Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1

Nat Cell Biol. 2000 Dec;2(12):893-8. doi: 10.1038/35046542.

Abstract

One of the critical responses to insulin treatment is the stimulation of protein synthesis through induced phosphorylation of the eIF-4E-binding protein 1 (4E-BP1), and the subsequent release of the translation initiation factor, eIF-4E. Here we report that ATM, the protein product of the ATM gene that is mutated in the disease ataxia telangiectasia, phosphorylates 4E-BP1 at Ser 111 in vitro and that insulin treatment induces phosphorylation of 4E-BP1 at Ser 111 in vivo in an ATM-dependent manner. In addition, insulin treatment of cells enhances the specific kinase activity of ATM. Cells lacking ATM kinase activity exhibit a significant decrease in the insulin-induced dissociation of 4E-BP1 from eIF-4E. These results suggest an unexpected role for ATM in an insulin-signalling pathway that controls translation initiation. Through this mechanism, a lack of ATM activity probably contributes to some of the metabolic abnormalities, such as poor growth and insulin resistance, reported in ataxia telangiectasia cells and patients with ataxia telangiectasia.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Ataxia Telangiectasia / genetics
  • Ataxia Telangiectasia / metabolism
  • Ataxia Telangiectasia Mutated Proteins
  • Carrier Proteins*
  • Cell Cycle Proteins
  • Cell Line
  • DNA-Binding Proteins
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Humans
  • In Vitro Techniques
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Insulin Resistance / genetics
  • Mice
  • Models, Biological
  • Peptide Initiation Factors / metabolism
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Serine / chemistry
  • Signal Transduction
  • Transfection
  • Tumor Suppressor Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • EIF4EBP1 protein, human
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Insulin
  • Peptide Initiation Factors
  • Phosphoproteins
  • Tumor Suppressor Proteins
  • Serine
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases