RGD Reference Report - FAK dimerization controls its kinase-dependent functions at focal adhesions. - Rat Genome Database

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FAK dimerization controls its kinase-dependent functions at focal adhesions.

Authors: Brami-Cherrier, K  Gervasi, N  Arsenieva, D  Walkiewicz, K  Boutterin, MC  Ortega, A  Leonard, PG  Seantier, B  Gasmi, L  Bouceba, T  Kadare, G  Girault, JA  Arold, ST 
Citation: Brami-Cherrier K, etal., EMBO J. 2014 Feb 18;33(4):356-70. doi: 10.1002/embj.201386399. Epub 2014 Jan 30.
RGD ID: 8693377
Pubmed: PMID:24480479   (View Abstract at PubMed)
PMCID: PMC3989642   (View Article at PubMed Central)
DOI: DOI:10.1002/embj.201386399   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
identical protein binding enablesIPIUniProtKB:O353468693377PMID:24480479IntAct 

Objects Annotated

Genes (Rattus norvegicus)
Ptk2  (protein tyrosine kinase 2)


Additional Information