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Molecular and Cellular Biology, February 2003, p. 933-949, Vol. 23, No. 3
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.3.933-949.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

R-Ras Promotes Focal Adhesion Formation through Focal Adhesion Kinase and p130Cas by a Novel Mechanism That Differs from Integrins

Lina Kwong, Michele A. Wozniak, Asha S. Collins, Siobhan D. Wilson, and Patricia J. Keely*

Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin 53706

Received 22 April 2002/ Returned for modification 4 September 2002/ Accepted 30 October 2002

R-Ras regulates integrin function, but its effects on integrin signaling pathways have not been well described. We demonstrate that activation of R-Ras promoted focal adhesion formation and altered localization of the {alpha}2ß1 integrin from cell-cell to cell-matrix adhesions in breast epithelial cells. Constitutively activated R-Ras(38V) dramatically enhanced focal adhesion kinase (FAK) and p130Cas phosphorylation upon collagen stimulation or clustering of the {alpha}2ß1 integrin, even in the absence of increased ligand binding. Signaling events downstream of R-Ras differed from integrins and K-Ras, since pharmacological inhibition of Src or disruption of actin inhibited integrin-mediated FAK and p130Cas phosphorylation, focal adhesion formation, and migration in control and K-Ras(12V)-expressing cells but had minimal effect in cells expressing R-Ras(38V). Therefore, signaling from R-Ras to FAK and p130Cas has a component that is Src independent and not through classic integrin signaling pathways and a component that is Src dependent. R-Ras effector domain mutants and pharmacological inhibition suggest a partial role for phosphatidylinositol 3-kinase (PI3K), but not Raf, in R-Ras signaling to FAK and p130Cas. However, PI3K cannot account for the Src-independent pathway, since simultaneous inhibition of both PI3K and Src did not completely block effects of R-Ras on FAK phosphorylation. Our results suggest that R-Ras promotes focal adhesion formation by signaling to FAK and p130Cas through a novel mechanism that differs from but synergizes with the {alpha}2ß1 integrin.

* Corresponding author. Mailing address: Department of Pharmacology, University of Wisconsin, 3630 MSC, 1300 University Ave., Madison, WI 53706. Phone: (608) 265-2398. Fax: (608) 262-1257. E-mail: pjkeely{at}facstaff.wisc.edu.

Molecular and Cellular Biology, February 2003, p. 933-949, Vol. 23, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.3.933-949.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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