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J Cell Sci

Publication date: 2005-10
Volume: 118 Pages: 4689 - 4700
ISSN: 0021-9533, 1477-9137 PMID: 16188938
DOI: 10.1242/jcs.02590
Publisher: Co. of Biologists


Barberis, Davide
Casazza, Andrea ; Sordella, Raffaella ; Corso, Simona ; Artigiani, Stefania ; Settleman, Jeff ; Comoglio, Paolo M ; Tamagnone, Luca


Animals, Antigens, CD, Carrier Proteins, Cell Adhesion, Cell Movement, Chemotaxis, DNA-Binding Proteins, Down-Regulation, Endothelial Cells, Epithelial Cells, Fibroblasts, Focal Adhesions, GTPase-Activating Proteins, Guanine Nucleotide Exchange Factors, Humans, Intracellular Signaling Peptides and Proteins, Mice, NIH 3T3 Cells, Nerve Growth Factor, Neurites, PC12 Cells, Protein Binding, RNA, Small Interfering, Rats, Receptors, Cell Surface, Repressor Proteins, Semaphorins, Signal Transduction, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology


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.