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Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis

Jianling Xie1, Kaikai Shen2,3, Ashley T Jones4

  • 1Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia.

Cellular and Molecular Life Sciences : CMLS
|March 15, 2020
PubMed

Insights

The mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway directly phosphorylates and inhibits MNK2, a kinase that activates eIF4E. This feedback loop suppresses oncogenic signaling and tumor progression, offering new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • eIF4E is crucial for protein synthesis and cancer development.
  • eIF4E is phosphorylated by MNK1 and MNK2 kinases.
  • mTORC1 is a key regulator of translation and oncogenesis.

Purpose of the Study:

  • To investigate the regulatory relationship between mTORC1 and MNK2.
  • To elucidate the mechanism by which mTORC1 signaling impacts eIF4E phosphorylation.
  • To explore the role of this interaction in cancer progression.

Main Methods:

  • Phosphorylation site mapping of MNK2 by mTORC1.
  • Generation and analysis of MNK2[S74A] knock-in cells.
  • Correlation analysis of MNK2[Ser74] phosphorylation with prostate cancer progression.
  • In vitro assessment of MNK inhibition in prostate cancer cells.

Main Results:

  • mTORC1 directly phosphorylates MNK2 on Ser74, suppressing its activity and binding to eIF4G.
  • MNK2[S74A] knock-in cells exhibit increased eIF4E and S6K1 phosphorylation, larger cell size, and enhanced invasive/transformative potential.
  • MNK2[Ser74] phosphorylation inversely correlates with prostate tumor progression.
  • MNK inhibition shows anti-proliferative effects in prostate cancer cells.

Conclusions:

  • mTORC1 signaling provides a negative feedback loop by inhibiting MNK2 activity and subsequently decreasing eIF4E phosphorylation.
  • This interaction represents a novel mechanism for reciprocal regulation of two key oncogenic pathways.
  • Targeting MNK could be a therapeutic strategy for prostate cancer.
Keywords:
Prostate cancerProtein synthesisRapamycineIF4EmRNA translation

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