Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases

By Eléonore Beurel, S. Grieco, R. Jope. Pharmacology and Therapeutics, 2014

1,586 citations recorded by the source corpus.

Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0e8e44b4a3b278f024dd1be8aa55de23a0958e1d

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Citations in the corpus

• Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “Moreover, use of tau kinase inhibitors such as the GSK-3 inhibitor Tideglusib to attenuate pathological tau hyperphosphorylation also showed little or no efficacy in Phase 2 trials, probably due to the critical role of GSK-3 in multifunctional signaling pathways [650, 651].”
• Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies (2024, background): “493,494 For example, compound 34 demonstrated these bene fi ts. 495 As the role of GSK-3 α in promoting A β production and tau phosphorylation in AD models is recognized, selective inhibition of GSK-3 α has emerged as a promising therapeutic strategy.”