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

Abstract

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.

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

“…It is a critical downstream element of the PI3K/AKT pathway, and phosphorylation of GSK3b by AKT promotes cell growth and survival; hence, its dysregulation has been implicated in tumorigenesis. However, the role of GSK3b in tumorigenesis and cancer progression remains controversial; it either promotes or inhibits tumor growth in different tumor models (33). Our results suggest that an inactive GSK3b that is phosphorylated at serine 9 is important for tumor cell survival (Fig.…”

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

“…GSK3 is the first identified Akt substrate and refers to two isoforms, GSK3α and GSK3β. GSK3α is mainly involved in the process of glycogen synthesis, whereas GSK3β exhibits more complex biological functions (Beurel et al 2015). The inactivation of GSK3α induces the activation of glycogen synthase (GS).…”

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior

“…In both the periphery and the CNS, TLR4 signaling depends on active glycogen synthase kinase-3 (GSK3), a kinase linked to depression (Beurel, 2011;Beurel et al, 2015). GSK3 inhibition reduced the production of pro-inflammatory cytokines after TLR4 stimulation in human monocytes (Martin et al 2005) and in mouse microglia (Yuskaitis et al 2009) and astrocytes (Beurel et al 2009).…”