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

• Published in: Nature communications Vol. 11; no. 1; pp. 1733 - 16
• Main Authors: Tomasovic, Angela, Brand, Theresa, Schanbacher, Constanze, Kramer, Sofia, Hümmert, Martin W, Godoy, Patricio, Schmidt-Heck, Wolfgang, Nordbeck, Peter, Ludwig, Jonas, Homann, Susanne, Wiegering, Armin, Shaykhutdinov, Timur, Kratz, Christoph, Knüchel, Ruth, Müller-Hermelink, Hans-Konrad, Rosenwald, Andreas, Frey, Norbert, Eichler, Jutta, Dobrev, Dobromir, El-Armouche, Ali, Hengstler, Jan G, Müller, Oliver J, Hinrichs, Karsten, Cuello, Friederike, Zernecke, Alma, Lorenz, Kristina
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 07.04.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Cancer; Cardiomyocytes; Cardiotoxicity; Cell Culture Techniques; Cell proliferation; Cell-Penetrating Peptides - chemical synthesis; Cell-Penetrating Peptides - pharmacology; Cell-Penetrating Peptides - toxicity; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Congestive heart failure; Coronary artery disease; Dimerization; Disorders; Drug delivery; Drug Delivery Systems; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - drug effects; Extracellular Signal-Regulated MAP Kinases - metabolism; Heart failure; Heart Failure - drug therapy; Heart Failure - metabolism; Humans; Hypertrophy; Interference; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mice; Mice, Inbred C57BL; Molecular Medicine; Phosphorylation; Rats; Rats, Sprague-Dawley; Side effects; Signal Transduction; Signaling; Strategy
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15505-4

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. ERK -autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERK -phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERK -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, ERK -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.