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A Mek1–Mek2 heterodimer determines the strength and duration of the Erk signal

Nature Structural & Molecular Biology volume 16, pages 294–303 (2009)Cite this article

Abstract

Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. Here we describe a previously uncharacterized, unexpected role of Mek1 in downregulating Mek2-dependent Erk signaling. Mek1 mediates the regulation of Mek2 in the context of a previously undiscovered Mek1–Mek2 complex. The Mek heterodimer is negatively regulated by Erk-mediated phosphorylation of Mek1 on Thr292, a residue missing in Mek2. Disabling this Erk-proximal negative-feedback step stabilizes the phosphorylation of both Mek2 and Erk in cultured cells and in vivo in Mek1 knockout embryos and mice. Thus, in disagreement with the current perception of the pathway, the role of Mek1 and Mek2 in growth factor–induced Erk phosphorylation is not interchangeable. Our data establish Mek1 as the crucial modulator of Mek and Erk signaling and have potential implications for the role of Mek1 and Mek2 in tumorigenesis.

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Figure 1: Mek1 ablation affects fibroblast shape and impairs haptotaxis and adhesion-dependent Erk signaling.
Figure 2: Mek1 ablation increases growth factor–stimulated migration and Erk phosphorylation.
Figure 3: Mek1 regulates Mek2 phosphorylation.
Figure 4: Mek1 and Mek2 form heterodimers in wild-type cells.
Figure 5: Erk-mediated negative-feedback regulation in the context of the Mek heterodimer.
Figure 6: Mek1 ablation deregulates signaling in vivo.

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Acknowledgements

We thank T. Decker for critical reading of the manuscript, T. Zoranovic, C. Wasinger, M. Hamerl and the Max F. Perutz Laboratories (MFPL) animal house for outstanding technical assistance, I. Ebersberger (MFPL) for providing all ortholog Mek sequences listed in HaMSTR. This work was supported by FWF grants P19530 (to M.B.) and T196 (to V.J.).

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Author notes

  1. Gloria Reyes

    Present address: Present address: Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, Department 0636, La Jolla, California 92093-0636, USA.,

  2. Federica Catalanotti and Gloria Reyes: These authors contributed equally to this work.

Authors and Affiliations

  1. Max F. Perutz Laboratories, University of Vienna, Doktor-Bohr-Gasse 9, Vienna, 1030, Austria

    Federica Catalanotti, Gloria Reyes, Veronika Jesenberger, Gergana Galabova-Kovacs, Ricardo de Matos Simoes, Oliviero Carugo & Manuela Baccarini

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Contributions

F.C., G.R., V.J., and G.G.-K. performed research; M.B. designed research; R.d.M.S. analyzed sequence information; O.C. performed molecular modelling; M.B. wrote the paper.

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Correspondence to Manuela Baccarini.

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Catalanotti, F., Reyes, G., Jesenberger, V. et al. A Mek1–Mek2 heterodimer determines the strength and duration of the Erk signal. Nat Struct Mol Biol 16, 294–303 (2009). https://doi.org/10.1038/nsmb.1564

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