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

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

Shu-Chin Yip^1,2,*, Mirvat El-Sibai^1,*, Salvatore J. Coniglio³, Ghassan Mouneimne², Robert J. Eddy², Beth E. Drees³, Paul O. Neilsen³, Sumanta Goswami⁴, Marc Symons⁵, John S. Condeelis² and Jonathan M. Backer^1,

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

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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