title: Grb2 mediates semaphorin-4D-dependent RhoA inactivation.
abstract: Signaling through the semaphorin 4D (Sema4D) receptor plexin-B1 is modulated by its interaction with tyrosine kinases ErbB-2 and Met. In cells expressing the plexin-B1-ErbB-2 receptor complex, ligand stimulation results in the activation of small GTPase RhoA and stimulation of cellular migration. By contrast, in cells expressing plexin-B1 and Met, ligand stimulation results in an association with the RhoGTPase-activating protein p190 RhoGAP and subsequent RhoA inactivation--a process that involves the tyrosine phosphorylation of plexin-B1 by Met. Inactivation of RhoA is necessary for Sema4D-mediated inhibition of cellular migration. It is, however, unknown how plexin-B1 phosphorylation regulates RhoGAP interaction and activity. Here we show that the activation of plexin-B1 by Sema4D and its subsequent tyrosine phosphorylation by Met creates a docking site for the SH2 domain of growth factor receptor bound-2 (Grb2). Grb2 is thereby recruited into the plexin-B1 receptor complex and, through its SH3 domain, interacts with p190 RhoGAP and mediates RhoA deactivation. Phosphorylation of plexin-B1 by Met and the recruitment of Grb2 have no effect on the R-RasGAP activity of plexin-B1, but are required for Sema4D-induced, RhoA-dependent antimigratory effects of Sema4D on breast cancer cells. These data show Grb2 as a direct link between plexin and p190-RhoGAP-mediated downstream signaling.
authors.affiliation: Department of Pharmacology, Max-Planck Institute for Heart and Lung Research, Ludwigstr 43, 61231 Bad Nauheim, Germany.
authors.forename: Tianliang
authors.initials: T
authors.lastname: Sun
authors.forename: Rameshkumar
authors.initials: R
authors.lastname: Krishnan
authors.forename: Jakub M
authors.initials: JM
authors.lastname: Swiercz
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D039961:Semaphorins / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011956:Receptors, Cell Surface; D039961:Semaphorins; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020742:rhoA GTP-Binding Protein