The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity

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Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
08:47

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells

Published on: May 1, 2020

David Shahbazian1, Philippe P Roux, Virginie Mieulet

  • 1Department of Biochemistry, McGill Cancer Centre, McGill University, Montreal, Quebec, Canada.

The EMBO Journal
|June 10, 2006
PubMed

Insights

The p90 ribosomal S6 kinase (RSK) and S6K both phosphorylate eukaryotic translation initiation factor 4B (eIF4B) at Ser422. This phosphorylation enhances eIF4B

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Protein Kinase Research

Background:

  • Eukaryotic translation initiation factor 4B (eIF4B) is crucial for initiating protein synthesis by recruiting the 40S ribosomal subunit to mRNA.
  • Insulin signaling activates S6K, which phosphorylates eIF4B at Ser422, a key regulatory event in translation.
  • Understanding the upstream kinases and regulation of eIF4B phosphorylation is vital for comprehending translational control.

Purpose of the Study:

  • To investigate the role of p90 ribosomal protein S6 kinase (RSK) in the phosphorylation of eIF4B.
  • To compare the contribution and kinetics of RSK and S6K in phosphorylating eIF4B at Ser422.
  • To determine the physiological significance of RSK- and S6K-mediated eIF4B phosphorylation.

Main Methods:

  • Phosphorylation assays using recombinant proteins and cell-based systems.
  • Analysis of eIF4B phosphorylation in wild-type and PDK1 null embryonic stem cells.
  • Co-immunoprecipitation to assess the interaction between eIF4B and eukaryotic translation initiation factor 3 (eIF3).

Main Results:

  • RSK, a member of the AGC protein kinase family, phosphorylates eIF4B on Ser422, the same residue targeted by S6K.
  • The relative contribution of RSK and S6K to eIF4B phosphorylation is dependent on growth factor signaling and exhibits distinct kinetics.
  • Phosphorylation of eIF4B Ser422 is dependent on PDK1 activation for both RSK and S6K, and this phosphorylation enhances eIF4B's interaction with eIF3.

Conclusions:

  • RSK is a novel kinase that phosphorylates eIF4B at Ser422, adding another layer to the regulation of translation initiation.
  • RSK and S6K-mediated phosphorylation of eIF4B at Ser422 plays a significant physiological role by promoting eIF4B-eIF3 complex formation.
  • This study highlights the intricate crosstalk between different signaling pathways in controlling protein synthesis.

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