Phosphorylation of Eukaryotic Translation Initiation Factor 4E Is Critical for Growth

Abstract

Eukaryotic translation initiation factor 4E (eIF4E) binds to the cap structure at the 5′ end of mRNAs and is a critical target for the control of protein synthesis. eIF4E is phosphorylated in many systems in response to extracellular stimuli, but biochemical evidence to date has been equivocal as to the biological significance of this modification. Here we use a genetic approach to this problem. We show that, in Drosophila melanogaster, homozygous eIF4E mutants arrest growth during larval development. In Drosophila eIF4EI, Ser251 corresponds to Ser209 of mammalian eIF4E, which is phosphorylated in response to extracellular signals. We find that, in vivo, eIF4EI Ser251 mutants cannot incorporate labeled phosphate. Furthermore, transgenic Drosophila organisms expressing eIF4E^Ser251Ala in an eIF4E mutant background have reduced viability. Escapers develop more slowly than control siblings and are smaller. These genetic data provide evidence that eIF4E phosphorylation is biologically significant and is essential for normal growth and development.

We thank Francis Poulin for critically reading the manuscript.

This work was supported by a research grant from the Canadian Institutes of Health Research (CIHR) to P.L. and N.S., by graduate fellowships from the Natural Sciences and Engineering Research Council of Canada and McGill University to P.E.D.L. and from les Fonds de la recherche en santé du Québec and the Cancer Research Society to M.M. P.L. is a CIHR Investigator. N.S. is a CIHR Distinguished Scientist and a Howard Hughes Medical Institute International Scholar.