Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis

Jianling Xie, Kaikai Shen, Ashley T. Jones, Jian Yang, Andrew R. Tee, Ming Hong Shen, Mengyuan Yu, Swati Irani, Derick Wong, James E. Merrett, Roman V. Lenchine, Stuart De Poi, Kirk B. Jensen, Paul J. Trim, Marten F. Snel, Makoto Kamei, Sally Kim Martin, Stephen Fitter, Shuye Tian, Xuemin WangLisa M. Butler, Andrew C.W. Zannettino, Christopher G. Proud

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Abstract

eIF4E plays key roles in protein synthesis and tumorigenesis. It is phosphorylated by the kinases MNK1 and MNK2. Binding of MNKs to eIF4G enhances their ability to phosphorylate eIF4E. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. These effects provide a novel mechanism by which mTORC1 signaling impairs the function of MNK2 and thereby decreases eIF4E phosphorylation. MNK2[S74A] knock-in cells show enhanced phosphorylation of eIF4E and S6K1 (i.e., increased mTORC1 signaling), enlarged cell size, and increased invasive and transformative capacities. MNK2[Ser74] phosphorylation was inversely correlated with disease progression in human prostate tumors. MNK inhibition exerted anti-proliferative effects in prostate cancer cells in vitro. These findings define a novel feedback loop whereby mTORC1 represses MNK2 activity and oncogenic signaling through eIF4E phosphorylation, allowing reciprocal regulation of these two oncogenic pathways.

Original languageEnglish
Number of pages22
JournalCellular and Molecular Life Sciences
Early online date13 Mar 2020
DOIs
Publication statusE-pub ahead of print - 13 Mar 2020
Externally publishedYes

Keywords

  • eIF4E
  • mRNA translation
  • Prostate cancer
  • Protein synthesis
  • Rapamycin

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    Xie, J., Shen, K., Jones, A. T., Yang, J., Tee, A. R., Shen, M. H., Yu, M., Irani, S., Wong, D., Merrett, J. E., Lenchine, R. V., De Poi, S., Jensen, K. B., Trim, P. J., Snel, M. F., Kamei, M., Martin, S. K., Fitter, S., Tian, S., ... Proud, C. G. (2020). Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-020-03491-1