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

  1. Anne-Claude Gingras,
  2. Scott G. Kennedy,
  3. Maura A. O’Leary,
  4. Nahum Sonenberg, and
  5. Nissim Hay
  1. Department of Biochemistry, McGill University Montreal, Quebec, Canada H3G 1Y6; and Department of Pharmacological and Physiological Sciences and The Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois 60637 USA

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.

Keywords

Footnotes

  • These authors made an equal contribution to the work.

  • Corresponding author. Present address: Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607.

  • E-MAIL nhay{at}ben-may.bsd.uchicago.edu; FAX (773) 702-6260.

    • Received November 13, 1997.
    • Accepted December 19, 1997.
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