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 - Caracterizacao topologica e funcional da interacao entre a tirosina quinase fak e o fator de transcricao mef2.
• Beneficiário: Alisson Campos Cardoso
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 08/53583-5 - Efeito do silenciamento genico do fator de transcricao mef2c na hipertrofia e insuficiencia cardiaca induzida por sobrecarga pressorica cronica.
• Beneficiário: Ana Helena Macedo Pereira
• Modalidade de apoio: Bolsas no Brasil - Doutorado