoptotic protein MCL1, GSK3B may control cell apoptosis in response to growth factor deprivation. GSK3B phosphorylates MUC1 in breast cancer cells, decreasing its interaction with CTNNB1/beta-catenin. It is essential for establishing neuronal polarity and axon outgrowth. GSK3B phosphorylates MARK2, inhibiting its activity. It phosphorylates SIK1 at 'Thr-182', sustaining its activity. GSK3B phosphorylates ZC3HAV1, enhancing its antiviral activity. It phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation. GSK3B phosphorylates SFPQ at 'Thr-687' upon T-cell activation. It phosphorylates NR1D1 at 'Ser-55' and 'Ser-59', stabilizing it by protecting it from proteasomal degradation. GSK3B regulates the circadian clock by phosphorylating key clock components, including BMAL1, CLOCK, and PER2. It phosphorylates FBXL2 at 'Thr-404', priming it for ubiquitination by the SCF(FBXO3) complex and proteasomal degradation. GSK3B phosphorylates CLOCK at 'Ser-427', targeting it for proteasomal degradation. It phosphorylates BMAL1 at 'Ser-17' and 'Ser-21', priming it for ubiquitination and proteasomal degradation. GSK3B phosphorylates OGT at 'Ser-3' or 'Ser-4', positively regulating its activity. It phosphorylates MYCN in neuroblastoma cells, potentially promoting its degradation. GSK3B regulates the circadian rhythmicity of hippocampal long-term potentiation and BMAL1 and PER2 expression. It acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. GSK3B negatively regulates the extrinsic apoptotic signaling pathway via death domain receptors. It promotes the formation of an anti-apoptotic complex, composed of DDX3X, BRIC2, and GSK3B, at death receptors, including TNFRSF10B. This anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation. GSK3B phosphorylates E2F1, promoting its interaction with USP11, stabilizing E2F1, and enhancing its activity. It phosphorylates the mTORC2 complex component RICTOR at 'Thr-1695', facilitating FBXW7-mediated ubiquitination and subsequent degradation of RICTOR. GSK3B phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4) complex and FXR1 degradation by the proteasome. It phosphorylates interleukin-22 receptor subunit IL22RA1, preventing its proteasomal degradation. GSK3B exists as a monomer and interacts with various proteins, including ARRB2, DISC1, ZBED3, CABYR, MMP2, MUC1, NIN, PRUNE1, AXIN1, SNAI1, DNM1L, MACF1, SGK3, DAB2IP, PPP2CA, CLOCK-BMAL1 heterodimer, BMAL1, CTNND2, NCYM, JPT1, PRKAR2A, PRKAR2B, GSKIP, GID8, PIWIL2, LMBR1L, DDX3X, BIRC2, TNFRSF10B, RICTOR, SLC39A6, SLC39A10, and PKP3.

GSK3B is also known as -.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing