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J. Biol. Chem., Vol. 280, Issue 41, 34735-34740, October 14, 2005

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ALS2/Alsin Regulates Rac-PAK Signaling and Neurite Outgrowth^*

Elizabeth L. Tudor1, Michael S. Perkinton, Anja Schmidt¶, Steven Ackerley, Janet Brownlees, Nicholas J. O. Jacobsen, Helen L. Byers||, Malcolm Ward||, Alan Hall¶, P. Nigel Leigh, Christopher E. Shaw, Declan M. McLoughlin**, and Christopher C. J. Miller2

From the Departments of Neuroscience and Neurology and ^**Section of Old Age Psychiatry, Institute of Psychiatry, Kings College, London SE5 8AF, United Kingdom, ^¶Medical Research Council Laboratory for Molecular Cell Biology, University College, London WC1E 6BT, United Kingdom, and ^||Proteome Sciences plc, Institute of Psychiatry, London SE5 8AF, United Kingdom

Rac and its downstream effectors p21-activated kinase (PAK) family kinases regulate actin dynamics within growth cones to control neurite outgrowth during development. The activity of Rac is stimulated by guanine nucleotide exchange factors (GEFs) that promote GDP release and GTP binding. ALS2/Alsin is a recently described GEF that contains a central domain that is predicted to regulate the activities of Rac and/or Rho and Cdc42 activities. Mutations in ALS2 cause some recessive familial forms of amyotrophic lateral sclerosis (ALS) but the function of ALS2 is poorly understood. Here we demonstrate that ALS2 is present within growth cones of neurons, in which it co-localizes with Rac. Furthermore, ALS2 stimulates Rac but not Rho or Cdc42 activities, and this induces a corresponding increase in PAK1 activity. Finally, we demonstrate that ALS2 promotes neurite outgrowth. Defects in these functions may therefore contribute to motor neuron demise in ALS.

Received for publication, June 7, 2005 , and in revised form, July 25, 2005.

^* This work was supported by grants from the Medical Research Council and Wellcome Trust (to C. C. J. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbs.org) contains supplemental Figs. S1-S4.

¹ Supported by a Jim Tew Memorial Studentship and the UK Motor Neurone Disease Association.

² To whom correspondence should be addressed: Dept. of Neuroscience, P. O. Box P037, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, United Kingdom. Tel.: 44-2078480393; Fax: 44-2077080017; E-mail: chris.miller{at}iop.kcl.ac.uk.

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