GSK-3

Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase, GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways. In mammals GSK-3 is encoded by two paralogous genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B). GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimer's Disease, inflammation, cancer, and bipolar disorder.IC50=4-80nM: Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase, GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways. In mammals GSK-3 is encoded by two paralogous genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B). GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimer's Disease, inflammation, cancer, and bipolar disorder. As of 2019, GSK-3 is the only type of glycogen synthase kinase named and recognized. The gene symbols for GSK1 and GSK2 has been withdrawn by the HUGO Gene Nomenclature Committee, and no new names for these 'genes' nor their locations have been specified. GSK-3 functions by phosphorylating a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a 'priming' phosphate group attached to a serine or threonine four residues C-terminal of the target phosphorylation site. The active site, at residues 181, 200, 97, and 85, binds the terminal phosphate of ATP and transfers it to the target location on the substrate (see figure 1). Phosphorylation of a protein by GSK-3 usually inhibits the activity of its downstream target. GSK-3 is active in a number of central intracellular signaling pathways, including cellular proliferation, migration, glucose regulation, and apoptosis. GSK-3 was originally discovered in the context of its involvement in regulating glycogen synthase. After being primed by casein kinase 2 (CK2), glycogen synthase gets phosphorylated at a cluster of three C-terminal serine residues, reducing its activity. In addition to its role in regulating glycogen synthase, GSK-3 has been implicated in other aspects of glucose homeostasis, including the phosphorylation of insulin receptor IRS1 and of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose 6 phosphatase. However, these interactions have not been confirmed, as these pathways can be inhibited without the up-regulation of GSK-3. GSK-3 has also been shown to regulate immune and migratory processes. GSK-3 participates in a number of signaling pathways in the innate immune response, including pro-inflammatory cytokine and interleukin production. The inactivation of GSK3B by various protein kinases also affects the adaptive immune response by inducing cytokine production and proliferation in naïve and memory CD4+ T cells. In cellular migration, an integral aspect of inflammatory responses, the inhibition of GSK-3 has been reported to play conflicting roles, as local inhibition at growth cones has been shown to promote motility while global inhibition of cellular GSK-3 has been shown to inhibit cell spreading and migration. GSK-3 is also integrally tied to pathways of cell proliferation and apoptosis. GSK-3 has been shown to phosphorylate Beta-catenin, thus targeting it for degradation. GSK-3 is therefore a part of the canonical Beta-catenin/Wnt pathway, which signals the cell to divide and proliferate. GSK-3 also participates in a number of apoptotic signaling pathways by phosphorylating transcription factors that regulate apoptosis. GSK-3 can promote apoptosis by both activating pro-apoptotic factors such as p53 and inactivating survival-promoting factors through phosphorylation. The role of GSK-3 in regulating apoptosis is controversial, however, as some studies have shown that GSK-3β knockout mice are overly sensitized to apoptosis and die in the embryonic stage, while others have shown that overexpression of GSK-3 can induce apoptosis. Overall, GSK-3 appears to both promote and inhibit apoptosis, and this regulation varies depending on the specific molecular and cellular context.