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First published online 14 August 2007
doi: 10.1242/jcs.005298

Journal of Cell Science 120, 3138-3146 (2007)
Published by The Company of Biologists 2007
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Research Article

The distinct roles of Ras and Rac in PI 3-kinase-dependent protrusion during EGF-stimulated cell migration

Shu-Chin Yip1,2,*, Mirvat El-Sibai1,*, Salvatore J. Coniglio3, Ghassan Mouneimne2, Robert J. Eddy2, Beth E. Drees3, Paul O. Neilsen3, Sumanta Goswami4, Marc Symons5, John S. Condeelis2 and Jonathan M. Backer1,{ddagger}

1 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
2 Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
3 Echelon Biosciences, Inc., Salt Lake City, UT, USA
4 Department of Biology, Yeshiva University, NY, USA
5 Center for Oncology and Cell Biology, Institute for Medical Research at North Shore-LIJ, Manhasset, NY, USA

{ddagger} Author for correspondence (e-mail: backer{at}aecom.yu.edu)

Accepted 18 June 2007

Cell migration involves the localized extension of actin-rich protrusions, a process that requires Class I phosphoinositide 3-kinases (PI 3-kinases). Both Rac and Ras have been shown to regulate actin polymerization and activate PI 3-kinase. However, the coordination of Rac, Ras and PI 3-kinase activation during epidermal growth factor (EGF)-stimulated protrusion has not been analyzed. We examined PI 3-kinase-dependent protrusion in MTLn3 rat adenocarcinoma cells. EGF-stimulated phosphatidyl-inositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] levels showed a rapid and persistent response, as PI 3-kinase activity remained elevated up to 3 minutes. The activation kinetics of Ras, but not Rac, coincided with those of leading-edge PtdIns(3,4,5)P3 production. Small interfering RNA (siRNA) knockdown of K-Ras but not Rac1 abolished PtdIns(3,4,5)P3 production at the leading edge and inhibited EGF-stimulated protrusion. However, Rac1 knockdown did inhibit cell migration, because of the inhibition of focal adhesion formation in Rac1 siRNA-treated cells. Our data show that in EGF-stimulated MTLn3 carcinoma cells, Ras is required for both PtdIns(3,4,5)P3 production and lamellipod extension, whereas Rac1 is required for formation of adhesive structures. These data suggest an unappreciated role for Ras during protrusion, and a crucial role for Rac in the stabilization of protrusions required for cell motility.

Key words: Ras, Rac, Cdc42, Rho, Lamellipodia


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