title: ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics.
abstract: 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.
authors.affiliation: Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Corporation (JST), Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Otomo
authors.forename: Shinji
authors.initials: S
authors.lastname: Hadano
authors.forename: Takeya
authors.initials: T
authors.lastname: Okada
authors.forename: Hikaru
authors.initials: H
authors.lastname: Mizumura
authors.forename: Ryota
authors.initials: R
authors.lastname: Kunita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishijima
authors.forename: Junko
authors.initials: J
authors.lastname: Showguchi-Miyata
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yanagisawa
authors.forename: Eri
authors.initials: E
authors.lastname: Kohiki
authors.forename: Etsuko
authors.initials: E
authors.lastname: Suga
authors.forename: Masanori
authors.initials: M
authors.lastname: Yasuda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osuga
authors.forename: Takeharu
authors.initials: T
authors.lastname: Nishimoto
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Joh-E
authors.initials: JE
authors.lastname: Ikeda
mesh_terms: D011992:Endosomes / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D033921:Vesicular Transport Proteins; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C438187:ALS2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D020696:rab5 GTP-Binding Proteins