FARP2 triggers signals for Sema3A-mediated axonal repulsion

Nat Neurosci. 2005 Dec;8(12):1712-9. doi: 10.1038/nn1596. Epub 2005 Nov 13.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Adhesion / physiology
  • Cell Communication / physiology
  • Cell Line
  • Cells, Cultured
  • Chick Embryo
  • Cues
  • GTP Phosphohydrolases / metabolism
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / embryology
  • Ganglia, Spinal / metabolism
  • Growth Cones / metabolism*
  • Growth Cones / ultrastructure
  • Growth Inhibitors / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Nervous System / cytology
  • Nervous System / embryology*
  • Nervous System / metabolism*
  • Neuropilin-1 / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Binding / physiology
  • Receptors, Cell Surface / metabolism*
  • Rho Guanine Nucleotide Exchange Factors
  • Semaphorin-3A / metabolism*
  • Signal Transduction / physiology
  • Talin / metabolism
  • rac GTP-Binding Proteins / metabolism
  • ras Proteins / metabolism
  • rho GTP-Binding Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • FARP2 protein, human
  • FARP2 protein, mouse
  • Growth Inhibitors
  • Guanine Nucleotide Exchange Factors
  • Nerve Tissue Proteins
  • Plxna1 protein, mouse
  • Receptors, Cell Surface
  • Rho Guanine Nucleotide Exchange Factors
  • Rnd1 protein, mouse
  • Semaphorin-3A
  • Talin
  • Neuropilin-1
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • GTP Phosphohydrolases
  • RRAS protein, human
  • Rras protein, mouse
  • rac GTP-Binding Proteins
  • ras Proteins
  • rho GTP-Binding Proteins