Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Adhesion / physiology
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Cell Communication / physiology
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Cell Line
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Cells, Cultured
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Chick Embryo
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Cues
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GTP Phosphohydrolases / metabolism
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Ganglia, Spinal / cytology
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Ganglia, Spinal / embryology
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Ganglia, Spinal / metabolism
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Growth Cones / metabolism*
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Growth Cones / ultrastructure
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Growth Inhibitors / metabolism
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Guanine Nucleotide Exchange Factors / metabolism*
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Humans
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Mice
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Nerve Tissue Proteins / metabolism*
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Nervous System / cytology
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Nervous System / embryology*
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Nervous System / metabolism*
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Neuropilin-1 / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Protein Binding / physiology
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Receptors, Cell Surface / metabolism*
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Rho Guanine Nucleotide Exchange Factors
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Semaphorin-3A / metabolism*
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Signal Transduction / physiology
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Talin / metabolism
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rac GTP-Binding Proteins / metabolism
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ras Proteins / metabolism
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rho GTP-Binding Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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FARP2 protein, human
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FARP2 protein, mouse
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Growth Inhibitors
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Guanine Nucleotide Exchange Factors
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Nerve Tissue Proteins
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Plxna1 protein, mouse
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Receptors, Cell Surface
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Rho Guanine Nucleotide Exchange Factors
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Rnd1 protein, mouse
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Semaphorin-3A
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Talin
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Neuropilin-1
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Phosphotransferases (Alcohol Group Acceptor)
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1-phosphatidylinositol-4-phosphate 5-kinase
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GTP Phosphohydrolases
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RRAS protein, human
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Rras protein, mouse
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rac GTP-Binding Proteins
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ras Proteins
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rho GTP-Binding Proteins