期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 37, 页码 15213-15218出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105689108
关键词
adhesion receptor; epidermis; cancer; signal transduction
资金
- Mayo Clinic
- EC
- Max Planck Society
beta 1 integrin tyrosine phosphorylation by oncogenic kinases, such as Src, has been predicted to induce tumorigenesis by disrupting adhesion and modifying integrin signaling. We directly tested this hypothesis by subjecting mice with nonphosphorylatable tyrosineto-phenylalanine substitutions in the conserved beta 1 cytoplasmic tail NPxY motifs to a model of cutaneous carcinogenesis in the presence or absence of elevated Src activity. We found that hydrophobic phenylalanine substitutions of both tyrosines diminished the binding of tail-interacting proteins, including talins and kindlins, resulting in reduced beta 1-mediated adhesion, focal adhesion kinase (FAK) signaling, and epidermal progenitor cell-derived skin tumors. However, increased Src activity drove tumor formation independent of the phenylalanine substitutions by enhancing FAK activity, which in turn maintained the epidermal progenitor state and blocked keratinocyte differentiation. We conclude that a Src/FAK signaling unit inhibits differentiation to promote tumorigenesis downstream of beta 1 integrin and independent of beta 1 integrin tyrosine phosphorylation.
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