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Human Molecular Genetics, 2003, Vol. 12, No. 14 1671-1687
DOI: 10.1093/hmg/ddg184
© 2003 Oxford University Press

ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics

Asako Otomo1,2, Shinji Hadano1,2, Takeya Okada2, Hikaru Mizumura1, Ryota Kunita1, Hitoshi Nishijima3, Junko Showguchi-Miyata2, Yoshiko Yanagisawa1, Eri Kohiki1, Etsuko Suga1, Masanori Yasuda4, Hitoshi Osuga1,2, Takeharu Nishimoto3, Shuh Narumiya5 and Joh-E Ikeda1,2,6,*

1Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Corporation (JST), Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan, 2Department of Molecular Neuroscience, The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa 259-1193, Japan, 3Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan, 4Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan, 5Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan and 6Department of Paediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

Received March 7, 2003; Accepted May 10, 2003

ALS2 mutations account for a number of recessive motor neuron diseases including forms of amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. Although computational predictions suggest that ALS2 encodes a protein containing multiple guanine nucleotide exchange factor (GEF) domains [RCC1-like domain (RLD), the Dbl homology and pleckstrin homology (DH/PH), and the vacuolar protein sorting 9 (VPS9)], the functions of the ALS2 protein have not been revealed as yet. Here we show that the ALS2 protein specifically binds to small GTPase Rab5 and functions as a GEF for Rab5. Ectopically expressed ALS2 protein localizes with Rab5 and early endosome antigen-1 (EEA1) onto early endosomal compartments and stimulates the enlargement of endosomes in cultured cortical neurons. The carboxy-terminus of ALS2 protein carrying a VPS9 domain mediates not only the activation of Rab5 via a guanine-nucleotide exchanging reaction but also the endosomal localization of the ALS2 protein, while the amino-terminal half containing RLD acts suppressive in its membranous localization. Further, the DH/PH domain in the middle portion of ALS2 protein enhances the VPS9 domain-mediated endosome fusions. Taken together, the ALS2 protein as a novel Rab5–GEF, ALS2rab5GEF seems to be implicated in the endosomal dynamics in vivo. Notably, a feature common to eight reported ALS2 mutations among motor neuron diseases is the loss of VPS9 domain, resulting in the failure of Rab5 activation. Thus, a perturbation of endosomal dynamics caused by loss of ALS2 rab5GEF activity might underlie neuronal dysfunction and degeneration in a number of motor neuron diseases.

* To whom correspondence should be addressed at: Department of Molecular Neuroscience, The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa 259-1193, Japan. Tel: +81 463915095; Fax: +81 463914993; Email: joh-e{at}nga.med.u-tokai.ac.jp


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