ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration

• Published in: Nature cell biology Vol. 22; no. 11; pp. 1346 - 1356
• Main Authors: Aharonov, Alla, Shakked, Avraham, Umansky, Kfir Baruch, Savidor, Alon, Genzelinakh, Alexander, Kain, David, Lendengolts, Daria, Revach, Or-Yam, Morikawa, Yuka, Dong, Jixin, Levin, Yishai, Geiger, Benjamin, Martin, James F., Tzahor, Eldad
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2020; Nature Publishing Group
• Subjects: 13/95; 14/63; 45/47; 45/91; 631/80/128; 631/80/386; 631/80/641; 631/80/84; 631/80/86; 64/60; 82/58; 96/106; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Biomedical and Life Sciences; Cancer Research; Cardiomyocytes; Cell Biology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Proliferation; Cells, Cultured; Congestive heart failure; Crosstalk; Cytoskeleton; Cytoskeleton - metabolism; Cytoskeleton - pathology; Developmental Biology; Disease Models, Animal; Epithelial-Mesenchymal Transition; ErbB-2 protein; Extracellular matrix; Extracellular Signal-Regulated MAP Kinases - metabolism; Fibrosis; Genetic aspects; Health aspects; Heart cells; Heart failure; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - pathology; Heart Failure - physiopathology; Life Sciences; Mechanotransduction; Mechanotransduction, Cellular; Medical research; Medicine, Experimental; Mesenchyme; Metaphase; Mice, Transgenic; Muscles; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neuregulin; Phosphorylation; Physiological aspects; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Regeneration; Regenerative medicine; Signal transduction; Signaling; Stem Cells; Transcription factors; Yes-associated protein; United States; Israel
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-020-00588-4

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. Aharonov et al. use in vivo genetic approaches to show that ErBB2-mediated YAP activation initiates epithelial–mesenchymal transition-like processes and dedifferentiation of cardiomyocytes to drive heart regeneration.