Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects

Tomasovic A, Brand T, Schanbacher C, Kramer S, Hümmert MW, Godoy P, Schmidt-Heck W, Nordbeck P, Ludwig J, Homann S, Wiegering A, Shaykhutdinov T, Kratz C, Knüchel R, Müller-Hermelink HK, Rosenwald A, Frey N, Eichler J, Dobrev D, El-Armouche A, Hengstler JG, Müller OJ, Hinrichs K, Cuello F, Zernecke A, Lorenz K (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 11

Article Number: 1733

Journal Issue: 1

DOI: 10.1038/s41467-020-15505-4

Abstract

Dysregulation of extracellular signal-regulated kinases (ERK1/2) is linked to several diseases including heart failure, genetic syndromes and cancer. Inhibition of ERK1/2, however, can cause severe cardiac side-effects, precluding its wide therapeutic application. ERKT188-autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERKT188-phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERKT188-phosphorylation, nuclear ERK1/2-signaling and cardiomyocyte hypertrophy, protecting from pressure-overload-induced heart failure in mice whilst preserving ERK1/2-activity and cytosolic survival signaling. We also examine this alternative ERK1/2-targeting strategy in cancer: indeed, ERKT188-phosphorylation is strongly upregulated in cancer and EDI efficiently suppresses cancer cell proliferation without causing cardiotoxicity. This powerful cardio-safe strategy of interfering with ERK-dimerization thus combats pathological ERK1/2-signaling in heart and cancer, and may potentially expand therapeutic options for ERK1/2-related diseases, such as heart failure and genetic syndromes.

Authors with CRIS profile

Jonas Ludwig Lehrstuhl für Pharmazeutische Chemie Jutta Eichler Professur für Pharmazeutische Chemie

Involved external institutions

Julius-Maximilians-Universität Würzburg DE Germany (DE) Technische Universität Dortmund DE Germany (DE) Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie (Hans-Knöll-Institut (HKI)) / Leibniz Institute for Natural Product Research and Infection Biology DE Germany (DE) Fraunhofer-Institut für Biomedizinische Technik (IBMT) / Fraunhofer Institute for Biomedical Engineering DE Germany (DE) Universitätsklinikum Würzburg DE Germany (DE) Leibniz-Institut für Analytische Wissenschaften / Leibniz Institute for Analytical Sciences (ISAS) DE Germany (DE) Universitätsklinikum Aachen (UKA) DE Germany (DE) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Universität Duisburg-Essen (UDE) DE Germany (DE) Technische Universität Dresden DE Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE)

How to cite

APA:

Tomasovic, A., Brand, T., Schanbacher, C., Kramer, S., Hümmert, M.W., Godoy, P.,... Lorenz, K. (2020). Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects. Nature Communications, 11(1). https://dx.doi.org/10.1038/s41467-020-15505-4

MLA:

Tomasovic, Angela, et al. "Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects." Nature Communications 11.1 (2020).

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