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First published online 27 September 2005
doi: 10.1242/jcs.02590

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p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling

Davide Barberis^1,*, Andrea Casazza^1,*, Raffaella Sordella², Simona Corso¹, Stefania Artigiani¹, Jeff Settleman², Paolo M. Comoglio¹ and Luca Tamagnone^1,

¹ Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Candiolo, Torino 10060, Italy
² Harvard Medical School, MGH Cancer Center, 149 13th Street, Charlestown, MA 02129, USA

Author for correspondence (e-mail: luca.tamagnone{at}ircc.it)

Accepted 13 July 2005

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.

Key words: GAP, p190, Plexin, Rho, Semaphorin

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