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A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy

Nature Medicine volume 15, pages 7583 (2009) | Download Citation

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Abstract

The extracellular-regulated kinases ERK1 and ERK2 (commonly referred to as ERK1/2) have a crucial role in cardiac hypertrophy. ERK1/2 is activated by mitogen-activated protein kinase kinase-1 (MEK1) and MEK2 (commonly referred to as MEK1/2)-dependent phosphorylation in the TEY motif of the activation loop, but how ERK1/2 is targeted toward specific substrates is not well understood. Here we show that autophosphorylation of ERK1/2 on Thr188 directs ERK1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. Thr188 autophosphorylation requires the activation and assembly of the entire Raf-MEK-ERK kinase cascade, phosphorylation of the TEY motif, dimerization of ERK1/2 and binding to G protein βγ subunits released from activated Gq. Thr188 phosphorylation of ERK1/2 was observed in isolated cardiomyocytes induced to undergo hypertrophic growth, in mice upon stimulation of Gq-coupled receptors or after aortic banding and in failing human hearts. Experiments using transgenic mouse models carrying mutations at the Thr188 phosphorylation site of ERK2 suggested a causal relationship to cardiac hypertrophy. We propose that specific phosphorylation events on ERK1/2 integrate differing upstream signals (Raf1-MEK1/2 or G protein–coupled receptor–Gq) to induce cardiac hypertrophy.

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Acknowledgements

We wish to thank U. Quitterer for stimulating discussions during the early phase of this work; M. Maier-Peuschel, M. Vidal, K. Deiß, D. Calebiro, K. Hadameck, M. Frank, K. von Hayn and A. Zürn for their help; M. Fischer, M. Babl, M. Hoffmann, N. Ziegler and C. Dees for excellent technical assistance; S. Jacobs for help with the immunohistochemistry; and U. Zabel and R. Schreck for helpful discussion. This work was supported by the Deutsche Forschungsgemeinschaft, the Leducq Foundation and the Fonds der Chemischen Industrie.

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Affiliations

  1. Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Straße 9, 97078 Würzburg, Germany.

    • Kristina Lorenz
    • , Joachim P Schmitt
    • , Eva M Schmitteckert
    •  & Martin J Lohse
  2. Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Versbacher Straße 9, 97078 Würzburg, Germany.

    • Eva M Schmitteckert
    •  & Martin J Lohse

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Contributions

K.L. performed all of the experiments and their analyses; J.P.S. performed the aortic banding surgery and provided advice for echocardiography; E.M.S. generated the transgenic mouse lines; and M.J.L. and K.L. conceived the study and wrote the manuscript. E.M.S. and particularly J.P.S. provided critical comments on the manuscript.

Corresponding author

Correspondence to Kristina Lorenz.

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DOI

https://doi.org/10.1038/nm.1893

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