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

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.

journal_name

Biochem Soc Trans

authors

Patel S,Doble B,Woodgett JR

doi

10.1042/BST0320803

keywords:

subject

Has Abstract

pub_date

2004-11-01 00:00:00

pages

803-8

issue

Pt 5

eissn

0300-5127

issn

1470-8752

pii

BST0320803

journal_volume

32

pub_type

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