title: FERM domain interaction with myosin negatively regulates FAK in cardiomyocyte hypertrophy.
abstract: Focal adhesion kinase (FAK) regulates cellular processes that affect several aspects of development and disease. The FAK N-terminal FERM (4.1 protein-ezrin-radixin-moesin homology) domain, a compact clover-leaf structure, binds partner proteins and mediates intramolecular regulatory interactions. Combined chemical cross-linking coupled to MS, small-angle X-ray scattering, computational docking and mutational analyses showed that the FAK FERM domain has a molecular cleft (~998 Å(2)) that interacts with sarcomeric myosin, resulting in FAK inhibition. Accordingly, mutations in a unique short amino acid sequence of the FERM myosin cleft, FP-1, impaired the interaction with myosin and enhanced FAK activity in cardiomyocytes. An FP-1 decoy peptide selectively inhibited myosin interaction and increased FAK activity, promoting cardiomyocyte hypertrophy through activation of the AKT-mammalian target of rapamycin pathway. Our findings uncover an inhibitory interaction between the FAK FERM domain and sarcomeric myosin that presents potential opportunities to modulate the cardiac hypertrophic response through changes in FAK activity.
authors.affiliation: Department of Internal Medicine, School of Medicine, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Aline M
authors.initials: AM
authors.lastname: Santos
authors.forename: Deborah
authors.initials: D
authors.lastname: Schechtman
authors.forename: Alisson C
authors.initials: AC
authors.lastname: Cardoso
authors.forename: Carolina F M Z
authors.initials: CF
authors.lastname: Clemente
authors.forename: Júlio C
authors.initials: JC
authors.lastname: Silva
authors.forename: Mariana
authors.initials: M
authors.lastname: Fioramonte
authors.forename: Michelle B M
authors.initials: MB
authors.lastname: Pereira
authors.forename: Talita M
authors.initials: TM
authors.lastname: Marin
authors.forename: Paulo S L
authors.initials: PS
authors.lastname: Oliveira
authors.forename: Ana Carolina M
authors.initials: AC
authors.lastname: Figueira
authors.forename: Saulo H P
authors.initials: SH
authors.lastname: Oliveira
authors.forename: Íris L
authors.initials: ÍL
authors.lastname: Torriani
authors.forename: Fábio C
authors.initials: FC
authors.lastname: Gozzo
authors.forename: José
authors.initials: J
authors.lastname: Xavier Neto
authors.forename: Kleber G
authors.initials: KG
authors.lastname: Franchini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002645:Chickens; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D006984:Hypertrophy / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D032383:Myocytes, Cardiac / Q000737:chemistry* / Q000378:metabolism; D009218:Myosins / Q000737:chemistry* / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051416:Focal Adhesion Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D009218:Myosins
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