TY - JOUR
T1 - FAK dimerization controls its kinase-dependent functions at focal adhesions
AU - Brami-Cherrier, Karen
AU - Gervasi, Nicolas
AU - Arsenieva, Diana
AU - Walkiewicz, Katarzyna
AU - Boutterin, Marie Claude
AU - Ortega, Alvaro
AU - Leonard, Paul G.
AU - Seantier, Bastien
AU - Gasmi, Laila
AU - Bouceba, Tahar
AU - Kadaré, Gress
AU - Girault, Jean Antoine
AU - Arold, Stefan T.
PY - 2014/2/18
Y1 - 2014/2/18
N2 - 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.
AB - 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.
KW - Cell adhesion
KW - Focal adhesion
KW - Focal adhesion kinase
KW - Non-receptor tyrosine kinase
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=84897862926&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84897862926&partnerID=8YFLogxK
U2 - 10.1002/embj.201386399
DO - 10.1002/embj.201386399
M3 - Article
C2 - 24480479
AN - SCOPUS:84897862926
SN - 0261-4189
VL - 33
SP - 356
EP - 370
JO - EMBO Journal
JF - EMBO Journal
IS - 4
ER -