FAK dimerization controls its kinase-dependent functions at focal adhesions

Karen Brami-Cherrier, Nicolas Gervasi, Diana A. Arsenieva, Katarzyna Walkiewicz, Marie Claude Boutterin, Álvaro Darío Ortega, Paul G. Leonard, Bastien Seantier, Laïla Gasmi, Tahar Bouceba, Gress Kadaré, Jean Antoine Girault -, Stefan T. Arold

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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. © 2014 The Authors.
Original languageEnglish (US)
Pages (from-to)356-370
Number of pages15
JournalThe EMBO Journal
Volume33
Issue number4
DOIs
StatePublished - Jan 30 2014

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Molecular Biology
  • Immunology and Microbiology(all)

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