ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration.
Nat Cell Biol
; 22(11): 1346-1356, 2020 11.
Article
en En
| MEDLINE
| ID: mdl-33046882
ABSTRACT
Cardiomyocyte loss after injury results in adverse remodelling and fibrosis, inevitably leading to heart failure. The ERBB2-Neuregulin and Hippo-YAP signalling pathways are key mediators of heart regeneration, yet the crosstalk between them is unclear. We demonstrate that transient overexpression of activated ERBB2 in cardiomyocytes (OE CMs) promotes cardiac regeneration in a heart failure model. OE CMs present an epithelial-mesenchymal transition (EMT)-like regenerative response manifested by cytoskeletal remodelling, junction dissolution, migration and extracellular matrix turnover. We identified YAP as a critical mediator of ERBB2 signalling. In OE CMs, YAP interacts with nuclear-envelope and cytoskeletal components, reflecting an altered mechanical state elicited by ERBB2. We identified two YAP-activating phosphorylations on S352 and S274 in OE CMs, which peak during metaphase, that are ERK dependent and Hippo independent. Viral overexpression of YAP phospho-mutants dampened the proliferative competence of OE CMs. Together, we reveal a potent ERBB2-mediated YAP mechanotransduction signalling, involving EMT-like characteristics, resulting in robust heart regeneration.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Regeneración
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Receptor ErbB-2
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Proteínas de Ciclo Celular
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Miocitos Cardíacos
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Proteínas Adaptadoras Transductoras de Señales
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Proliferación Celular
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Transición Epitelial-Mesenquimal
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Insuficiencia Cardíaca
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Infarto del Miocardio
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Nat Cell Biol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Israel