GSK3

Glycogen synthase kinase 3 (GSK-3) refers to two closely related serine/threonine kinases, GSK-3 alpha and GSK-3 beta, encoded by GSK3A and GSK3B. They are widely expressed in tissues and share a common catalytic core, but differ in regulation and tissue distribution. In humans, GSK-3 alpha and GSK-3 beta are found on chromosomes 3p24.1 and 4q27, respectively.

GSK-3 is unusual among kinases in that it is constitutively active in many cells and is primarily controlled by inhibitory phosphorylation. Insulin and other growth factors activate the PI3K-Akt pathway, which inhibits GSK-3 by phosphorylating Ser21 (GSK-3 alpha) or Ser9 (GSK-3 beta). Tyrosine phosphorylation at Tyr279 (alpha) and Tyr216 (beta) enhances activity. GSK-3 phosphorylates a broad set of substrates, including glycogen synthase, beta-catenin, tau, and various transcription factors, and it often acts to mark proteins for degradation or alter their activity.

In signaling networks, GSK-3 plays a central role in the Wnt pathway. In the absence of Wnt signaling, GSK-3 participates in a destruction complex that phosphorylates beta-catenin, promoting its degradation. Wnt signaling inhibits GSK-3 activity, leading to stabilization and nuclear translocation of beta-catenin and transcription of target genes.

Physiological roles for GSK-3 span metabolism, development, and neuronal function, including synaptic plasticity and neuroprotection. Dysregulation has been implicated in conditions such as diabetes, cancer, and neurodegenerative diseases, notably Alzheimer's disease due to tau phosphorylation.

GSK-3 inhibitors have been studied for therapeutic potential. Lithium is a mood stabilizer that inhibits GSK-3 among other targets. Others include small-molecule inhibitors such as CHIR99021, AR-A014418, Tideglusib, and Kenpaullone, used in research and, in some cases, clinical contexts.