FAK Forms a Complex with MEF2 to Couple Biomechanical Signaling to Transcription in Cardiomyocytes

Alisson Campos Cardoso; Ana Helena Macedo Pereira; Andre Luis Berteli Ambrosio; Silvio Roberto Consonni; Renata Rocha de Oliveira; Marcio Chain Bajgelman; Sandra Martha Gomes Dias; Kleber Gomes Franchini

doi:10.1016/j.str.2016.06.003

FAK Forms a Complex with MEF2 to Couple Biomechanical Signaling to Transcription in Cardiomyocytes

Structure. 2016 Aug 2;24(8):1301-1310. doi: 10.1016/j.str.2016.06.003. Epub 2016 Jul 14.

Authors

Alisson Campos Cardoso¹, Ana Helena Macedo Pereira¹, Andre Luis Berteli Ambrosio¹, Silvio Roberto Consonni¹, Renata Rocha de Oliveira¹, Marcio Chain Bajgelman¹, Sandra Martha Gomes Dias¹, Kleber Gomes Franchini²

Affiliations

¹ Brazilian National Laboratory for Biosciences, Center for Research in Energy and Materials, Campinas, São Paulo 13084-971, Brazil.
² 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: [email protected].

PMID: 27427476
DOI: 10.1016/j.str.2016.06.003

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.

MeSH terms

Amino Acid Motifs
Animals
Animals, Newborn
Binding Sites
Cell Line
Cell Nucleus / metabolism
Cloning, Molecular
Crystallography, X-Ray
Escherichia coli / genetics
Escherichia coli / metabolism
Focal Adhesion Kinase 1 / chemistry*
Focal Adhesion Kinase 1 / genetics
Focal Adhesion Kinase 1 / metabolism
Gene Expression
Gene Expression Regulation
Kinetics
MEF2 Transcription Factors / chemistry
MEF2 Transcription Factors / genetics
MEF2 Transcription Factors / metabolism
Mechanotransduction, Cellular*
Mice
Models, Molecular
Myocytes, Cardiac / cytology
Myocytes, Cardiac / metabolism*
Primary Cell Culture
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Proto-Oncogene Proteins c-jun / chemistry*
Proto-Oncogene Proteins c-jun / genetics
Proto-Oncogene Proteins c-jun / metabolism
Rats
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Transcription, Genetic*

Substances

MEF2 Transcription Factors
Mef2c protein, mouse
Proto-Oncogene Proteins c-jun
Recombinant Proteins
Focal Adhesion Kinase 1
Ptk2 protein, mouse