Does phosphorylation of the cap-binding protein eIF4E play a role in translation initiation?
Eukaryotic initiation factor 4E (eIF4E) plays an important role in mRNA translation by binding the 5'-cap structure of the mRNA and facilitating the recruitment to the mRNA of other translation factors and the 40S ribosomal subunit. eIF4E can interact either with the scaffold protein eIF4G or with repressor proteins termed eIF4E-binding proteins (4E-BPs). High levels of expression can disrupt cellular growth control and are associated with human cancers. A fraction of the cellular eIF4E is found in the nucleus where it may play a role in the transport of certain mRNAs to the cytoplasm. eIF4E undergoes regulated phosphorylation (at Ser209) by members of the Mnk group of kinases, which are activated by multiple MAP kinases (hence Mnk = MAP-kinase signal integrating kinase). The functional significance of its phosphorylation has been the subject of considerable interest. Recent genetic studies in Drosophila point to a key role for phosphorylation of eIF4E in growth and viability. Initial structural data suggested that phosphorylation of Ser209 might allow formation of a salt bridge with a basic residue (Lys159) that would clamp eIF4E onto the mRNA and increase its affinity for ligand. However, more recent structural data place Ser209 too far away from Lys159 to form such an interaction, and biophysical studies indicate that phosphorylation actually decreases the affinity of eIF4E for cap or capped RNA. The implications of these studies are discussed in the light of other, in vitro and in vivo, investigations designed to address the role of eIF4E phosphorylation in mRNA translation or its control.
Scheper
Gert C
GC
Division of Molecular Physiology, School of Life Sciences, University of Dundee, MSI/WTB Complex, Dow Street, UK.
Proud
Christopher G
CG
D000818:Animals; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism
D039561:Eukaryotic Initiation Factor-4E; D012333:RNA, Messenger