Direct interaction with FAK couples MEF2 transcriptional activity to mechanical sensing in cardiac myocytes

Informações

Data: 06/10/2014 – 08:30:00

Fim: 06/10/2014 – 17:00:00

Onde: CNPEM – Rua Giuseppe Máximo Scolfaro, 10.000 – Campinas, SÃO PAULO 13280000 Brazil – Telefone: 19 35121267

Detalhes

Abstract: The heart and individual myocytes undergo structural remodelling in response to mechanical loading, a process fundamental to cardiac homeostasis but also linked to an increased risk of heart failure in clinical settings of hypertension and myocardial infarction. Focal adhesion kinase (FAK), a tyrosine kinase that senses the mechanical stimuli, and the transcription factor myocyte enhancer factor-2 (MEF2) are key participants in this process. Notably, FAK plays an important role in regulating the load-induced activation of MEF2, supporting the notion that they mechanistically integrate into a signalling pathway to control the response of cardiac myocytes to mechanical loading. Yet how FAK regulates the MEF2 activity remains unknown. Here, we show that FAK shuttles to the nucleus, binds and regulates the transcriptional activity of MEF2 in cardiac myocytes exposed to cyclic stretch through an interaction with the FAK’s C-terminal focal adhesion targeting (FAT) domain. To shed light on the structural determinants of this interaction we present the X-ray crystal structure of the FAK FAT domain bound to the conserved MADS box/MEF2 domain of MEF2C, to 2.9-Å maximum resolution. The molecular model reveals that the α2 helix of the FAK FAT domain binds to a hydrophobic groove of a stably folded MADS box/MEF2 dimer, forming a triple-helix bundle with the H2 helices of the MEF2 domains. Mutational analysis confirmed the critical importance of the FAK FAT K955, L959 and R962 residues to the interaction with MADS box/MEF2 dimer. Chromatin immunoprecipitation and reporter gene assays revealed a role for FAK-MEF2 complex in the stretch-induced transcriptional regulation of the immediate early response gene c-jun, which is critical in triggering the load-induced remodelling of cardiac myocytes. These results provide a novel biochemical pathway through which the interaction between FAK and MEF2 transcription factor directly links the sensing of mechanical stimuli to the regulation of early stress response genes in cardiac myocytes.

Speaker: Dr. Alisson Campos Cardoso (LNBio)

6th October 2014 at 8:30am

Room 69 – LNBio
Campus – Centro Nacional de Pesquisa em Energia e Materiais – CNPEM
Rua Giuseppe M. Scolfaro, 10.000 – Guará
Telefone: (19) 3512-1010