期刊
EMBO JOURNAL
卷 33, 期 4, 页码 356-370出版社
WILEY
DOI: 10.1002/embj.201386399
关键词
cell adhesion; signal transduction; non-receptor tyrosine kinase; focal adhesion kinase; focal adhesion
资金
- European Community [RII3/CT/2004/5060008]
- Agence Nationale de la Recherche [ANR-05-2_42589]
- Association pour la Recherche sur le Cancer (ARC) [A05/3/3138]
- Fondation pour la Recherche Medicale
- European Research Council
- Inserm
- University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center
- NIH/NCI [R03 CA169969-01]
- National Institutes of Health through MD Anderson's Cancer Center [CA016672]
- ARC
- Region Ile de France
Abstract Focal adhesion kinase (FAK) controls adhesion-dependent cell motility, survival, and proliferation. FAK has kinase-dependent and kinase-independent functions, both of which play major roles in embryogenesis and tumor invasiveness. The precise mechanisms of FAK activation are not known. Using x-ray crystallography, small angle x-ray scattering, and biochemical and functional analyses, we show that the key step for activation of FAK's kinase-dependent functions-autophosphorylation of tyrosine-397-requires site-specific dimerization of FAK. The dimers form via the association of the N-terminal FERM domain of FAK and are stabilized by an interaction between FERM and the C-terminal FAT domain. FAT binds to a basic motif on FERM that regulates co-activation and nuclear localization. FAK dimerization requires local enrichment, which occurs specifically at focal adhesions. Paxillin plays a dual role, by recruiting FAK to focal adhesions and by reinforcing the FAT:FERM interaction. Our results provide a structural and mechanistic framework to explain how FAK combines multiple stimuli into a site-specific function. The dimer interfaces we describe are promising targets for blocking FAK activation.
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