title: p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling.
abstract: Plexins are transmembrane receptors for semaphorins, guiding cell migration and axon extension. Plexin activation leads to the disassembly of integrin-based focal adhesive structures and to actin cytoskeleton remodelling and inhibition of cell migration; however, the underlying molecular mechanisms are unclear. We consistently observe a transient decrease of cellular RhoA-GTP levels upon plexin activation in adherent cells. One of the main effectors of RhoA downregulation is p190, a ubiquitously expressed GTPase activating protein (GAP). We show that, in p190-deficient fibroblasts, the typical functional activities mediated by plexins (such as cell collapse and inhibition of integrin-based adhesion) are blocked or greatly impaired. Notably, the functional response can be rescued in these cells by re-expressing exogenous p190, but not a mutant form specifically lacking RhoGAP activity. We furthermore demonstrate that semaphorin function is blocked in epithelial cells, primary endothelial cells and neuroblasts upon treatment with small interfering RNAs that knockdown p190 expression. Finally, we show that p190 transiently associates with plexins, and its RhoGAP activity is increased in response to semaphorin stimulation. We conclude that p190-RhoGAP is crucially involved in semaphorin signalling to the actin cytoskeleton, via interaction with plexins.
authors.affiliation: Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Candiolo, Torino 10060, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Barberis
authors.forename: Andrea
authors.initials: A
authors.lastname: Casazza
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sordella
authors.forename: Simona
authors.initials: S
authors.lastname: Corso
authors.forename: Stefania
authors.initials: S
authors.lastname: Artigiani
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Luca
authors.initials: L
authors.lastname: Tamagnone
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D022001:Focal Adhesions; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D041681:NIH 3T3 Cells; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites; D016716:PC12 Cells; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012097:Repressor Proteins; D039961:Semaphorins / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: C074560:ARHGAP35 protein, human; C513043:ARHGAP5 protein, human; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C513041:Arhgap35 protein, mouse; C513040:Arhgap35 protein, rat; C513042:Arhgap5 protein, mouse; C093224:CD100 antigen; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; C488752:Plxnb1 protein, rat; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C498395:Rtkn protein, mouse; D039961:Semaphorins; D020932:Nerve Growth Factor; D019204:GTP-Binding Proteins