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

EMBO J. 2006 Jun 21;25(12):2781-91. doi: 10.1038/sj.emboj.7601166. Epub 2006 Jun 8.

Abstract

The eukaryotic translation initiation factor 4B (eIF4B) plays a critical role in recruiting the 40S ribosomal subunit to the mRNA. In response to insulin, eIF4B is phosphorylated on Ser422 by S6K in a rapamycin-sensitive manner. Here we demonstrate that the p90 ribosomal protein S6 kinase (RSK) phosphorylates eIF4B on the same residue. The relative contribution of the RSK and S6K modules to the phosphorylation of eIF4B is growth factor-dependent, and the two phosphorylation events exhibit very different kinetics. The S6K and RSK proteins are members of the AGC protein kinase family, and require PDK1 phosphorylation for activation. Consistent with this requirement, phosphorylation of eIF4B Ser422 is abrogated in PDK1 null embryonic stem cells. Phosphorylation of eIF4B on Ser422 by RSK and S6K is physiologically significant, as it increases the interaction of eIF4B with the eukaryotic translation initiation factor 3.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Amino Acid Sequence
  • Animals
  • Catalysis
  • Eukaryotic Initiation Factor-3 / metabolism
  • Eukaryotic Initiation Factors / chemistry
  • Eukaryotic Initiation Factors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HeLa Cells
  • Humans
  • MAP Kinase Signaling System*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutation / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Protein Binding
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / deficiency
  • Ribosomal Protein S6 Kinases, 90-kDa / chemistry
  • Ribosomal Protein S6 Kinases, 90-kDa / deficiency
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases

Substances

  • Eukaryotic Initiation Factor-3
  • Eukaryotic Initiation Factors
  • eIF-4B
  • Phosphoserine
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human
  • Pdpk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3
  • Extracellular Signal-Regulated MAP Kinases
  • Sirolimus