The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways.
Initiation factor eIF4E binds to the 5'-cap of eukaryotic mRNAs and plays a key role in the mechanism and regulation of translation. It may be regulated through its own phosphorylation and through inhibitory binding proteins (4E-BPs), which modulate its availability for initiation complex assembly. eIF4E phosphorylation is enhanced by phorbol esters. We show, using specific inhibitors, that this involves both the p38 mitogen-activated protein (MAP) kinase and Erk signaling pathways. Cell stresses such as arsenite and anisomycin and the cytokines tumor necrosis factor-alpha and interleukin-1beta also cause increased phosphorylation of eIF4E, which is abolished by the specific p38 MAP kinase inhibitor, SB203580. These changes in eIF4E phosphorylation parallel the activity of the eIF4E kinase, Mnk1. However other stresses such as heat shock, sorbitol, and H2O2, which also stimulate p38 MAP kinase and increase Mnk1 activity, do not increase phosphorylation of eIF4E. The latter stresses increase the binding of eIF4E to 4E-BP1, and we show that this blocks the phosphorylation of eIF4E by Mnk1 in vitro, which may explain the absence of an increase in eIF4E phosphorylation under these conditions.
Wang
X
X
Department of Biosciences, University of Kent at Canterbury, Canterbury, CT2 7NJ, United Kingdom.
Flynn
A
A
Waskiewicz
A J
AJ
Webb
B L
BL
Vries
R G
RG
Baines
I A
IA
Cooper
J A
JA
Proud
C G
CG
D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D016207:Cytokines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E; D005419:Flavonoids / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney; D020928:Mitogen-Activated Protein Kinases; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013012:Sorbitol / Q000494:pharmacology; D013312:Stress, Physiological; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D018053:Arsenites; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016207:Cytokines; D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D005419:Flavonoids; D006861:Hydrogen Peroxide; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D010448:Peptide Initiation Factors; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D011994:Recombinant Proteins; D013012:Sorbitol; D013755:Tetradecanoylphorbol Acetate; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C491395:MKNK1 protein, human; C015001:arsenite; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one