Semaphorin 4D signaling requires the recruitment of phospholipase C gamma into the plexin-B1 receptor complex

Mol Cell Biol. 2009 Dec;29(23):6321-34. doi: 10.1128/MCB.00103-09. Epub 2009 Oct 5.

Abstract

The semaphorin 4D (Sema4D) receptor plexin-B1 constitutively interacts with particular Rho guanine nucleotide exchange factors (RhoGEFs) and thereby mediates Sema4D-induced RhoA activation, a process which involves the tyrosine phosphorylation of plexin-B1 by ErbB-2. It is, however, unknown how plexin-B1 phosphorylation regulates RhoGEF activity. We show here that activation of plexin-B1 by Sema4D and its subsequent tyrosine phosphorylation creates docking sites for the SH2 domains of phospholipase Cgamma (PLCgamma). PLCgamma is thereby recruited into the plexin-B1 receptor complex and via its SH3 domain activates the Rho guanine nucleotide exchange factor PDZ-RhoGEF. PLCgamma-dependent RhoGEF activation is independent of its lipase activity. The recruitment of PLCgamma has no effect on the R-Ras GTPase-activating protein activity of plexin-B1 but is required for Sema4D-induced axonal growth cone collapse as well as for the promigratory effects of Sema4D on cancer cells. These data demonstrate a novel nonenzymatic function of PLCgamma as an important mechanism of plexin-mediated signaling which links tyrosine phosphorylation of plexin-B1 to the regulation of a RhoGEF protein and downstream cellular processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Binding Sites
  • Cell Line
  • Cell Movement
  • Enzyme Activation
  • Growth Cones / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phospholipase C gamma / metabolism*
  • Phosphotyrosine / metabolism
  • Protein Binding
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Rho Guanine Nucleotide Exchange Factors
  • Semaphorins / metabolism*
  • Signal Transduction*
  • ras Proteins / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Antigens, CD
  • CD100 antigen
  • Guanine Nucleotide Exchange Factors
  • Nerve Tissue Proteins
  • PLXNB1 protein, human
  • Receptors, Cell Surface
  • Rho Guanine Nucleotide Exchange Factors
  • Semaphorins
  • Phosphotyrosine
  • Phospholipase C gamma
  • RRAS protein, human
  • ras Proteins
  • rhoA GTP-Binding Protein