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Article Dans Une Revue EMBO Journal Année : 2014

FAK dimerization controls its kinase-dependent functions at focal adhesions

Nicolas Gervasi
Diana Arsenieva
  • Fonction : Auteur
Katarzyna Walkiewicz
  • Fonction : Auteur
Alvaro Ortega
  • Fonction : Auteur
Paul G. Leonard
  • Fonction : Auteur
Bastien Seantier
  • Fonction : Auteur
Laila Gasmi
  • Fonction : Auteur
Jean-Antoine Girault
Stefan T. Arold
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-01537170 , version 1 (12-06-2017)

Identifiants

Citer

Karen Brami-Cherrier, Nicolas Gervasi, Diana Arsenieva, Katarzyna Walkiewicz, Marie-Claude Boutterin, et al.. FAK dimerization controls its kinase-dependent functions at focal adhesions. EMBO Journal, 2014, 33 (4), pp.356-370. ⟨10.1002/embj.201386399⟩. ⟨hal-01537170⟩
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