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J. Biol. Chem., Vol. 282, Issue 22, 16599-16611, June 1, 2007

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The Rab5 Activator ALS2/alsin Acts as a Novel Rac1 Effector through Rac1-activated Endocytosis^*

Ryota Kunita¹, Asako Otomo², Hikaru Mizumura, Kyoko Suzuki-Utsunomiya¹, Shinji Hadano^¶3, and Joh-E Ikeda^¶||4

From the Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan, the Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, the ^¶Department of Molecular Neuroscience, The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa 259-1193, Japan, and the ^||Department of Paediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

Mutations in the ALS2 gene cause a number of recessive motor neuron diseases, indicating that the ALS2 protein (ALS2/alsin) is vital for motor neurons. ALS2 acts as a guanine nucleotide exchange factor (GEF) for Rab5 (Rab5GEF) and is involved in endosome dynamics. However, the spatiotemporal regulation of the ALS2-mediated Rab5 activation is unclear. Here we identified an upstream activator for ALS2 and showed a functional significance of the ALS2 activation in endosome dynamics. ALS2 preferentially interacts with activated Rac1. In the cells activated Rac1 recruits cytoplasmic ALS2 to membrane ruffles and subsequently to nascent macropinosomes via Rac1-activated macropinocytosis. At later endocytic stages macropinosomal ALS2 augments fusion of the ALS2-localized macropinosomes with the transferrin-positive endosomes, depending on the ALS2-associated Rab5GEF activity. These results indicate that Rac1 promotes the ALS2 membranous localization, thereby rendering ALS2 active via Rac1-activated endocytosis. Thus, ALS2 is a novel Rac1 effector and is involved in Rac1-activated macropinocytosis. All together, loss of ALS2 may perturb macropinocytosis and/or the following membrane trafficking, which gives rise to neuronal dysfunction in the ALS2-linked motor neuron diseases.

Received for publication, November 17, 2006 , and in revised form, March 14, 2007.

^* This work was funded in part by Japan Science and Technology Agency (to J.-E. I.) and the Ministry of Health, Labour, and Welfare (to J.-E. I.). 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.jbc.org) contains supplemental Figs. 1-4.

¹ Supported by a 2006 Tokai University School of Medicine Research Aid.

² Supported by a Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science.

³ Supported by a grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science, a grant-in-aid for Scientific Research on Priority Areas-Research on Pathomechanisms for Brain Disorders from MEXT, Takeda Science Foundation, Novartis Foundation (Japan) for the Promotion of Science, Japan Brain Foundation, and The Ichiro Kanehara Foundation.

⁴ To whom correspondence should be addressed: Dept. of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. Tel.: 81-463-91-5095; Fax: 81-463-91-4993; E-mail: jeikeda3{at}is.icc.u-tokai.ac.jp.

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