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J. Biol. Chem., Vol. 283, Issue 19, 13243-13251, May 9, 2008

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Integrins Uncouple Src-induced Morphological and Oncogenic Transformation^*

Stephan Huveneers, Serdar Arslan, Bob van de Water, Arnoud Sonnenberg, and Erik H. J. Danen¹

From the Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands and Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

Expression of activated mutants of c-Src in epithelial cells can induce tumorigenicity. In addition to such oncogenic transformation, the cells undergo a dramatic morphological transformation: cell-cell contacts are disrupted, spreading on extracellular matrix proteins is suppressed, actin stress fibers and focal contacts are lost, and podosomes are formed. We have previously shown that integrin vβ3 strongly supports Src-mediated oncogenic transformation through an interaction at the β3 cytoplasmic tail. Our current findings demonstrate that this interaction does not affect Src-mediated morphological alterations, thus separating oncogenic from morphological transformation. Moreover, β1 and β3 integrins differently affect the various aspects of Src-induced morphological transformation. High levels of β3, but not β1, integrins can prevent Src-induced cell rounding although stress fiber disassembly and podosome formation still occur. Studies using chimeric integrin subunits demonstrate that this protection requires the β3 extracellular domain. Finally, like tumor formation, podosome assembly occurs independent of β3 phosphorylation. Instead, phosphorylation of β1 is required to suppress Rho-mediated contractility in order to assemble podosomes. Thus, integrins regulate Src-mediated oncogenic transformation and various aspects of morphological transformation through dissociable pathways.

Received for publication, February 5, 2008 , and in revised form, March 6, 2008.

^* This work was supported by Dutch Cancer Society Grant 2003-2858. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P. O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail: e.danen{at}lacdr.leidenuniv.nl.

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