GSK3A

Description

The GSK3A (glycogen synthase kinase 3 alpha) is a protein-coding gene located on chromosome 19.

Glycogen synthase kinase-3 alpha is an enzyme that in humans is encoded by the GSK3A gene. Glycogen synthase kinase 3-alpha EC 2.7.1.37 is a multifunctional protein serine kinase, homologous to Drosophila 'shaggy' (zeste-white3) and implicated in the control of several regulatory proteins including glycogen synthase and various transcription factors (e.g., JUN). It also plays a role in the WNT and phosphoinositide 3-kinase (especially PIK3CG) signaling pathways.

GSK3A is a constitutively active protein kinase that acts as a negative regulator in several cellular processes, including glucose homeostasis, Wnt signaling, and regulation of transcription factors and microtubules. It achieves this by phosphorylating and inactivating key proteins involved in these pathways, such as glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC, and AXIN1. GSK3A requires primed phosphorylation of most of its substrates for optimal activity. It plays a significant role in insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity, thereby reducing glycogen synthesis. While regulating glycogen metabolism in the liver, it does not affect muscle metabolism. GSK3A might also contribute to the development of insulin resistance by regulating the activation of transcription factors. In the context of Wnt signaling, GSK3A controls the levels and transcriptional activity of nuclear CTNNB1/beta-catenin. Furthermore, it facilitates the processing of amyloid precursor protein (APP), contributing to the formation of APP-derived amyloid plaques associated with Alzheimer's disease. It might be involved in regulating replication in pancreatic beta-cells and is crucial for establishing neuronal polarity and axon outgrowth. GSK3A regulates cell apoptosis by phosphorylating the anti-apoptotic protein MCL1 in response to growth factor deprivation. It functions as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, which activates KAT5/TIP60 acetyltransferase activity and promotes acetylation of key autophagy regulators such as ULK1 and RUBCNL/Pacer. GSK3A negatively regulates extrinsic apoptotic signaling pathways via death domain receptors, promoting 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 but can be overcome by stronger stimulation. GSK3A phosphorylates the mTORC2 complex component RICTOR at Thr-1695, facilitating FBXW7-mediated ubiquitination and subsequent degradation of RICTOR.

GSK3A is also known as -.

Associated Diseases

WES Whole Exome Sequencing