FAK dimerization controls its kinase‐dependent functions at focal adhesions. (30th January 2014)

• Record Type: Journal Article
• Authors: Brami‐Cherrier, Karen; Gervasi, Nicolas; Arsenieva, Diana; Walkiewicz, Katarzyna; Boutterin, Marie‐Claude; Ortega, Alvaro; Leonard, Paul G.; Seantier, Bastien; Gasmi, Laila; Bouceba, Tahar; Kadaré, Gress; Girault, Jean‐Antoine; Arold, Stefan T.
• Is Part Of: EMBO journal. Volume 33:Number 4(2014)
• Page Start: 356
• Page End: 370
• Publication Date: 2014-01-30
• Subjects: Molecular biology -- Periodicals; 572.805
• DOI: 10.1002/embj.201386399
• Languages: English
• ISSNs: 0261-4189

Abstract

<abstract abstract-type="main" id="embj201386399-abs-0001"> <title>Abstract</title> <p>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.</p> </abstract>