Abstract
Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded in mammals by two genes that generate two related proteins: GSK-3α and GSK-3β. GSK-3 is active in cells under resting conditions and is primarily regulated through inhibition or diversion of its activity. While GSK-3 is one of the few protein kinases that can be inactivated by phosphorylation, the mechanisms of GSK-3 regulation are more varied and not fully understood. Precise control appears to be achieved by a combination of phosphorylation, localization, and sequestration by a number of GSK-3-binding proteins. GSK-3 lies downstream of several major signaling pathways including the phosphatidylinositol 3′ kinase pathway, the Wnt pathway, Hedgehog signaling and Notch. Specific pools of GSK-3, which differ in intracellular localization, binding partner affinity, and relative amount are differentially sensitized to several distinct signaling pathways and these sequestration mechanisms contribute to pathway insulation and signal specificity. Dysregulation of signaling pathways involving GSK-3 is associated with the pathogenesis of numerous neurological and psychiatric disorders and there are data suggesting GSK-3 isoform-selective roles in several of these. Here, we review the current knowledge of GSK-3 regulation and targets and discuss the various animal models that have been employed to dissect the functions of GSK-3 in brain development and function through the use of conventional or conditional knockout mice as well as transgenic mice. These studies have revealed fundamental roles for these protein kinases in memory, behavior, and neuronal fate determination and provide insights into possible therapeutic interventions.
Highlights
This inhibitory mechanism is induced by agonists such as neurotrophins and growth factors that activate protein kinases that act on the N-terminal domain of Glycogen synthase kinase-3 (GSK-3) such as PKB/Akt, p90rsk, cyclic-AMP-dependent protein kinase, p70 S6 kinase, as well as regulators of phosphatase-1 (Sutherland et al, 1993; Stambolic and Woodgett, 1994; Alessi et al, 1996; Li et al, 2000; Svenningsson et al, 2003; see Figure 2)
SUMMARY The emergence of sophisticated animal models with tissue and developmentally selective expression of GSK-3 has allowed direct assessment of the roles of this protein kinase in a variety of neurological processes and conditions
While GSK-3 was first implicated in a neurological disorder in 1992 through its capacity to phosphorylate residues on Tau that are associated with neurofibrillary tangles in AD, the potential importance of this kinase in brain function and disease took off with the identification by Klein and Melton of GSK-3 as a direct target of lithium (Klein and Melton, 1996; Stambolic et al, 1996)
Summary
Reviewed by: Urs Albrecht, University of Fribourg, Switzerland Hagit Eldar-Finkelman, Tel Aviv University, Israel. Phosphorylation of GSK-3 within its N-terminal region creates a “pseudosubstrate”which intramolecularly binds to a“phosphoprotein binding pocket” within the active site of the kinase, suppressing activity by occluding primed substrate access to the binding pocket (Frame et al, 2001) This inhibitory mechanism is induced by agonists such as neurotrophins and growth factors that activate protein kinases that act on the N-terminal domain of GSK-3 such as PKB/Akt, p90rsk, cyclic-AMP-dependent protein kinase, p70 S6 kinase, as well as regulators of phosphatase-1 (Sutherland et al, 1993; Stambolic and Woodgett, 1994; Alessi et al, 1996; Li et al, 2000; Svenningsson et al, 2003; see Figure 2). Cryptochromes (Cry 1, Cry2) and Period genes (Per, Per, Per3) are clock-controlled genes that encode proteins that form the
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