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J. Biol. Chem., Vol. 279, Issue 23, 24612-24623, June 4, 2004

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Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor^*

Justin D. Topp, Noah W. Gray, Robert D. Gerard, and Bruce F. Horazdovsky¶||

From the Department of Biochemistry and Molecular Biology, the ^¶Mayo Clinic Cancer Center, Mayo Clinic, Rochester, Minnesota 55905 and the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390

ALS2 is the gene mutated in a recessive juvenile form of amyotrophic lateral sclerosis (ALS2). ALS2 encodes a large protein termed alsin, which contains a number of predicted cell signaling and protein trafficking sequence motifs. To gain insight into the overall function of alsin and to begin to evaluate its role in motor neuron maintenance, we examined the subcellular localization of alsin and the biochemical activities associated with its individual subdomains. We found that the Vps9p domain of alsin has Rab5 guanine nucleotide exchange activity. In addition, alsin interacted specifically with and acted as a guanine nucleotide exchange factor for Rac1. Immunofluorescence and fractionation experiments in both fibroblasts and neurons revealed that alsin is a cytosolic protein, with a significant portion associated with small, punctate membrane structures. Many of these membrane structures also contained Rab5 or Rac1. Upon overexpression of full-length alsin, the overexpressed material was largely cytosolic, indicating that the association with membrane structures could be saturated. We also found that alsin was present in membrane ruffles and lamellipodia. These data suggest that alsin is involved in membrane transport events, potentially linking endocytic processes and actin cytoskeleton remodeling.

Received for publication, December 10, 2003 , and in revised form, March 5, 2004.

^* This work was supported by a National Science Foundation predoctoral fellowship (to J. D. T.) and National Institutes of Health Neuroscience Training Grant NS07424 (to N. W. G.). 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.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Mayo Clinic, 200 1st St. S.W., Rochester, MN 55905. Tel.: 507-284-0308; Fax: 507-284-2053; E-mail: horazdovsky.bruce{at}mayo.edu.

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