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, Patricio 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 and Kristina Lorenz ()
Additional contact information
Angela Tomasovic: University of Würzburg
Theresa Brand: University of Würzburg
Constanze Schanbacher: University of Würzburg
Sofia Kramer: University of Würzburg
Martin W. Hümmert: University of Würzburg
Patricio Godoy: IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund
Wolfgang Schmidt-Heck: Leibniz Institute for Natural Product Research and Infection Biology -Hans Knoell Institute-
Peter Nordbeck: Comprehensive Heart Failure Center
Jonas Ludwig: Friedrich-Alexander-Universität Erlangen-Nürnberg
Susanne Homann: University of Würzburg
Armin Wiegering: University Hospital of Würzburg
Timur Shaykhutdinov: Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V.
Christoph Kratz: Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V.
Ruth Knüchel: University Hospital Aachen, RWTH Aachen
Hans-Konrad Müller-Hermelink: University of Würzburg
Andreas Rosenwald: University of Würzburg
Norbert Frey: University of Kiel
Jutta Eichler: Friedrich-Alexander-Universität Erlangen-Nürnberg
Dobromir Dobrev: University Duisburg-Essen
Ali El-Armouche: TU Dresden
Jan G. Hengstler: IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund
Oliver J. Müller: University of Kiel
Karsten Hinrichs: Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V.
Friederike Cuello: University Medical Center Hamburg-Eppendorf
Alma Zernecke: University Hospital Würzburg, University of Würzburg
Kristina Lorenz: University of Würzburg

Nature Communications, 2020, vol. 11, issue 1, 1-16

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. 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.

Date: 2020
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DOI: 10.1038/s41467-020-15505-4

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