CONTROL OF GENE EXPRESSION, CELL GROWTH AND METABOLISM VIA FRAP/mTOR　SIGNALING TO TRANSLATION INITIATION FACTORS

In higher eukaryotes extracellular stimuli, including hormones, growth factors, mitogens and G-protein coupled receptor agonists, modulate the rate of translation. These effects are largely mediated via the phosphorylation of translation initiation factors.

The eIF4 group of initiation factors catalyzes recruitment of the mRNA by the 40S ribosomal subunit. eIF4E is the mRNA cap binding protein and a major target for translational control. Extracellular stimuli modulate eIF4E activity by hosphorylation of members of a family of proteins called 4E-BPs (eIF4E-binding proteins). 4E-BPs repress cap-dependent translation by binding to eIF4E. Upon their phosphorylation 4E-BPs dissociate from eIF4E, with consequent relief of translational repression. Phosphorylation of 4E-BPs is effected by the PI3 kinase pathway, which controls cell growth. Akt/PKB, and FRAP/mTOR (the target of rapamycin), which lie downstream of PI3 kinase, mediate 4E-BPs phosphorylation. Rapamycin exhibits anti-tumor and anti-angiogenic activities.