Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin.
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.
Brunn
G J
GJ
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Hudson
C C
CC
Sekulić
A
A
Williams
J M
JM
Hosoi
H
H
Houghton
P J
PJ
Lawrence
J C
JC
Abraham
R T
RT
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E; D016193:G1 Phase; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011090:Polyenes / Q000494:pharmacology*; D011494:Protein Kinases; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D022021:Tacrolimus Binding Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C087000:EIF4EBP1 protein, human; C499526:Eif4ebp1 protein, rat; D039561:Eukaryotic Initiation Factor-4E; D006360:Heat-Shock Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D011090:Polyenes; D011994:Recombinant Proteins; D012097:Repressor Proteins; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D000077191:Wortmannin