Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects
Angela Tomasovic, Theresa Brand, Constanze Schanbacher, Sofia Kramer, Martin W. Hümmert, Patrício Godoy, Wolfgang Schmidt‐Heck, Peter Nordbeck, Jonas Ludwig, Susanne Homann, Armin Wiegering, Timur Shaykhutdinov, Christoph Kratz, Ruth Knüchel, Hans–Konrad Müller–Hermelink, Andreas Rosenwald, Norbert Frey, Jutta Eichler, Dobromir Dobrev, Ali El‐Armouche, Jan G. Hengstler, Oliver J. Müller, Karsten Hinrichs, Friederike Cuello, Alma Zernecke, Kristina Lorenz
Abstract
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. ERK T188 -autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERK T188 -phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERK T188 -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 T188 -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.