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RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent

Philippe P Roux1, David Shahbazian, Hieu Vu

  • 1Department of Pathology and Cell Biology, Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montréal, Québec, Canada. philippe.roux@umontreal.ca

The Journal of Biological Chemistry
|March 16, 2007
PubMed

Insights

The Ras/ERK pathway signals through p90 ribosomal S6 kinases (RSKs) to phosphorylate ribosomal protein S6 (rpS6), independently of mTOR. This phosphorylation promotes rpS6 recruitment to the translation preinitiation complex.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • The mammalian target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K) pathways are known regulators of translation initiation.
  • The role of other signaling cascades, such as Ras/extracellular signal-regulated kinase (ERK), in protein synthesis regulation is less understood.
  • Ribosomal protein S6 (rpS6) phosphorylation is linked to mitogen stimulation, but the underlying mechanisms and functional consequences remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms by which the Ras/ERK signaling cascade regulates rpS6 phosphorylation.
  • To determine the specific kinases involved in rpS6 phosphorylation downstream of Ras/ERK.
  • To elucidate the functional significance of rpS6 phosphorylation at specific sites.

Main Methods:

  • Utilized cell-based assays to study signaling pathways.
  • Employed in vitro and in vivo phosphorylation assays.
  • Performed site-directed mutagenesis of rpS6.

Main Results:

  • Activation of p90 ribosomal S6 kinases (RSKs) by serum, growth factors, phorbol esters, and oncogenic Ras is essential for rpS6 phosphorylation via the Ras/ERK pathway.
  • While ribosomal S6 kinase 1 (S6K1) phosphorylates rpS6 at all sites, RSK specifically phosphorylates rpS6 at Ser(235/236) through an mTOR-independent mechanism.
  • Mutation of rpS6 at Ser(235/236) impairs its recruitment to the 7-methylguanosine cap complex, indicating a role in translation preinitiation complex assembly.

Conclusions:

  • RSK acts as a key mediator, providing an mTOR-independent pathway that connects the Ras/ERK signaling cascade to the translational machinery.
  • Phosphorylation of rpS6 at Ser(235/236) by RSK is a critical step regulated by Ras/ERK signaling, influencing translation initiation.
  • These findings reveal a novel mechanism by which growth factor signaling impacts protein synthesis.

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