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

doi:10.1083/jcb.200201098

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

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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 kinasethat has been implicated in several aspects in embryonic developmentand several growth factor signaling cascades. We now reportthat an inactive phosphorylated pool of the enzyme colocalizeswith F-actin in both neuronal and nonneuronal cells. Semaphorin3A (Sema 3A), a molecule that inhibits axonal growth, activatesGSK-3 at the leading edge of neuronal growth cones and in Sema3A–responsive human breast cancer cells, suggesting thatGSK-3 activity might play a role in coupling Sema 3A signalingto changes in cell motility. We show that three different GSK-3antagonists (LiCl, SB-216763, and SB-415286) can inhibit thegrowth cone collapse response induced by Sema 3A. These studiesreveal a novel compartmentalization of inactive GSK-3 in cellsand demonstrate for the first time a requirement for GSK-3 activityin the Sema 3A signal transduction pathway.

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

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