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

Authors:

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

Keywords:

Epidermal growth factor receptor, erlotinib, desmoglein 2, desmoplakin, arrhythmogenic cardiomyopathy, ROCK

Abstract:

Arrhythmogenic cardiomyopathy (AC) is a familial heart disease partly caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity may provide potential 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 knockout AC model, in which EGFR was upregulated. EGFR inhibition enhanced cardiomyocyte cohesion. Immunoprecipitation showed an interaction of EGFR and desmoglein 2 (DSG2). Immunostaining and 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 cells treated with Erlotinib, an EGFR inhibitor, revealed upregulation of RhoA associated protein kinase (ROCK). Erlotinib-mediated desmosome assembly and cardiomyocyte cohesion were abolished upon ROCK inhibition. Thus, inhibiting EGFR, thereby stabilizing desmosome integrity via ROCK, might provide new treatment options for AC

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