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

Alla Aharonov, Avraham Shakked, Kfir Baruch Umansky, Alexander Genzelinakh, David Kain, Daria Lendengolts, Or Yam Revach, Yuka Morikawa, Jixin Dong, Yishai Levin, Benjamin Geiger, James F. Martin, Eldad Tzahor

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1346-1356
Number of pages11
JournalNature Cell Biology
Volume22
Issue number11
Early online date12 Oct 2020
DOIs
StatePublished - Nov 2020

All Science Journal Classification (ASJC) codes

  • Cell Biology

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