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*

*Korrespondierende/r Autor/-in für diese Arbeit
1 Zitat (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.

OriginalspracheEnglisch
Aufsatznummere163763
ZeitschriftJCI insight
Jahrgang8
Ausgabenummer6
ISSN2379-3708
DOIs
PublikationsstatusVeröffentlicht - 22.03.2023

Strategische Forschungsbereiche und Zentren

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

DFG-Fachsystematik

  • 205-19 Dermatologie

Fingerprint

Untersuchen Sie die Forschungsthemen von „EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation“. Zusammen bilden sie einen einzigartigen Fingerprint.

Zitieren