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.

Keywords: Alzheimer's disease; Depression; G protein-coupled receptors; Glycogen synthase kinase-3; Lithium; Neuroinflammation.

Figure 1. Serine9-phosphorylation of GSK3β inhibits its phosphorylation of primed substrates

(A) Representation of GSK3β based on a recently reported crystal structure (Stamos et al., 2014) showing the adjacent kinase domain and primed-substrate binding domain (based on PDB ID: 4nm0). (B) Phosphorylated serine-9 in the N-terminal tail of GSK3β binds the primed substrate binding domain (based on PDB ID: 4nm3). (C) Primed substrates first associate with the primed substrate binding domain of GSK3β, which places a Ser/Thr four residues N-terminal to the primed phosphorylated Ser/Thr adjacent to the kinase domain of GSK3β to facilitate substrate phosphorylation. (D) Phosphorylated serine-9 in the N-terminal tail of GSK3β inhibits the association of primed substrates with the primed substrate binding domain of GSK3β.

Figure 2. The Axin-β-catenin destruction complex

A simplified scheme is shown of the preassembled complex of Axin, Adenomatous Polyposis Coli (APC), casein kinase 1 (CK1), GSK3β, and β-catenin, which allows GSK3 to phosphorylate β-catenin sequentially on residues 41, 37, and 33. Phosphorylation leads to the release of β-catenin from the complex and targets it for proteasomal degradation. Activation of Wnt signaling disrupts the complex (not shown), blocking phosphorylation of β-catenin by GSK3, resulting in β-catenin stabilization (MacDonald et al., 2009; Valvezan and Klein, 2012; Willert and Nusse, 2012).

Figure 3. Axin associates with several GSK3 substrates

Axin binds to several GSK3 substrates to facilitate their phosphorylation, such as (A) Smad3, (B) tuberous sclerosis complex-1 (TSC1), and (C) TSC2. (D) The GSK3 substrate Tip60 also binds to Axin, which may facilitate its phosphorylation by GSK3 that activates Tip60. Tip60-mediated regulation of p53 is also modulated by Axin-bound HIPK2 (homeodomain-interacting protein kinase 2), raising the hypothetical possibility depicted here of a multi-protein complex that regulates both Tip60 and p53. (A-D) It is not known if these GSK3 substrates compete with β-catenin to bind the same domain of Axin, or if distinct binding sites on Axin exist for each substrate. Binding of all substrates to the same region of Axin is depicted here because this places the substrates adjacent to GSK3 for phosphorylation.

Figure 4. GSK3 interactions with G protein-coupled receptor-induced signaling mechanisms

Dopaminergic D2 receptor activation induces the association of β-arrestin, Akt, GSK3, and protein phosphatase 2A (PP2A). This facilitates PP2A-mediated dephosphorylation of Akt and GSK3, deactivating Akt and activating GSK3. GSK3 facilitates the formation of this complex, providing a mechanism for GSK3 to induce its own activation. Self-activation by GSK3 is also exemplified by its phosphorylation of the protein phosphatase 1 (PP1) inhibitor I-2, resulting in increased PP1 activity, which dephosphorylates the inhibitory serine-phosphorylation of GSK3 to increase GSK3 activity. Serotonin (5HT) 2A receptor activation reduces serine-phosphorylation of GSK3, thereby increasing its activity. 5HT1A and cholinergic muscarinic receptor activation increase the inhibitory serine-phosphorylation of GSK3. GSK3 promotes 5HT1B receptor-mediated activation of the heterotrimeric G protein, Gi, which inhibits cyclic AMP production.