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

被引：196

作者：

Aharonov, Alla ^{[1
]}

Shakked, Avraham ^{[1
]}

Umansky, Kfir Baruch ^{[1
]}

Savidor, Alon ^{[2
,3
]}

Genzelinakh, Alexander ^{[1
]}

Kain, David ^{[1
]}

Lendengolts, Daria ^{[1
]}

Revach, Or-Yam ^{[1
]}

Morikawa, Yuka ^{[4
]}

Dong, Jixin ^{[5
]}

Levin, Yishai ^{[2
,3
]}

Geiger, Benjamin ^{[1
]}

Martin, James F. ^{[4
,6
]}

Tzahor, Eldad ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel

[2] Weizmann Inst Sci, De Botton Prot Profiling Inst Nancy, Rehovot, Israel

[3] Weizmann Inst Sci, Stephen Grand Israel Natl Ctr Personalized Med, Rehovot, Israel

[4] Texas Heart Inst, Cardiomyocyte Renewal Lab, Houston, TX 77025 USA

[5] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Eppley Inst Res Canc, Omaha, NE USA

[6] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA

来源：

NATURE CELL BIOLOGY | 2020年 / 22卷 / 11期

基金：

美国国家卫生研究院; 欧洲研究理事会; 欧盟地平线“2020”; 以色列科学基金会;

关键词：

HEART REGENERATION; HIPPO PATHWAY; CARDIOMYOCYTE PROLIFERATION; PHOSPHORYLATION; YAP/TAZ; GROWTH; DEDIFFERENTIATION; ONCOPROTEIN; EXPRESSION; NUCLEUS;

D O I：

10.1038/s41556-020-00588-4

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：1346 / +

页数：20

共 68 条

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