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Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Affects Translation of

Nadejda L Korneeva1, Anren Song2, Hermann Gram3

  • 1From the Departments of Emergency Medicine and Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, and nkorne@lsuhsc.edu.

The Journal of Biological Chemistry
|December 16, 2015
PubMed

Insights

MAPK-interacting kinases (MNK1/2) regulate mRNA translation by phosphorylating eIF4E. MNK activity specifically enhances translation of capped mRNAs with 5'-terminal hairpins, impacting cell cycle and cancer progression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • MAPK-interacting kinases 1 and 2 (MNK1 and MNK2) are activated by ERK1/2 or p38 signaling pathways.
  • MNK modulates mRNA translation, influencing processes like cell cycle, cancer progression, and cell survival.
  • The precise mechanism of MNK's selective mRNA translation regulation remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which MNK selectively affects mRNA translation.
  • To investigate the role of eIF4E phosphorylation in MNK-mediated translation control.
  • To determine the structural requirements of mRNA 5'-ends for MNK-dependent translation stimulation.

Main Methods:

  • Utilized a cell-free translation system with rabbit reticulocytes.
  • Programmed the system with mRNAs featuring diverse 5'-end structures (cap, hairpin).
  • Employed an MNK inhibitor (CGP57380) and an eIF4G-1 fragment (eIF4G(1357-1600)).
  • Analyzed protein-RNA interactions using m(7)GTP-Sepharose pulldown assays.

Main Results:

  • MNK inhibition or eIF4G fragment treatment selectively impaired translation of mRNAs containing both a 5' cap and a hairpin structure.
  • eIF4G(1357-1600) reduced eIF4E phosphorylation and inhibited translation of capped, hairpin-containing mRNAs.
  • Both CGP57380 and the eIF4G fragment decreased the binding of eIF4E to eIF4G.

Conclusions:

  • MNK stimulates the translation of specific mRNAs (capped with 5'-terminal RNA duplex) through eIF4E phosphorylation.
  • This phosphorylation enhances the cap-binding and RNA-unwinding activities of the eIF4F complex.
  • MNK's action provides a mechanism for selective mRNA translation control in response to cellular signals.
Keywords:
eukaryotic translation initiationeukaryotic translation initiation factor 4E (eIF4E)eukaryotic translation initiation factor 4G (eIF4G)mRNAphosphorylation

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