EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation

Maria Shoykhet; Orsela Dervishi; Philipp Menauer; Matthias Hiermaier; Sina Moztarzadeh; Colin Osterloh; Ralf J. Ludwig; Tatjana Williams; Brenda Gerull; Stefan Kääb; Sebastian Clauss; Dominik Schüttler; Jens Waschke; Sunil Yeruva

doi:10.1172/jci.insight.163763

EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation

Maria Shoykhet, Orsela Dervishi, Philipp Menauer, Matthias Hiermaier, Sina Moztarzadeh, Colin Osterloh, Ralf J. Ludwig, Tatjana Williams, Brenda Gerull, Stefan Kääb, Sebastian Clauss, Dominik Schüttler, Jens Waschke, Sunil Yeruva^*

^*Corresponding author for this work

Institute of Experimental Dermatology

11 Citations (Scopus)

Abstract

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.

Original language	English
Article number	e163763
Journal	JCI Insight
Volume	8
Issue number	6
ISSN	2379-3708
DOIs	https://doi.org/10.1172/jci.insight.163763
Publication status	Published - 22.03.2023

Funding

This work was supported by the LMU Munich through the FöFoLe program (to JW and DS), the Deutsche Forschungsgemeinschaft (grant WA2474/11-1 to JW; EXC 2167, GRK 2633, and LU 877/23-1 to RJL; grant CRC1525, project no. 453989101 to BG; and the Clinician Scientist Program In Vascular Medicine [PRIME, MA 2186/14-1] to DS), by the Schleswig-Holstein Excellence-Chair Program from the State of Schleswig Holstein to RJL, and grant CRSII5_202301/1 from the Swiss National Science Foundation to RJL. Furthermore, this work was supported by the German Center for Cardiovascular Research (81X2600255, 81X2600270, and 81X2600266 to SC; 81Z0600206 and 81X2600265 to SK), the Corona Foundation (S199/10079/2019 to SC), and ERA-NET on Cardiovascular Diseases (ERA-CVD; 01KL1910 to SC). We thank Bianca Hildebrandt, Martina Hitzenbichler, Daniela Kugelmann, Kathleen Plietz, Kilian Skowranek, and the AFM tip-coating team for their help and technical assistance.

Research Areas and Centers

Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

2.22-19 Dermatology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/jci.insight.163763

Cite this

Shoykhet, M., Dervishi, O., Menauer, P., Hiermaier, M., Moztarzadeh, S., Osterloh, C., Ludwig, R. J., Williams, T., Gerull, B., Kääb, S., Clauss, S., Schüttler, D., Waschke, J., & Yeruva, S. (2023). EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation. JCI Insight, 8(6), Article e163763. https://doi.org/10.1172/jci.insight.163763

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title = "EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation",

abstract = "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.",

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T1 - EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation

AU - Shoykhet, Maria

AU - Dervishi, Orsela

AU - Menauer, Philipp

AU - Hiermaier, Matthias

AU - Moztarzadeh, Sina

AU - Osterloh, Colin

AU - Ludwig, Ralf J.

AU - Williams, Tatjana

AU - Gerull, Brenda

AU - Kääb, Stefan

AU - Clauss, Sebastian

AU - Schüttler, Dominik

AU - Waschke, Jens

AU - Yeruva, Sunil

PY - 2023/3/22

Y1 - 2023/3/22

N2 - 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.

AB - 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.

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EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

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