| Translation control provides a fundamental function of cell metabolism. Protein synthesis is regulated by PI3K/AKT and Ras/MAPK pathways in response to extra- and intracellular stimuli, such as hormone and growth factors, cell cycle progression and various physiological stresses.;Translation is tightly controlled by assembly of an intricate ribonucleoprotein (RNP) complex on eukaryotic mRNAs, which mediates recruitment of the mRNA to ribosomes for subsequent translation. Ribosomal recruitment is generally mediated by the interaction between the 5' m7GTP-cap structure of mRNAs with the cap-binding protein, eukaryotic translation initiation factor (eIF) 4E. In addition, cap-independent ribosomal recruitment to 5' untranslated sequences (internal ribosome entry sites, IRES) of several eukaryotic mRNAs has emerged as an alternative translation control mechanism. Cap-independent ribosomal recruitment prevents translation repression of specific mRNAs with IRES elements when eIF4E-cap binding is inhibited. My work demonstrates that IRES-mediated ribosomal recruitment relies on eIF4G, which is capable of directly binding to the 5' leader of IRES-containing eukaryotic mRNAs. Thus, eIF4G:RNA interaction can replace the function of eIF4E:cap binding in ribosomal recruitment. Both, eIF4E and eIF4G are phosphoproteins controlled by protein kinases in the PI3K/AKT and Ras/MAPK oncogenic signalling pathways and the modulation of their phosphorylation status is likely to impinge on their function in translation control. Indeed, I show that crosstalk between both pathways coordinate eIF4G and eIF4E phosphorylation. This suggests that both major oncogenic signaling pathways converge on organizing control over translation initiation mechanisms. |
