mTOR-dependent stimulation of the association of eIF4G and eIF3 by insulin.
Insulin stimulates protein synthesis by increasing translation initiation. This response is mediated by mTOR and is believed to result from 4EBP1 phosphorylation, which allows eIF4E to bind eIF4G. Here, we present evidence that mTOR interacts directly with eIF3 and that mTOR controls the association of eIF3 and eIF4G. Activating mTOR signaling with insulin increased by as much as five-fold the amount of eIF4G bound to eIF3. This novel effect was blocked by rapamycin and other inhibitors of mTOR, and it required neither eIF4E binding to eIF4G nor eIF3 binding to the 40S ribosomal subunit. The increase in eIF4G associated with eIF3 occurred rapidly and at physiological concentrations of insulin. Moreover, the magnitude of the response was similar to the increase in eIF4E binding to eIF4G produced by insulin. Thus, increasing eIF4G association with eIF3 represents a potentially important mechanism by which insulin, as well as amino acids and growth factors that activate mTOR, stimulate translation.
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908-0735, USA.
Thurl E
TE
Harris
An
A
Chi
Jeffrey
J
Shabanowitz
Donald F
DF
Hunt
Robert E
RE
Rhoads
John C
JC
Lawrence
D017667:Adipocytes / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D020798:Two-Hybrid System Techniques
D039621:Eukaryotic Initiation Factor-3; D039603:Eukaryotic Initiation Factor-4G; D007328:Insulin; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D012269:Ribosomal Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus