Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin

Science. 1997 Jul 4;277(5322):99-101. doi: 10.1126/science.277.5322.99.

Abstract

The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells.

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
  • Animals
  • Carrier Proteins / pharmacology
  • Cell Line
  • DNA-Binding Proteins / pharmacology
  • Eukaryotic Initiation Factor-4E
  • G1 Phase
  • Heat-Shock Proteins / pharmacology
  • Humans
  • Insulin / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Peptide Initiation Factors / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Polyenes / pharmacology*
  • Protein Kinases*
  • Rats
  • Recombinant Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Sirolimus
  • TOR Serine-Threonine Kinases
  • Tacrolimus Binding Proteins
  • Transfection
  • Tumor Cells, Cultured
  • Wortmannin

Substances

  • Adaptor Proteins, Signal Transducing
  • Androstadienes
  • Carrier Proteins
  • DNA-Binding Proteins
  • EIF4EBP1 protein, human
  • Eif4ebp1 protein, rat
  • Eukaryotic Initiation Factor-4E
  • Heat-Shock Proteins
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • Peptide Initiation Factors
  • Phosphoproteins
  • Polyenes
  • Recombinant Proteins
  • Repressor Proteins
  • Protein Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Tacrolimus Binding Proteins
  • Sirolimus
  • Wortmannin