FAK dimerization controls its kinase-dependent functions at focal adhesions

Handle URI:
http://hdl.handle.net/10754/563361
Title:
FAK dimerization controls its kinase-dependent functions at focal adhesions
Authors:
Brami-Cherrier, Karen; Gervasi, Nicolas; Arsenieva, Diana A.; Walkiewicz, Katarzyna; Boutterin, Marie Claude; Ortega, Álvaro Darío; Leonard, Paul G.; Seantier, Bastien; Gasmi, Laïla; Bouceba, Tahar; Kadaré, Gress; Girault -, Jean Antoine; Arold, Stefan T. ( 0000-0001-5278-0668 )
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. © 2014 The Authors.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Computational Bioscience Research Center (CBRC); Bioscience Program; Structural Biology and Engineering
Publisher:
Wiley-Blackwell
Journal:
The EMBO Journal
Issue Date:
30-Jan-2014
DOI:
10.1002/embj.201386399
PubMed ID:
24480479
PubMed Central ID:
PMC3989642
Type:
Article
ISSN:
02614189
Sponsors:
We thank S. Lachkar for help with SEC, K. Muller and V. Unkefer for editorial assistance, J.E. Ladbury for access to the MicroCal iTC200, L. Ponchon for help with DLS, D. Svergun and his colleagues for assistance with SAXS data recording and analysis at the x33 beamline at the European Molecular Biology Laboratory/Deutsches Elektronen-Synchrotron, G. Meigs for help with X-ray crystallography data recording at the Advanced Light Source beamline bl.8.3.1., Berkeley, CA, D. Ilic for the gift of Ptk2<SUP>-/-</SUP> fibroblasts, and A. Sobel and R.M. Mege for critical reading of the manuscript. We acknowledge support with data recording at the European Synchrotron Radiation Facility beamline ID14 and from the European Community Research Infrastructure Action under the Sixth Framework Program (RII3/CT/2004/5060008) for access to the European Molecular Biology Laboratory/Deutsches Elektronen-Synchrotron. This work was supported by Agence Nationale de la Recherche (ANR-05-2_42589), Association pour la Recherche sur le Cancer (ARC, A05/3/3138), Fondation pour la Recherche Medicale, European Research Council, Inserm, the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center, by NIH/NCI grant R03 CA169969-01, and, in part, by the National Institutes of Health through MD Anderson's Cancer Center Support Grant (CA016672). KBC was recipient of fellowships from ARC and Region Ile de France (NeRF). J.A. Girault's group is affiliated with the Ecole des Neurosciences de Paris-Ile-de-France and the Bio-Psy Laboratory of Excellence.
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989642
Appears in Collections:
Articles; Bioscience Program; Computational Bioscience Research Center (CBRC); Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorBrami-Cherrier, Karenen
dc.contributor.authorGervasi, Nicolasen
dc.contributor.authorArsenieva, Diana A.en
dc.contributor.authorWalkiewicz, Katarzynaen
dc.contributor.authorBoutterin, Marie Claudeen
dc.contributor.authorOrtega, Álvaro Daríoen
dc.contributor.authorLeonard, Paul G.en
dc.contributor.authorSeantier, Bastienen
dc.contributor.authorGasmi, Laïlaen
dc.contributor.authorBouceba, Taharen
dc.contributor.authorKadaré, Gressen
dc.contributor.authorGirault -, Jean Antoineen
dc.contributor.authorArold, Stefan T.en
dc.date.accessioned2015-08-03T11:46:41Zen
dc.date.available2015-08-03T11:46:41Zen
dc.date.issued2014-01-30en
dc.identifier.issn02614189en
dc.identifier.pmid24480479en
dc.identifier.doi10.1002/embj.201386399en
dc.identifier.urihttp://hdl.handle.net/10754/563361en
dc.description.abstractFocal 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. © 2014 The Authors.en
dc.description.sponsorshipWe thank S. Lachkar for help with SEC, K. Muller and V. Unkefer for editorial assistance, J.E. Ladbury for access to the MicroCal iTC200, L. Ponchon for help with DLS, D. Svergun and his colleagues for assistance with SAXS data recording and analysis at the x33 beamline at the European Molecular Biology Laboratory/Deutsches Elektronen-Synchrotron, G. Meigs for help with X-ray crystallography data recording at the Advanced Light Source beamline bl.8.3.1., Berkeley, CA, D. Ilic for the gift of Ptk2<SUP>-/-</SUP> fibroblasts, and A. Sobel and R.M. Mege for critical reading of the manuscript. We acknowledge support with data recording at the European Synchrotron Radiation Facility beamline ID14 and from the European Community Research Infrastructure Action under the Sixth Framework Program (RII3/CT/2004/5060008) for access to the European Molecular Biology Laboratory/Deutsches Elektronen-Synchrotron. This work was supported by Agence Nationale de la Recherche (ANR-05-2_42589), Association pour la Recherche sur le Cancer (ARC, A05/3/3138), Fondation pour la Recherche Medicale, European Research Council, Inserm, the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center, by NIH/NCI grant R03 CA169969-01, and, in part, by the National Institutes of Health through MD Anderson's Cancer Center Support Grant (CA016672). KBC was recipient of fellowships from ARC and Region Ile de France (NeRF). J.A. Girault's group is affiliated with the Ecole des Neurosciences de Paris-Ile-de-France and the Bio-Psy Laboratory of Excellence.en
dc.publisherWiley-Blackwellen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989642en
dc.subjectCell adhesionen
dc.subjectFocal adhesionen
dc.subjectFocal adhesion kinaseen
dc.subjectNon-receptor tyrosine kinaseen
dc.subjectSignal transductionen
dc.titleFAK dimerization controls its kinase-dependent functions at focal adhesionsen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.contributor.departmentBioscience Programen
dc.contributor.departmentStructural Biology and Engineeringen
dc.identifier.journalThe EMBO Journalen
dc.identifier.pmcidPMC3989642en
dc.contributor.institutionInserm UMR-S839, Paris, Franceen
dc.contributor.institutionUniversité Pierre et Marie Curie (UPMC), Paris, Franceen
dc.contributor.institutionInstitut du Fer à Moulin, Paris, Franceen
dc.contributor.institutionInserm U554, Montpellier, Franceen
dc.contributor.institutionCNRS, UMR5048, Centre de Biochimie Structurale, Montpellier, Franceen
dc.contributor.institutionUniversités Montpellier 1 and 2, Montpellier, Franceen
dc.contributor.institutionDepartment of Biochemistry and Molecular Biology, Center for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX, United Statesen
dc.contributor.institutionIFR83, Institut de Biologie Intégrative, Paris, Franceen
dc.contributor.institutionCenter for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, United Statesen
dc.contributor.institutionDepartment of Environmental Protection, CSIC-Estación Experimental del Zaidín, Granada, Spainen
dc.contributor.institutionLIMATB, EA 4250, Université de Bretagne Sud, Lorient, Franceen
kaust.authorArold, Stefan T.en

Related articles on PubMed

All Items in KAUST are protected by copyright, with all rights reserved, unless otherwise indicated.