FAK dimerization controls its kinase-dependent functions at focal adhesions

Autor: Katarzyna W. Walkiewicz, Stefan T. Arold, Álvaro Ortega, Jean-Antoine Girault, Laïla Gasmi, Paul G. Leonard, Nicolas Gervasi, Karen Brami-Cherrier, Gress Kadaré, Bastien Seantier, Diana A. Arsenieva, Marie Claude Boutterin, Tahar Bouceba
Přispěvatelé: Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ingénierie des protéines, PCR, Interaction Moléculaires [IBPS] (IBPS-IPIM), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Community [RII3/CT/2004/5060008], Agence Nationale de la Recherche [ANR-05-2\₄2589], Region Ile de France, Association pour la Recherche sur le Cancer (ARC) [A05/3/3138], Fondation pour la Recherche Medicale, European Research Council, Inserm, University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center, NIH/NCI [R03 CA169969-01], National Institutes of Health through MD Anderson's Cancer Center [CA016672], ARC
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Models
Molecular
Non-receptor tyrosine kinase
Protein Conformation
Recombinant Fusion Proteins
[SDV]Life Sciences [q-bio]
Amino Acid Motifs
Crystallography
X-Ray
General Biochemistry
Genetics and Molecular Biology
Focal adhesion
03 medical and health sciences
0302 clinical medicine
Animals
Humans
Scattering
Radiation
Phosphorylation
focal adhesion
Phosphotyrosine
Cell adhesion
Molecular Biology
Paxillin
030304 developmental biology
Focal Adhesions
0303 health sciences
General Immunology and Microbiology
biology
FERM domain
General Neuroscience
focal adhesion kinase
cell adhesion
Articles
Protein Structure
Tertiary
Rats
Cell biology
Enzyme Activation
HEK293 Cells
Focal Adhesion Kinase 1
030220 oncology & carcinogenesis
non-receptor tyrosine kinase
biology.protein
Signal transduction
biological phenomena
cell phenomena
and immunity
Dimerization
Protein Processing
Post-Translational
Nuclear localization sequence
signal transduction
Zdroj: EMBO Journal
EMBO Journal, EMBO Press, 2014, 33 (4), pp.356-370. ⟨10.1002/embj.201386399⟩
EMBO Journal, 2014, 33 (4), pp.356-370. ⟨10.1002/embj.201386399⟩
The EMBO Journal
ISSN: 0261-4189
1460-2075
DOI: 10.1002/embj.201386399⟩
Popis: International audience; Abstract 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.
Databáze: OpenAIRE
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