4.8 Article

FAK dimerization controls its kinase-dependent functions at focal adhesions

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

  1. European Community [RII3/CT/2004/5060008]
  2. Agence Nationale de la Recherche [ANR-05-2_42589]
  3. Association pour la Recherche sur le Cancer (ARC) [A05/3/3138]
  4. Fondation pour la Recherche Medicale
  5. European Research Council
  6. Inserm
  7. University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center
  8. NIH/NCI [R03 CA169969-01]
  9. National Institutes of Health through MD Anderson's Cancer Center [CA016672]
  10. ARC
  11. Region Ile de France

向作者/读者索取更多资源

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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