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Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects

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Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects. / Tomasovic, Angela; Brand, Theresa; Schanbacher, Constanze; Kramer, Sofia; Hümmert, Martin W; Godoy, Patricio; Schmidt-Heck, Wolfgang; Nordbeck, Peter; Ludwig, Jonas; Homann, Susanne; Wiegering, Armin; Shaykhutdinov, Timur; Kratz, Christoph; Knüchel, Ruth; Müller-Hermelink, Hans-Konrad; Rosenwald, Andreas; Frey, Norbert; Eichler, Jutta; Dobrev, Dobromir; El-Armouche, Ali; Hengstler, Jan G; Müller, Oliver J; Hinrichs, Karsten; Cuello, Friederike; Zernecke, Alma; Lorenz, Kristina.

in: NAT COMMUN, Jahrgang 11, Nr. 1, 07.04.2020, S. 1733.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Tomasovic, A, Brand, T, Schanbacher, C, Kramer, S, Hümmert, MW, Godoy, P, Schmidt-Heck, W, Nordbeck, P, Ludwig, J, Homann, S, Wiegering, A, Shaykhutdinov, T, Kratz, C, Knüchel, R, Müller-Hermelink, H-K, Rosenwald, A, Frey, N, Eichler, J, Dobrev, D, El-Armouche, A, Hengstler, JG, Müller, OJ, Hinrichs, K, Cuello, F, Zernecke, A & Lorenz, K 2020, 'Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects', NAT COMMUN, Jg. 11, Nr. 1, S. 1733. https://doi.org/10.1038/s41467-020-15505-4

APA

Tomasovic, A., Brand, T., Schanbacher, C., Kramer, S., Hümmert, M. W., Godoy, P., Schmidt-Heck, W., Nordbeck, P., Ludwig, J., Homann, S., Wiegering, A., Shaykhutdinov, T., Kratz, C., Knüchel, R., Müller-Hermelink, H-K., Rosenwald, A., Frey, N., Eichler, J., Dobrev, D., ... Lorenz, K. (2020). Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects. NAT COMMUN, 11(1), 1733. https://doi.org/10.1038/s41467-020-15505-4

Vancouver

Tomasovic A, Brand T, Schanbacher C, Kramer S, Hümmert MW, Godoy P et al. Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects. NAT COMMUN. 2020 Apr 7;11(1):1733. https://doi.org/10.1038/s41467-020-15505-4

Bibtex

@article{82df4f496c9440009ca44d6565057858,
title = "Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects",
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.",
keywords = "Animals, Cardiotoxicity, Cell Culture Techniques, Cell-Penetrating Peptides/chemical synthesis, Colonic Neoplasms/drug therapy, Dimerization, Drug Delivery Systems, Extracellular Signal-Regulated MAP Kinases/drug effects, Heart Failure/drug therapy, Humans, Lung Neoplasms/drug therapy, MAP Kinase Signaling System/drug effects, Mice, Mice, Inbred C57BL, Molecular Medicine, Rats, Rats, Sprague-Dawley, Signal Transduction",
author = "Angela Tomasovic and Theresa Brand and Constanze Schanbacher and Sofia Kramer and H{\"u}mmert, {Martin W} and Patricio Godoy and Wolfgang Schmidt-Heck and Peter Nordbeck and Jonas Ludwig and Susanne Homann and Armin Wiegering and Timur Shaykhutdinov and Christoph Kratz and Ruth Kn{\"u}chel and Hans-Konrad M{\"u}ller-Hermelink and Andreas Rosenwald and Norbert Frey and Jutta Eichler and Dobromir Dobrev and Ali El-Armouche and Hengstler, {Jan G} and M{\"u}ller, {Oliver J} and Karsten Hinrichs and Friederike Cuello and Alma Zernecke and Kristina Lorenz",
year = "2020",
month = apr,
day = "7",
doi = "10.1038/s41467-020-15505-4",
language = "English",
volume = "11",
pages = "1733",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects

AU - Tomasovic, Angela

AU - Brand, Theresa

AU - Schanbacher, Constanze

AU - Kramer, Sofia

AU - Hümmert, Martin W

AU - Godoy, Patricio

AU - Schmidt-Heck, Wolfgang

AU - Nordbeck, Peter

AU - Ludwig, Jonas

AU - Homann, Susanne

AU - Wiegering, Armin

AU - Shaykhutdinov, Timur

AU - Kratz, Christoph

AU - Knüchel, Ruth

AU - Müller-Hermelink, Hans-Konrad

AU - Rosenwald, Andreas

AU - Frey, Norbert

AU - Eichler, Jutta

AU - Dobrev, Dobromir

AU - El-Armouche, Ali

AU - Hengstler, Jan G

AU - Müller, Oliver J

AU - Hinrichs, Karsten

AU - Cuello, Friederike

AU - Zernecke, Alma

AU - Lorenz, Kristina

PY - 2020/4/7

Y1 - 2020/4/7

N2 - 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.

AB - 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.

KW - Animals

KW - Cardiotoxicity

KW - Cell Culture Techniques

KW - Cell-Penetrating Peptides/chemical synthesis

KW - Colonic Neoplasms/drug therapy

KW - Dimerization

KW - Drug Delivery Systems

KW - Extracellular Signal-Regulated MAP Kinases/drug effects

KW - Heart Failure/drug therapy

KW - Humans

KW - Lung Neoplasms/drug therapy

KW - MAP Kinase Signaling System/drug effects

KW - Mice

KW - Mice, Inbred C57BL

KW - Molecular Medicine

KW - Rats

KW - Rats, Sprague-Dawley

KW - Signal Transduction

U2 - 10.1038/s41467-020-15505-4

DO - 10.1038/s41467-020-15505-4

M3 - SCORING: Journal article

C2 - 32265441

VL - 11

SP - 1733

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -