Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects
| Autor: | Constanze Schanbacher, Wolfgang Schmidt-Heck, Susanne Homann, Jonas Ludwig, Norbert Frey, Theresa Brand, Dobromir Dobrev, Armin Wiegering, Christoph Kratz, Kristina Lorenz, Timur Shaykhutdinov, Martin W. Hümmert, Jutta Eichler, Angela Tomasovic, Hans Konrad Müller-Hermelink, Patricio Godoy, Alma Zernecke, Peter Nordbeck, Andreas Rosenwald, Friederike Cuello, Jan G. Hengstler, Ali El-Armouche, Karsten Hinrichs, Ruth Knüchel, Sofia Kramer, Oliver J. Müller |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Lung Neoplasms MAP Kinase Signaling System Science Cell Culture Techniques Medizin General Physics and Astronomy Cell-Penetrating Peptides Article General Biochemistry Genetics and Molecular Biology Rats Sprague-Dawley Mice 03 medical and health sciences Drug Delivery Systems 0302 clinical medicine Downregulation and upregulation molecular medicine target identification pharmacology Target identification medicine Animals Humans Extracellular Signal-Regulated MAP Kinases lcsh:Science Heart Failure Pharmacology Cardiotoxicity Multidisciplinary Molecular medicine business.industry Kinase Cancer General Chemistry medicine.disease Rats Mice Inbred C57BL 030104 developmental biology 030220 oncology & carcinogenesis Heart failure Colonic Neoplasms Cancer research lcsh:Q Signal transduction business Dimerization Signal Transduction |
| Zdroj: | Nature Communications, 11:1733 Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) Nature Communications |
| Popis: | 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. Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|