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Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway

Oncogene volume 27, pages 3685–3691 (2008)Cite this article

Abstract

MAP kinases phosphatases (MKPs) belong to the dual-specificity phosphatase family (DUSP) and dephosphorylate phosphothreonine and phosphotyrosine within MAP kinases. We had previously shown that DUSP6/MKP-3 was phosphorylated and degraded upon growth factor stimulation, in a MEK-dependent manner. Here we show that another pathway involved in growth factor signaling, the PI3K/mTOR signaling pathway, accounts for a part of the phosphorylation and degradation of DUSP6 induced by serum growth factors, as evidenced by experiments using pharmacological inhibitors of PI3 kinase and mammalian target of rapamycin (mTOR). Moreover, specific agonists of the mTOR pathway, such as amino acids or insulin/IGF-1, which do not activate extracellular signal regulated kinases (ERKs) in our cellular model, were also able to induce the phosphorylation and degradation of DUSP6. However, a basal activity of MEK was required for the mTOR pathway-mediated phosphorylation to occur. Mutagenesis studies identified serine 159 within DUSP6 as the target of the mTOR pathway. The ERK phosphatase DUSP6 may thus constitute a novel branch-point of the crosstalk between two major signaling pathways induced by growth factors, the MEK/ERK pathway and the PI3K/mTOR pathway.

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Acknowledgements

This work was supported by a grant from the French Association for Research on Cancer (ARC) and by a fellowship from the American Institute for Cancer Research to OB and GP. GP was also sponsored by the Ligue Nationale contre le Cancer (‘Equipe labellisée’). We are grateful to Dr Jean-Claude Chambard and Philippe Lenormand for helpful discussions about the manuscript.

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  1. S Marchetti

    Present address: 2Current address: INSERM, U526, Cell Death Differentiation and Cancer Team, Nice, France.,

Authors and Affiliations

  1. Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre Antoine Lacassagne, University of Nice-Sophia Antipolis, Nice, France

    O Bermudez, S Marchetti, G Pagès & C Gimond

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  1. O Bermudez
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  2. S Marchetti
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Correspondence to C Gimond.

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Bermudez, O., Marchetti, S., Pagès, G. et al. Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway. Oncogene 27, 3685–3691 (2008). https://doi.org/10.1038/sj.onc.1211040

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