THE PHOSPHORYLATION OF EUKARYOTIC INITIATION-FACTOR EIF4E IN RESPONSETO 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 pl ays a key role in the mechanism and regulation of translation. It may be regulated through its own phosphorylation and through inhibitory bi nding proteins (4E-BPs), which modulate its availability for initiatio n complex assembly. eIF4E phosphorylation is enhanced by phorbol ester s. We show, using specific inhibitors, that this involves both the p38 mitogen-activated protein (MAP) kinase and Erk signaling pathways. Ce ll stresses such as arsenite and anisomycin and the cytokines tumor ne crosis factor-alpha and interleukin-1 beta also cause increased phosph orylation of eIF4E, which is abolished by the specific p38 MAP kinase inhibitor, SB203580. These changes in eIF4E phosphorylation parallel t he activity of the eIF4E kinase, Mnk1. However other stresses such as heat shock, sorbitol, and H2O2, which also stimulate p38 MAP kinase an d increase Mnk1 activity, do not increase phosphorylation of eIF4E. Th e latter stresses increase the binding of eIF4E to 4E-BP1, and me 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.