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Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation

Nature Cell Biology volume 13, pages 282–291 (2011)Cite this article

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Abstract

The ERK (extracellular signal-regulated kinase) MAPK (mitogen-activated protein kinase) cascade (Raf–MEK–ERK) mediates mitogenic signalling, and is frequently hyperactivated by Ras oncogenes in human cancer. The entire range of activities of multifunctional Ras in carcinogenesis remains elusive. Here we report that the ERK pathway is downregulated by MEK (MAPK–ERK kinase) SUMOylation, which is inhibited by oncogenic Ras. MEK SUMOylation blocked ERK activation by disrupting the specific docking interaction between MEK and ERK. Expression of un-SUMOylatable MEK enhanced ERK activation, cell differentiation, proliferation and malignant transformation by oncogenic ErbB2 or Raf, but not by active Ras. Interestingly, MEK SUMOylation was abrogated in cancer cells harbouring Ras mutations. Oncogenic Ras inhibits MEK SUMOylation by impairing the function of the MEKK1 MAPKKK as a SUMO-E3 ligase specific for MEK. Furthermore, forced enhancement of MEK SUMOylation suppressed Ras-induced cell transformation. Thus, oncogenic Ras efficiently activates the ERK pathway both by activating Raf and by inhibiting MEK SUMOylation, thereby inducing carcinogenesis.

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Figure 1: SUMOylation of MEK.
Figure 2: SUMOylation of MEK1 inhibits MEK1 kinase activity.
Figure 3: Functional analysis of the SUMOylation-defective MEK1 mutant.
Figure 4: Oncogenic Ras inhibits MEK1 SUMOylation in vivo.
Figure 5: MEK1 SUMOylation inhibits Ras-dependent transformation.
Figure 6: MEKK1 is a SUMO-E3 for MEK.
Figure 7: Oncogenic Ras inhibits MEK SUMOylation and thereby sensitizes the ERK pathway.

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas and other grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (M.T. and H.S.), by the Takeda Science Foundation, the Naito foundation and the DAIKO foundation (M.T.) and by the Global COE Program from MEXT, Japan. We thank J. Charron (Université Laval, Québec) for the M E K1−/− MEFs, T. Kitamura (University of Tokyo) for Plat-E cells and H. Saitoh (Kumamoto University), T. Yamamoto (University of Tokyo), T. Kataoka (Kobe University) and S. Iwata (University of Tokyo) for plasmids.

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  1. Department of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

    Yuji Kubota, Pauline O’Grady, Haruo Saito & Mutsuhiro Takekawa

  2. Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

    Yuji Kubota, Haruo Saito & Mutsuhiro Takekawa

  3. Department of Cell Signaling and Molecular Medicine, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan

    Yuji Kubota & Mutsuhiro Takekawa

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Y.K., P.O’G. and M.T. designed and carried out the experiments; Y.K., P.O’G., H.S. and M.T. analysed the data and wrote the paper.

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Correspondence to Haruo Saito or Mutsuhiro Takekawa.

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Kubota, Y., O’Grady, P., Saito, H. et al. Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation. Nat Cell Biol 13, 282–291 (2011). https://doi.org/10.1038/ncb2169

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