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Integrin _vß₃ Controls Activity and Oncogenic Potential of Primed c-Src

¹ Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands and ² Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

Requests for reprints: Erik H.J. Danen, Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA, Leiden, The Netherlands. Phone: 31-71-527-4486; E-mail: e.danen{at}lacdr.leidenuniv.nl.

Increased activity of the proto-oncogene c-Src and elevated levels of integrin _vß₃ are found in melanomas and multiple carcinomas. Regulation of c-Src involves "priming" through disruption of intramolecular interactions followed by "activation" through phosphorylation in the kinase domain. Interactions with overexpressed receptor tyrosine kinases or mutations in the SRC gene can induce priming of c-Src in cancer. Here, we show that _vß₃ promotes activation of primed c-Src, causing enhanced phosphorylation of established Src substrates, survival, proliferation, and tumor growth. The ß₃ cytoplasmic tail is required and sufficient for integrin-mediated stimulation of all these events through a mechanism that is independent of ß₃ tyrosine phosphorylation. Instead, experiments using Src variants containing the v-Src Src homology 3 (SH3) domain and using mutant ß₃ subunits indicate that a functional interaction of the ß₃ cytoplasmic tail with the c-Src SH3 domain is required. These findings delineate a novel integrin-controlled oncogenic signaling cascade and suggest that the interaction of _vß₃ with c-Src may represent a novel target for therapeutic intervention. [Cancer Res 2007;67(6):2693–700]

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