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Cell, Tumor, and Stem Cell Biology |
vß3 Controls Activity and Oncogenic Potential of Primed c-Src1 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):2693700]
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