FARP2 triggers signals for Sema3A-mediated axonal repulsion.
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 PIPKIgamma661 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.
Toyofuku
Toshihiko
T
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. toyofuku@medone.med.osaka-u.ac.jp
Yoshida
Junko
J
Sugimoto
Tamiko
T
Zhang
Hong
H
Kumanogoh
Atsushi
A
Hori
Masatsugu
M
Kikutani
Hitoshi
H
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002642:Chick Embryo; D003463:Cues; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism* / Q000648:ultrastructure; D006131:Growth Inhibitors / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009420:Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D039942:Neuropilin-1 / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D040121:Semaphorin-3A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016608:Talin / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C577426:FARP2 protein, human; C507259:FARP2 protein, mouse; D006131:Growth Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C492114:Plxna1 protein, mouse; D011956:Receptors, Cell Surface; D064067:Rho Guanine Nucleotide Exchange Factors; C111871:Rnd1 protein, mouse; D040121:Semaphorin-3A; D016608:Talin; D039942:Neuropilin-1; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D020558:GTP Phosphohydrolases; C085929:RRAS protein, human; C513254:Rras protein, mouse; D020744:rac GTP-Binding Proteins; D018631:ras Proteins; D020741:rho GTP-Binding Proteins