Semaphorin 4D signaling requires the recruitment of phospholipase C gamma into the plexin-B1 receptor complex.
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.
Swiercz
Jakub M
JM
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany. jakub.swiercz@mpi-bn.mpg.de
Worzfeld
Thomas
T
Offermanns
Stefan
S
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D002465:Cell Movement; D004789:Enzyme Activation; D020439:Growth Cones / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D039961:Semaphorins / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D015703:Antigens, CD; C093224:CD100 antigen; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011956:Receptors, Cell Surface; D064067:Rho Guanine Nucleotide Exchange Factors; D039961:Semaphorins; D019000:Phosphotyrosine; D051966:Phospholipase C gamma; C085929:RRAS protein, human; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein