Regulation of eIF4F complex assembly by Mnk1/2 kinase

Abstract

The rate of translation initiation in most eukaryotic cells depends on both the features of the mRNA and the level and activity of the eIF4F complex, which consists of eIF4G, eIF4E and eIF4A. mRNAs with highly structured 5′UTR encode a disproportionate share of proteins involved in cell growth and cell cycle progression, growth factors, growth factor receptors, and cyclins. Translation of these mRNAs requires high levels of eIF4E that presumably acts through the eIF4F complex. One current model suggests that the eIF4F integrity is regulated by the PI3K/Akt/mTor cascade, while the MAPK pathway targets the eIF4F cap‐binding activity. The activation of mTor kinase leads to increase of eIF4E·eIF4G complex formation via phosphorylation of eIF4E‐binding protein 4E‐BP that releases eIF4E. MAPK signaling targets the Mnk kinase via Erk1/2 and p38 pathways. Mnk is the only known physiological kinase that phosphorylates eIF4E at single site (S209, human eIF4E). Mnk binds eIF4G and phosphorylates eIF4E primarily in a complex with eIF4G. Earlier we showed that inhibition of Mnk activity in cell‐free translation system affects translation of mRNA that contains both a cap‐ and a structured 5′UTR and also affects binding of eIF4E with eIF4G. We suggest the involvement of Mnk kinase in the dynamics of eIF4F assembly. Supported by grant R01GM20818 from the NIGMS.