Cargando…
EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation
Arrhythmogenic cardiomyopathy (AC) is a familial heart disease partly caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity may provide new treatment options. Desmosomes, apart from cellular cohesion, provide the structural framework of a signaling hub. Here, we investiga...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070108/ https://www.ncbi.nlm.nih.gov/pubmed/36795511 http://dx.doi.org/10.1172/jci.insight.163763 |
_version_ | 1785018966902571008 |
---|---|
author | Shoykhet, Maria Dervishi, Orsela Menauer, Philipp Hiermaier, Matthias Moztarzadeh, Sina Osterloh, Colin Ludwig, Ralf J. Williams, Tatjana Gerull, Brenda Kääb, Stefan Clauss, Sebastian Schüttler, Dominik Waschke, Jens Yeruva, Sunil |
author_facet | Shoykhet, Maria Dervishi, Orsela Menauer, Philipp Hiermaier, Matthias Moztarzadeh, Sina Osterloh, Colin Ludwig, Ralf J. Williams, Tatjana Gerull, Brenda Kääb, Stefan Clauss, Sebastian Schüttler, Dominik Waschke, Jens Yeruva, Sunil |
author_sort | Shoykhet, Maria |
collection | PubMed |
description | Arrhythmogenic cardiomyopathy (AC) is a familial heart disease partly caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity may provide new treatment options. Desmosomes, apart from cellular cohesion, provide the structural framework of a signaling hub. Here, we investigated the role of the epidermal growth factor receptor (EGFR) in cardiomyocyte cohesion. We inhibited EGFR under physiological and pathophysiological conditions using the murine plakoglobin-KO AC model, in which EGFR was upregulated. EGFR inhibition enhanced cardiomyocyte cohesion. Immunoprecipitation showed an interaction of EGFR and desmoglein 2 (DSG2). Immunostaining and atomic force microscopy (AFM) revealed enhanced DSG2 localization and binding at cell borders upon EGFR inhibition. Enhanced area composita length and desmosome assembly were observed upon EGFR inhibition, confirmed by enhanced DSG2 and desmoplakin (DP) recruitment to cell borders. PamGene Kinase assay performed in HL-1 cardiomyocytes treated with erlotinib, an EGFR inhibitor, revealed upregulation of Rho-associated protein kinase (ROCK). Erlotinib-mediated desmosome assembly and cardiomyocyte cohesion were abolished upon ROCK inhibition. Thus, inhibiting EGFR and, thereby, stabilizing desmosome integrity via ROCK might provide treatment options for AC. |
format | Online Article Text |
id | pubmed-10070108 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-100701082023-04-05 EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation Shoykhet, Maria Dervishi, Orsela Menauer, Philipp Hiermaier, Matthias Moztarzadeh, Sina Osterloh, Colin Ludwig, Ralf J. Williams, Tatjana Gerull, Brenda Kääb, Stefan Clauss, Sebastian Schüttler, Dominik Waschke, Jens Yeruva, Sunil JCI Insight Research Article Arrhythmogenic cardiomyopathy (AC) is a familial heart disease partly caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity may provide new treatment options. Desmosomes, apart from cellular cohesion, provide the structural framework of a signaling hub. Here, we investigated the role of the epidermal growth factor receptor (EGFR) in cardiomyocyte cohesion. We inhibited EGFR under physiological and pathophysiological conditions using the murine plakoglobin-KO AC model, in which EGFR was upregulated. EGFR inhibition enhanced cardiomyocyte cohesion. Immunoprecipitation showed an interaction of EGFR and desmoglein 2 (DSG2). Immunostaining and atomic force microscopy (AFM) revealed enhanced DSG2 localization and binding at cell borders upon EGFR inhibition. Enhanced area composita length and desmosome assembly were observed upon EGFR inhibition, confirmed by enhanced DSG2 and desmoplakin (DP) recruitment to cell borders. PamGene Kinase assay performed in HL-1 cardiomyocytes treated with erlotinib, an EGFR inhibitor, revealed upregulation of Rho-associated protein kinase (ROCK). Erlotinib-mediated desmosome assembly and cardiomyocyte cohesion were abolished upon ROCK inhibition. Thus, inhibiting EGFR and, thereby, stabilizing desmosome integrity via ROCK might provide treatment options for AC. American Society for Clinical Investigation 2023-03-22 /pmc/articles/PMC10070108/ /pubmed/36795511 http://dx.doi.org/10.1172/jci.insight.163763 Text en © 2023 Shoykhet et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Shoykhet, Maria Dervishi, Orsela Menauer, Philipp Hiermaier, Matthias Moztarzadeh, Sina Osterloh, Colin Ludwig, Ralf J. Williams, Tatjana Gerull, Brenda Kääb, Stefan Clauss, Sebastian Schüttler, Dominik Waschke, Jens Yeruva, Sunil EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation |
title | EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation |
title_full | EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation |
title_fullStr | EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation |
title_full_unstemmed | EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation |
title_short | EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation |
title_sort | egfr inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via rock activation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070108/ https://www.ncbi.nlm.nih.gov/pubmed/36795511 http://dx.doi.org/10.1172/jci.insight.163763 |
work_keys_str_mv | AT shoykhetmaria egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT dervishiorsela egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT menauerphilipp egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT hiermaiermatthias egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT moztarzadehsina egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT osterlohcolin egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT ludwigralfj egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT williamstatjana egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT gerullbrenda egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT kaabstefan egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT clausssebastian egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT schuttlerdominik egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT waschkejens egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation AT yeruvasunil egfrinhibitionleadstoenhanceddesmosomeassemblyandcardiomyocytecohesionviarockactivation |