Modulation of the mitogenic activity of eukaryotic translation initiation factor-4E by protein kinase C.
Eukaryotic initiation factor-4E (eIF-4E) binds to the cap structure of eukaryotic mRNAs and is a component of the cap-binding protein complex eIF-4F. eIF-4E is present in cells in limiting concentrations and is phosphorylated both in vivo and in vitro by protein kinase C (PKC). Recently, eIF-4E has been implicated as an intracellular transducer of extracellular growth signals; microinjection of recombinant eIF-4E into quiescent NIH 3T3 cells induced DNA synthesis. In the present report, the mitogenic activity of eIF-4E was examined after coinjection with PKC. Recombinant eIF-4E was phosphorylated by PKC at the same amino acid that is phosphorylated in cultured cells and reticulocytes in response to phorbol ester. At limiting concentrations of eIF-4E, coinjection with PKC induced a fivefold increase in the mitogenic activity of eIF-4E. Injection of PKC alone or coinjection of eIF-4E with cAMP-dependent protein kinase (PKA) or the Raf protein had no effect. These results suggest that the mitogenic activity of eIF-4E is enhanced by PKC-specific phosphorylation and that phosphate addition is a rate-limiting step in eIF-4E activity.
Smith
M R
MR
Biological Carcinogenesis and Development Program, National Cancer Institute, Frederick Cancer Research and Development Center, MD 21702-1201.
Jaramillo
M
M
Tuazon
P T
PT
Traugh
J A
JA
Liu
Y L
YL
Sonenberg
N
N
Kung
H F
HF
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D039561:Eukaryotic Initiation Factor-4E; D008845:Microinjections; D008934:Mitogens; D010448:Peptide Initiation Factors / Q000008:administration & dosage* / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D011493:Protein Kinase C / Q000008:administration & dosage* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D039561:Eukaryotic Initiation Factor-4E; D008934:Mitogens; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D004247:DNA; D011493:Protein Kinase C