Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects
Open Access
- 7 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-16
- https://doi.org/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.Funding Information
- Deutsche Forschungsgemeinschaft (SFB1116)
- Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (DZHI)
- Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen (DDHD)
This publication has 75 references indexed in Scilit:
- Interference with ERK Thr188 phosphorylation impairs pathological but not physiological cardiac hypertrophyProceedings of the National Academy of Sciences of the United States of America, 2013
- Comprehensive molecular characterization of human colon and rectal cancerNature, 2012
- Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivoProceedings of the National Academy of Sciences of the United States of America, 2011
- Small‐Molecule Inhibitors of the ERK Signaling Pathway: Towards Novel Anticancer TherapeuticsChemMedChem, 2010
- Role of ERK1/2 signaling in congenital valve malformations in Noonan syndromeProceedings of the National Academy of Sciences of the United States of America, 2008
- DUSP6 (MKP3) Null Mice Show Enhanced ERK1/2 Phosphorylation at Baseline and Increased Myocyte Proliferation in the Heart Affecting Disease SusceptibilityOnline Journal of Public Health Informatics, 2008
- MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targetsClinical Science, 2008
- Spatiotemporal Regulation of ERK2 by Dual Specificity PhosphatasesOnline Journal of Public Health Informatics, 2008
- Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivoProceedings of the National Academy of Sciences of the United States of America, 2007
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001