Nature Neuroscience 8, 1712 - 1719 (2005)
Published online: 13 November 2005; | doi:10.1038/nn1596
FARP2 triggers signals for Sema3A-mediated axonal repulsionToshihiko Toyofuku1, 2, 3, Junko Yoshida2, 3, Tamiko Sugimoto2, Hong Zhang1, 2, 4, Atsushi Kumanogoh2, 3, Masatsugu Hori1
& Hitoshi Kikutani2, 31
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. 2
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. 3
CREST, Japan Science and Technology Corporation, 4-1-8 Kawaguchi, Saitama 332-6612, Japan. 4
Present address: Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing 100083, China.
Correspondence should be addressed to Toshihiko Toyofuku toyofuku@medone.med.osaka-u.ac.jp or Hitoshi Kikutani kikutani@ragtime.biken.osaka-u.ac.jp Sema3A, a prototypical semaphorin, acts as a chemorepellent or a chemoattractant for axons by activating a receptor complex comprising neuropilin-1 as the ligand-binding subunit and plexin-A1 as the signal-transducing subunit. How the signals downstream of plexin-A1 are triggered upon Sema3A stimulation, however, is unknown. Here we show that, in the presence of neuropilin-1, the FERM domain–containing guanine nucleotide exchange factor (GEF) FARP2 associates directly with plexin-A1. Sema3A binding to neuropilin-1 induces the dissociation of FARP2 from plexin-A1, resulting in activation of FARP2's Rac GEF activity, Rnd1 recruitment to plexin-A1, and downregulation of R-Ras. Simultaneously, the FERM domain of FARP2 sequesters phosphatidylinositol phosphate kinase type I isoform PIPKI 661 from talin, thereby inhibiting its kinase activity. These activities are required for Sema3A-mediated repulsion of outgrowing axons and suppression of neuronal adhesion. We therefore conclude that FARP2 is a key molecule involved in the response of neuronal growth cones to class-3 semaphorins.
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