title: Integrin alpha v beta 3 controls activity and oncogenic potential of primed c-Src.
abstract: Increased activity of the proto-oncogene c-Src and elevated levels of integrin alpha(v)beta(3) 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 alpha(v)beta(3) promotes activation of primed c-Src, causing enhanced phosphorylation of established Src substrates, survival, proliferation, and tumor growth. The beta(3) cytoplasmic tail is required and sufficient for integrin-mediated stimulation of all these events through a mechanism that is independent of beta(3) tyrosine phosphorylation. Instead, experiments using Src variants containing the v-Src Src homology 3 (SH3) domain and using mutant beta(3) subunits indicate that a functional interaction of the beta(3) 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 alpha(v)beta(3) with c-Src may represent a novel target for therapeutic intervention.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Stephan
authors.initials: S
authors.lastname: Huveneers
authors.forename: Iman
authors.initials: I
authors.lastname: van den Bout
authors.forename: Petra
authors.initials: P
authors.lastname: Sonneveld
authors.forename: Ana
authors.initials: A
authors.lastname: Sancho
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
authors.forename: Erik H J
authors.initials: EH
authors.lastname: Danen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000081247:CSK Tyrosine-Protein Kinase; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction; D018909:src Homology Domains; D019061:src-Family Kinases
chemical_list: D039302:Integrin alphaVbeta3; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human