Glycogen synthase kinase 3: more than a namesake

Abstract

Glycogen synthase kinase 3 (GSK3), a constitutively acting multi-functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. These diverse multiple functions attributed to GSK3 can be explained by variety of substrates like glycogen synthase, tau protein and beta catenin that are phosphorylated leading to their inactivation. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti-diabetic but do not lead to up-regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti-diabetic therapeutic target.

Figure 2

Schematic illustration of role of GSK3 in Wnt signalling. In the unstimulated cells β catenin is present in a multi-protein complex with GSK3, Axin and APC. Phosphorylation of β catenin by GSK3 targets β catenin to proteosome-mediated degradation. In stimulated cells binding of Wnt to its receptor Frizzled and its co-receptor LRP5/6 leads to activation of Dishevelled (Dvl) leading to inhibition of phosphorylation of β catenin by the multimeric complex and its stabilization and accumulation in the cytosol. Stabilized β catenin translocates to the nucleus and in association with transcription factors LEF/TCF leads to increase in gene expression of target genes such as c-myc. APC, adenomatous polyposis coli; GSK3, glycogen synthase kinase 3; LEF/TCF, lymphoid enhancer factor/T cell factor; LRP, LDL receptor related protein.

Figure 1

Schematic representation of insulin-signalling events and role of GSK3. Binding of insulin to its receptor leads to autophosphorylation, followed by binding of IRS that is phosphorylated leading to activation of PI3 kinase and Akt/PKB that phosphorylates GSK3. Inactive phosphorylated GSK3 relieves glycogen synthase inhibition and eIF2B phosphorylation, leading to active form of GS and eIF2B, which leads to increase in glycogen and protein synthesis. eIF2B, eukaryotic initiation factor 2B; GS, glycogen synthase; GSK3, glycogen synthase kinase 3; IRS, insulin receptor substrates; PKB, protein kinase B.