Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects
Nature Communications, vol. 11, pp. 1733
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.
Authors 25
-
University of Würzburg · Leibniz Institute for Analytical Sciences - ISAS
Affiliation as printed
Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany
Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 44139, Dortmund, Germany
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V., 44139, Dortmund, Germany
-
University of Würzburg · Leibniz Institute for Analytical Sciences - ISAS
Affiliation as printed
Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany
Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 44139, Dortmund, Germany
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V., 44139, Dortmund, Germany
-
University of Würzburg · Leibniz Institute for Analytical Sciences - ISAS
Affiliation as printed
Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany
Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 44139, Dortmund, Germany
-
Affiliation as printed
Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany
-
University of Würzburg · Medizinische Hochschule Hannover
Affiliation as printed
Department of Neurology, Hannover Medical School, 30625, Hannover, Germany
Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany
-
TU Dortmund University · Leibniz Research Centre for Working Environment and Human Factors
Affiliation as printed
IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, 44139, Dortmund, Germany
-
Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)
Affiliation as printed
Leibniz Institute for Natural Product Research and Infection Biology -Hans Knoell Institute-, 07745, Jena, Germany
-
Affiliation as printed
Comprehensive Heart Failure Center, 97078, Würzburg, Germany
-
Friedrich-Alexander-Universität Erlangen-Nürnberg
Affiliation as printed
Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058, Erlangen, Germany
-
University of Würzburg · Universitätsklinikum Würzburg
Affiliation as printed
Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, 97080, Würzburg, Germany
-
Leibniz Institute for Analytical Sciences - ISAS
Affiliation as printed
Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 12489, Berlin, Germany
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V., 12489, Berlin, Germany
-
Leibniz Institute for Analytical Sciences - ISAS
Affiliation as printed
Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 12489, Berlin, Germany
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V., 12489, Berlin, Germany
-
Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Pathology, University Hospital Aachen, RWTH Aachen, 52074, Aachen, Germany
-
Affiliation as printed
Institute of Pathology, University of Würzburg, 97080, Würzburg, Germany
-
Affiliation as printed
Institute of Pathology, University of Würzburg, 97080, Würzburg, Germany
-
Christian-Albrechts-Universität zu Kiel · German Centre for Cardiovascular Research
Affiliation as printed
DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany
Department of Internal Medicine III, University of Kiel, 24105, Kiel, Germany
-
Friedrich-Alexander-Universität Erlangen-Nürnberg
Affiliation as printed
Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058, Erlangen, Germany
-
West German Heart and Vascular Center Essen · University of Duisburg-Essen
Affiliation as printed
Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, 45147, Essen, Germany
-
Technische Universität Dresden
Affiliation as printed
Department of Pharmacology and Toxicology, TU Dresden, 01307, Dresden, Germany
-
TU Dortmund University · Leibniz Research Centre for Working Environment and Human Factors
Affiliation as printed
IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, 44139, Dortmund, Germany
-
Christian-Albrechts-Universität zu Kiel · German Centre for Cardiovascular Research
Affiliation as printed
DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany
Department of Internal Medicine III, University of Kiel, 24105, Kiel, Germany
-
Leibniz Institute for Analytical Sciences - ISAS
Affiliation as printed
Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 12489, Berlin, Germany
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V., 12489, Berlin, Germany
-
University Medical Center Hamburg-Eppendorf · German Centre for Cardiovascular Research
Affiliation as printed
DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
-
University of Würzburg · Universitätsklinikum Würzburg
Affiliation as printed
Institute of Experimental Biomedicine, University Hospital Würzburg, University of Würzburg, 97080, Würzburg, Germany
-
Kristina Lorenz corresponding
University of Würzburg · Leibniz Institute for Analytical Sciences - ISAS
Affiliation as printed
Comprehensive Heart Failure Center, 97078, Würzburg, Germany. lorenz@toxi.uni-wuerzburg.de
Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany. lorenz@toxi.uni-wuerzburg.de
Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 44139, Dortmund, Germany. lorenz@toxi.uni-wuerzburg.de
Comprehensive Heart Failure Center, 97078, Würzburg, Germany
Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V., 44139, Dortmund, Germany
Cited by 62 stored of 63
No patents citing this paper on Lens.org (checked 2026-10-06).