title: FAK Forms a Complex with MEF2 to Couple Biomechanical Signaling to Transcription in Cardiomyocytes.
abstract: Focal adhesion kinase (FAK) has emerged as a mediator of mechanotransduction in cardiomyocytes, regulating gene expression during hypertrophic remodeling. However, how FAK signaling is relayed onward to the nucleus is unclear. Here, we show that FAK interacts with and regulates myocyte enhancer factor 2 (MEF2), a master cardiac transcriptional regulator. In cardiomyocytes exposed to biomechanical stimulation, FAK accumulates in the nucleus, binds to and upregulates the transcriptional activity of MEF2 through an interaction with the FAK focal adhesion targeting (FAT) domain. In the crystal structure (2.9 Å resolution), FAT binds to a stably folded groove in the MEF2 dimer, known to interact with regulatory cofactors. FAK cooperates with MEF2 to enhance the expression of Jun in cardiomyocytes, an important component of hypertrophic response to mechanical stress. These findings underscore a connection between the mechanotransduction involving FAK and transcriptional regulation by MEF2, with potential relevance to the pathogenesis of cardiac disease.
authors.affiliation: Brazilian National Laboratory for Biosciences, Center for Research in Energy and Materials, Campinas, São Paulo 13084-971, Brazil.
authors.forename: Alisson Campos
authors.initials: AC
authors.lastname: Cardoso
authors.affiliation: Brazilian National Laboratory for Biosciences, Center for Research in Energy and Materials, Campinas, São Paulo 13084-971, Brazil.
authors.forename: Ana Helena Macedo
authors.initials: AHM
authors.lastname: Pereira
authors.affiliation: Brazilian National Laboratory for Biosciences, Center for Research in Energy and Materials, Campinas, São Paulo 13084-971, Brazil.
authors.forename: Andre Luis Berteli
authors.initials: ALB
authors.lastname: Ambrosio
authors.affiliation: Brazilian National Laboratory for Biosciences, Center for Research in Energy and Materials, Campinas, São Paulo 13084-971, Brazil.
authors.forename: Silvio Roberto
authors.initials: SR
authors.lastname: Consonni
authors.affiliation: Brazilian National Laboratory for Biosciences, Center for Research in Energy and Materials, Campinas, São Paulo 13084-971, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Rocha de Oliveira
authors.affiliation: Brazilian National Laboratory for Biosciences, Center for Research in Energy and Materials, Campinas, São Paulo 13084-971, Brazil.
authors.forename: Marcio Chain
authors.initials: MC
authors.lastname: Bajgelman
authors.affiliation: Brazilian National Laboratory for Biosciences, Center for Research in Energy and Materials, Campinas, São Paulo 13084-971, Brazil.
authors.forename: Sandra Martha Gomes
authors.initials: SMG
authors.lastname: Dias
authors.affiliation: Brazilian National Laboratory for Biosciences, Center for Research in Energy and Materials, Campinas, São Paulo 13084-971, Brazil; Department of Internal Medicine, School of Medicine, University of Campinas, Campinas, São Paulo 13081-970, Brazil. Electronic address: kleber.franchini@lnbio.cnpem.br.
authors.forename: Kleber Gomes
authors.initials: KG
authors.lastname: Franchini
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D007700:Kinetics; D064326:MEF2 Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D008958:Models, Molecular; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D061251:Primary Cell Culture; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse