Glycogen synthase kinase-3 in insulin and Wnt signalling: a double-edged sword? - PubMed (original) (raw)

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Glycogen synthase kinase-3 in insulin and Wnt signalling: a double-edged sword?

S Patel et al. Biochem Soc Trans. 2004 Nov.

Abstract

Glycogen synthase kinase-3 is an unusual protein serine/threonine kinase that, unlike most of its 500-odd relatives in the genome, is active under resting conditions and is inactivated upon cell stimulation. The two mammalian isoforms, GSK-3alpha and beta, play largely overlapping roles and have been implicated in a variety of human pathologies, including Type II diabetes, Alzheimer's disease, bipolar disorder and cancer. Recently, the modes of regulation of this enzyme have been elucidated through a combination of structural and cell biological studies. A series of relatively selective small molecules have facilitated chemical manipulation of the enzyme in intact cells and tissues, and new roles for the protein kinase in embryonic stem cell differentiation and motility have emerged. Despite these advances, the therapeutic value of this enzyme as a drug target remains clouded by uncertainty over the potential of antagonists to promote tumorigenesis. This article describes the state of understanding of this intriguing enzyme, and weighs current evidence regarding whether there is a therapeutic window for amelioration of diseases in which it is implicated, in the absence of inducing new pathologies.

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Figures

Fig. 1

Fig. 1

A. GSK-3 preferentially phosphorylates substrates that are pre-phosphorylated by a priming kinase. For example, in the case of the GSK-3 substrate β-catenin, phosphorylation by CKI on S45 primes it for sequential phosphorylation on T41, S37 and S33 by GSK-3. B. Pseudosubstrate inactivation of GSK-3. The N-termini of GSK-3α and β contain serine residues (S21 and S9, respectively) that when phosphorylated by an inhibitory kinase, serve as primed-pseudosubstrates that can occupy the substrate binding pocket of GSK-3, inhibiting its activity towards true substrates.

Figure 2

Figure 2. Regulation of GSK-3 by the insulin-signal transduction pathway

The binding of insulin to its cell surface receptor triggers the recruitment and activation of PI3K. At the plasma membrane, PI3K stimulates the formation of phosphatidylinositol-3,4,5trisphosphate (PtdIns (3,4,5)P3) which triggers the colocalisation of phosphoinositide dependent kinase 1 (PDK1) and PKB allowing PDK1 to activate PKB. Upon activation, PKB phosphorylates and inactivates GSK-3 resulting in the dephosphorylation of glycogen synthase and eIF2B, two substrates of GSK-3 that control the rates of glycogen metabolism and protein synthesis respectively.

Fig. 3

Fig. 3. Central Role of GSK-3 in the Wnt/β-catenin Pathway

In unstimulated cells, a minimal complex of GSK-3, axin, APC and β-catenin is required for GSK-3-mediated phosphorylation of β-catenin which targets it for ubiqitination and degradation. Wnt stimulation activates the receptor Frizzled, and co-receptor LRP5/6, that then signal through Dishevelled, using an unclear mechanism, to inactivate β-catenin phosphorylation. Unphosphorylated β-catenin accumulates and translocates to the nucleus where it transactivates genes regulated by TCF/LEF transcription factors.

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