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Media type:
E-Article
Title:
Integrin αvβ3 Controls Activity and Oncogenic Potential of Primed c-Src
Contributor:
Huveneers, Stephan;
van den Bout, Iman;
Sonneveld, Petra;
Sancho, Ana;
Sonnenberg, Arnoud;
Danen, Erik H.J.
Published:
American Association for Cancer Research (AACR), 2007
Published in:
Cancer Research, 67 (2007) 6, Seite 2693-2700
Language:
English
DOI:
10.1158/0008-5472.can-06-3654
ISSN:
0008-5472;
1538-7445
Origination:
Footnote:
Description:
Abstract Increased activity of the proto-oncogene c-Src and elevated levels of integrin αvβ3 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 αvβ3 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 αvβ3 with c-Src may represent a novel target for therapeutic intervention. [Cancer Res 2007;67(6):2693–700]