Data from Integrin α<sub>v</sub>β<sub>3</sub> Controls Activity and Oncogenic Potential of Primed c-Src

Increased activity of the proto-oncogene c-Src and elevated levels of integrin α_vβ₃ 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 α_vβ₃ promotes activation of primed c-Src, causing enhanced phosphorylation of established Src substrates, survival, proliferation, and tumor growth. The β₃ cytoplasmic tail is required and sufficient for integrin-mediated stimulation of all these events through a mechanism that is independent of β₃ tyrosine phosphorylation. Instead, experiments using Src variants containing the v-Src Src homology 3 (SH3) domain and using mutant β₃ subunits indicate that a functional interaction of the β₃ 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 α_vβ₃ with c-Src may represent a novel target for therapeutic intervention. [Cancer Res 2007;67(6):2693–700]