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Published 15 April 2002. doi:10.1083/jcb.200201098
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© The Rockefeller University Press, 0021-9525/2002/4/211 $5.00
The Journal of Cell Biology, Volume 157, Number 2, April 15, 2002 211-217

Report

 An inactive pool of GSK-3 at the leading edge of growth cones is implicated in Semaphorin 3A signaling

Britta J. Eickholt1, Frank S. Walsh2 and Patrick Doherty1

1 Molecular Neurobiology Group, Medical Research Council Centre for Developmental Biology, King's College London, London SE1 1UL, United Kingdom
2 Neurology Centre of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM19 5AW, United Kingdom

Address correspondence to Britta J. Eickholt, Molecular Neurobiology Group, MRC Centre for Developmental Biology, King's College London, London SE1 1UL, UK. Tel.: 44-20-7848-6812. Fax: 44-20-7848-6816. E-mail: Britta.J.Eickholt{at}kcl.ac.uk

Glycogen synthase kinase (GSK)-3 is a serine/threonine kinase that has been implicated in several aspects in embryonic development and several growth factor signaling cascades. We now report that an inactive phosphorylated pool of the enzyme colocalizes with F-actin in both neuronal and nonneuronal cells. Semaphorin 3A (Sema 3A), a molecule that inhibits axonal growth, activates GSK-3 at the leading edge of neuronal growth cones and in Sema 3A–responsive human breast cancer cells, suggesting that GSK-3 activity might play a role in coupling Sema 3A signaling to changes in cell motility. We show that three different GSK-3 antagonists (LiCl, SB-216763, and SB-415286) can inhibit the growth cone collapse response induced by Sema 3A. These studies reveal a novel compartmentalization of inactive GSK-3 in cells and demonstrate for the first time a requirement for GSK-3 activity in the Sema 3A signal transduction pathway.

Key Words: GSK-3; axon guidance; actin; Semaphorin 3A; growth cone


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