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First published online 14 March 2006
doi: 10.1242/jcs.02835

Journal of Cell Science 119, 1307-1319 (2006)
Published by The Company of Biologists 2006
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Research Article

The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLC{epsilon}

Aude S. Ada-Nguema1, Harry Xenias2, Michael P. Sheetz2 and Patricia J. Keely1,*

1 Department of Pharmacology, University of Wisconsin-Madison, Madison, WI 53706, USA
2 Department of Biological Sciences, Columbia University, New York, NY 10027, USA

* Author for correspondence (e-mail: pjkeely{at}wisc.edu)

Accepted 13 December 2005

R-Ras, an atypical member of the Ras subfamily of small GTPases, enhances integrin-mediated adhesion and signaling through a poorly understood mechanism. Dynamic analysis of cell spreading by total internal reflection fluorescence (TIRF) microscopy demonstrated that active R-Ras lengthened the duration of initial membrane protrusion, and promoted the formation of a ruffling lamellipod, rich in branched actin structures and devoid of filopodia. By contrast, dominant-negative R-Ras enhanced filopodia formation. Moreover, RNA interference (RNAi) approaches demonstrated that endogenous R-Ras contributed to cell spreading. These observations suggest that R-Ras regulates membrane protrusions through organization of the actin cytoskeleton. Our results suggest that phospholipase C{epsilon} (PLC{epsilon}) is a novel R-Ras effector mediating the effects of R-Ras on the actin cytoskeleton and membrane protrusion, because R-Ras was co-precipitated with PLC{epsilon} and increased its activity. Knockdown of PLC{epsilon} with siRNA reduced the formation of the ruffling lamellipod in R-Ras cells. Consistent with this pathway, inhibitors of PLC activity, or chelating intracellular Ca2+ abolished the ability of R-Ras to promote membrane protrusions and spreading. Overall, these data suggest that R-Ras signaling regulates the organization of the actin cytoskeleton to sustain membrane protrusion through the activity of PLC{epsilon}.

Key words: R-Ras, Integrin, PLC, Ca2+, Actin, Cell spreading, Cell adhesion


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