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J. Biol. Chem., Vol. 278, Issue 48, 47946-47959, November 28, 2003

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v-Src Rescues Actin-based Cytoskeletal Architecture and Cell Motility and Induces Enhanced Anchorage Independence during Oncogenic Transformation of Focal Adhesion Kinase-null Fibroblasts^*

Konstadinos Moissoglu and Irwin H. Gelman

From the Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263

The ability of the focal adhesion kinase (FAK) to integrate signals from extracellular matrix and growth factor receptors requires the integrity of Tyr³⁹⁷, a major autophosphorylation site that mediates the Src homology 2-dependent binding of Src family kinases. However, the precise roles played by FAK in specific Srcinduced pathways, especially as they relate to oncogenic transformation, remain unclear. Here, we investigate the role of FAK in v-Src-induced oncogenic transformation by transducing temperature-sensitive v-Src (ts72v-Src) into p53-null FAK+/+ or FAK–/– mouse embryo fibroblasts (MEF). At the permissive temperature (PT), ts72v-Src induced abundant tyrosine phosphorylation, morphological transformation and cytoskeletal rearrangement in FAK–/– MEF, including the restoration of cell polarity, typical focal adhesion complexes, and longitudinal F-actin stress fibers. v-Src rescued the haptotactic, linear directional, and invasive motility defects of FAK–/– cells to levels found in FAK+/+ or FAK+/+-[ts72v-Src] cells, and, in the case of monolayer wound healing motility, there was an enhancement. Src activation failed to increase the high basal tyrosine phosphorylation of the Crk-associated substrate, CAS, found in FAK–/– MEF, indicating that CAS phosphorylation alone is insufficient to induce motility in the absence of FAK- or v-Src-induced cytoskeletal remodeling. Compared with FAK+/+[ts72v-Src] controls, FAK–/–[ts72v-Src] clones exhibited 7–10-fold higher anchorage-independent proliferation that could not be attributed to variations in either v-Src protein level or stability. Re-expression of FAK diminished the colony-forming activities of FAK–/–[ts72v-Src] without altering ts72v-Src expression levels, suggesting that FAK attenuates Srcinduced anchorage independence. Our data also indicate that the enhanced Pyk2 level found in FAK–/– MEF plays no role in v-Src-induced anchorage independence. Overall, our data indicate that FAK, although dispensable, attenuates v-Src-induced oncogenic transformation by modulating distinct signaling and cytoskeletal pathways.

Received for publication, March 17, 2003 , and in revised form, September 16, 2003.

^* This work was supported by Grants CA65787 and CA94108 from the NCI, National Institutes of Health (to I. H. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908.

To whom correspondence should be addressed: Dept. of Cancer Genetics, Roswell Park Cancer Inst., Elm and Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-7681; Fax: 716-716-1698; E-mail: irwin.gelman{at}roswellpark.org.

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