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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: Structure; v. 24, n. 8, p. 1301-1310, AUG 2 2016.
• Citações Web of Science: 11

Resumo

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 angstrom 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. (AU)

• Processo FAPESP: 08/53519-5 - Caracterização topológica e funcional da interação entre a tirosina quinase FAK e o fator de transcrição MEF2
• Beneficiário: Alisson Campos Cardoso
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 08/53583-5 - Efeito do silenciamento gênico do fator de transcrição MEF2C na hipertrofia e insuficiência cardíaca induzida por sobrecarga pressórica crônica
• Beneficiário: Ana Helena Macedo Pereira
• Linha de fomento: Bolsas no Brasil - Doutorado