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J Cell Sci. 2006 Apr 1;119(Pt 7):1307-19. Epub 2006 Mar 14.

The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLCepsilon.

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  • 1Department of Pharmacology, University of Wisconsin-Madison, Madison, WI 53706, USA.

Erratum in

  • J Cell Sci. 2006 Oct 15;119(Pt 20):4364. Hofman, Jake M [added]; Wiggins, Chris H [added].


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 Cepsilon (PLCepsilon) 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 PLCepsilon and increased its activity. Knockdown of PLCepsilon 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 PLCepsilon.

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