Integrin alpha v beta 3 controls activity and oncogenic potential of primed c-Src.
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.
Huveneers
Stephan
S
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
van den Bout
Iman
I
Sonneveld
Petra
P
Sancho
Ana
A
Sonnenberg
Arnoud
A
Danen
Erik H J
EH
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
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