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Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase

X Wang1, W Li, M Williams

  • 1Division of Molecular Physiology and MRC Protein Phosphorylation Unit, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee DD1 5EH, UK.

The EMBO Journal
|August 14, 2001
PubMed

Insights

Elongation factor 2 kinase (eEF2k) activity is regulated by two key kinases, p70 S6 kinase and p90(RSK1). Phosphoinositide-dependent kinase 1 (PDK1) is essential for this regulation, impacting protein synthesis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Elongation factor 2 kinase (eEF2k) regulates protein synthesis by phosphorylating and inactivating elongation factor 2 (eEF2).
  • Insulin signaling pathways influence eEF2k activity, but the underlying mechanisms remain unclear.
  • Phosphoinositide-dependent kinase 1 (PDK1) is crucial for eEF2k regulation, independent of mTOR signaling.

Purpose of the Study:

  • To elucidate the signaling mechanisms by which PDK1 regulates eEF2k activity.
  • To identify the specific kinases involved in the phosphorylation and inhibition of eEF2k.
  • To differentiate the roles of mTOR-dependent and Erk-dependent pathways in eEF2k regulation.

Main Methods:

  • Genetic knockout of PDK1 in cellular models.
  • Analysis of eEF2 and 4E-BP1 phosphorylation.
  • Inhibition studies using rapamycin (mTOR inhibitor) and MEK/Erk pathway inhibitors.
  • Investigating the activity of p70 S6 kinase and p90(RSK1) in response to growth factors.

Main Results:

  • PDK1 knockout abolishes the regulation of eEF2 phosphorylation and eEF2k activity.
  • p70 S6 kinase (mTOR-dependent) and p90(RSK1) (Erk-dependent) phosphorylate eEF2k at a conserved serine, inhibiting its activity.
  • Insulin-like growth factor 1 (IGF-1) signaling, activating p70 S6 kinase, leads to rapamycin-sensitive regulation of eEF2.
  • Erk pathway activation leads to rapamycin-insensitive regulation of eEF2, blocked by MEK/Erk inhibitors, implicating p90(RSK1).

Conclusions:

  • PDK1 is essential for the regulation of eEF2k activity through AGC kinase family members.
  • Both mTOR- and Erk-dependent pathways converge on eEF2k via p70 S6 kinase and p90(RSK1), respectively.
  • These findings reveal distinct signaling inputs controlling eEF2k activity and protein synthesis.

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