4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway

Genes Dev. 1998 Feb 15;12(4):502-13. doi: 10.1101/gad.12.4.502.

Abstract

Growth factors and hormones activate protein translation by phosphorylation and inactivation of the translational repressors, the eIF4E-binding proteins (4E-BPs), through a wortmannin- and rapamycin-sensitive signaling pathway. The mechanism by which signals emanating from extracellular signals lead to phosphorylation of 4E-BPs is not well understood. Here we demonstrate that the activity of the serine/threonine kinase Akt/PKB is required in a signaling cascade that leads to phosphorylation and inactivation of 4E-BP1. PI 3-kinase elicits the phosphorylation of 4E-BP1 in a wortmannin- and rapamycin-sensitive manner, whereas activated Akt-mediated phosphorylation of 4E-BP1 is wortmannin resistant but rapamycin sensitive. A dominant negative mutant of Akt blocks insulin-mediated phosphorylation of 4E-BP1, indicating that Akt is required for the in vivo phosphorylation of 4E-BP1. Importantly, an activated Akt induces phosphorylation of 4E-BP1 on the same sites that are phosphorylated upon serum stimulation. Similar to what has been observed with serum and growth factors, phosphorylation of 4E-BP1 by Akt inhibits the interaction between 4E-BP1 and eIF-4E. Furthermore, phosphorylation of 4E-BP1 by Akt requires the activity of FRAP/mTOR. FRAP/mTOR may lie downstream of Akt in this signaling cascade. These results demonstrate that the PI 3-kinase-Akt signaling pathway, in concert with FRAP/mTOR, induces the phosphorylation of 4E-BP1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Androstadienes / pharmacology
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Drug Resistance
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors*
  • Humans
  • Models, Genetic
  • Mutation
  • Peptide Initiation Factors / metabolism
  • Peptide Mapping
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphopeptides / isolation & purification
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Polyenes / pharmacology
  • Protein Biosynthesis*
  • Protein Kinases*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Sirolimus
  • TOR Serine-Threonine Kinases
  • Wortmannin

Substances

  • Adaptor Proteins, Signal Transducing
  • Androstadienes
  • Carrier Proteins
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • EIF4EBP2 protein, human
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Peptide Initiation Factors
  • Phosphopeptides
  • Phosphoproteins
  • Polyenes
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Protein Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Sirolimus
  • Wortmannin