Control of Translation by the Target of Rapamycin Proteins

Regulation of translation rates, the frequency with which a given mRNA is translated, plays an important role in the control of cell growth and differentiation. Translational control is exerted in most instances at the initiation phase, a rate-limiting step during which the ribosome is recruited to mRNA. Initiation is a complex process mediated by many translation initiation factors (at least 30 polypeptides), and the regulation of translation initiation factor activity involves modulation of gene expression, binding to other factors or repressors, proteolytic cleavage and changes in phosphorylation state. It has been known for some time that the phosphorylation state of various translation factors/inhibitors (and other proteins required for translation, such as ribosomal proteins) is modulated in response to hormonal/mitogenic signals and environmental or nutritional stresses, but the identity of the signaling pathways involved in translational regulation are only beginning to emerge. In this review, we describe a signaling module involved in translational control both in yeast and in mammalian cells, the TOR (or FRAP/mTOR) signaling pathway. In mammals, this pathway regulates the activity of several translation factors (eIF4B and eIF4GI), translation inhibitors (the 4E-BPs), and the ribosomal S6 kinases (S6K1 and 2). In yeast, inhibition of Tor activity leads to polysomal disaggregation and G 1 cell cycle arrest.