ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Cell Cycle Proteins
/ genetics
Cell Proliferation
Cells, Cultured
Cytoskeleton
/ metabolism
Disease Models, Animal
Epithelial-Mesenchymal Transition
Extracellular Signal-Regulated MAP Kinases
/ metabolism
Fibrosis
Heart Failure
/ genetics
Mechanotransduction, Cellular
Mice, Transgenic
Myocardial Infarction
/ genetics
Myocytes, Cardiac
/ metabolism
Phosphorylation
Receptor, ErbB-2
/ genetics
Regeneration
YAP-Signaling Proteins
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
04
02
2020
accepted:
01
09
2020
pubmed:
14
10
2020
medline:
26
1
2021
entrez:
13
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33046882
doi: 10.1038/s41556-020-00588-4
pii: 10.1038/s41556-020-00588-4
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Cycle Proteins
0
YAP-Signaling Proteins
0
Yap1 protein, mouse
0
Erbb2 protein, mouse
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1346-1356Commentaires et corrections
Type : CommentIn
Type : CommentIn
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