FAK dimerization controls its kinase-dependent functions at focal adhesions.
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.
Inserm UMR-S839, Paris, France.
Karen
K
Brami-Cherrier
Nicolas
N
Gervasi
Diana
D
Arsenieva
Katarzyna
K
Walkiewicz
Marie-Claude
MC
Boutterin
Alvaro
A
Ortega
Paul G
PG
Leonard
Bastien
B
Seantier
Laila
L
Gasmi
Tahar
T
Bouceba
Gress
G
Kadaré
Jean-Antoine
JA
Girault
Stefan T
ST
Arold
D020816:Amino Acid Motifs; D000818:Animals; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1 / Q000737:chemistry* / Q000502:physiology; D022001:Focal Adhesions; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000502:physiology; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012542:Scattering, Radiation
D011993:Recombinant Fusion Proteins; D019000:Phosphotyrosine; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496052:Ptk2 protein, rat