The Phosphorylation of Eukaryotic Initiation Factor eIF4E in Response to Phorbol Esters, Cell Stresses, and Cytokines Is Mediated by Distinct MAP Kinase Pathways

Abstract

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-␣ and interleukin-1␤ 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 H 2 O 2 , 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.

Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR, PKA and MEK signalling pathways

“…Indeed, incubations with the MEK inhibitor U0126 reduced glibenclamide-induced protein synthesis by 35%, without affecting the (de)phosphorylation of these four proteins. It has been reported that the activation of ERKs, which are the downstream targets of MEK, activates MAP kinase signalintegrating kinases (MNKs) and consequently induce phosphorylation of eIF4E [44] and translation [45]. Here, we did not find evidence for this pathway, since the glibenclamide-induced ERK phosphorylation was unaffected by the MEK inhibitors U0126 and PD98059.…”

Selective Modification of Eukaryotic Initiation Factor 4F (eIF4F) at the Onset of Cell Differentiation: Recruitment of eIF4GII and Long-Lasting Phosphorylation of eIF4E

“…Protein kinase C and the MAP kinase-activated protein kinase Mnk1 were previously shown to phosphorylate eIF4E on Ser209 in vitro and in vivo following mitogenic stimuli (50,51). p38 MAP kinase and mTOR (mammalian target of rapamycin) signaling pathways may also influence eIF4E Ser209 phosphorylation following cytokine or stress stimuli, as suggested previously (3,49). We tested whether any of these pathways participate in the induction of eIF4E phosphorylation at the onset of TPO-dependent cell differentiation.…”

DNA-damaging agents cause inactivation of translational regulators linked to mTOR signalling

“…Many such mRNAs have 5'-leader regions which are rich in secondary structure, which makes them highly dependent on the abundancy of the eIF4F complex needed for unimpeded ribosomal scanning (Flynn and Proud, 1996). 4E-BP1 and eIF4E are regulated under a variety of stress conditions (Feigenblum and Schneider, 1996;Scheper et al, 1997;Vries et al, 1997;Wang et al, 1998b).…”