Author
Listed:
- Angela Tomasovic
(University of Würzburg
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V.)
- Theresa Brand
(University of Würzburg
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V.)
- Constanze Schanbacher
(University of Würzburg
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V.)
- Sofia Kramer
(University of Würzburg)
- Martin W. Hümmert
(University of Würzburg
Hannover Medical School)
- 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
DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck)
- 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
DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck)
- Karsten Hinrichs
(Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V.)
- Friederike Cuello
(University Medical Center Hamburg-Eppendorf
partner site Hamburg/Kiel/Lübeck)
- Alma Zernecke
(University Hospital Würzburg, University of Würzburg)
- Kristina Lorenz
(University of Würzburg
Leibniz-Institut für Analytische Wissenschaften − ISAS−e.V.
Comprehensive Heart Failure Center)
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.
Suggested Citation
Angela Tomasovic & Theresa Brand & Constanze Schanbacher & Sofia Kramer & Martin W. Hümmert & Patricio Godoy & Wolfgang Schmidt-Heck & Peter Nordbeck & Jonas Ludwig & Susanne Homann & Armin Wiegering , 2020.
"Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects,"
Nature Communications, Nature, vol. 11(1), pages 1-16, December.
Handle:
RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15505-4
DOI: 10.1038/s41467-020-15505-4
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