FAK dimerization controls its kinase-dependent functions at focal adhesions

EMBO J. 2014 Feb 18;33(4):356-70. doi: 10.1002/embj.201386399. Epub 2014 Jan 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Crystallography, X-Ray
  • Dimerization
  • Enzyme Activation
  • Focal Adhesion Kinase 1 / chemistry*
  • Focal Adhesion Kinase 1 / physiology
  • Focal Adhesions
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Phosphorylation
  • Phosphotyrosine / physiology
  • Protein Conformation
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Rats
  • Recombinant Fusion Proteins / chemistry
  • Scattering, Radiation


  • Recombinant Fusion Proteins
  • Phosphotyrosine
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Ptk2 protein, rat