Ribosomal protein S6 kinase (S6K) has been implicated in the phosphorylation of multiple substrates and is subject to activation by a wide variety of signals that converge at mammalian target of rapamycin (mTOR). In the course of the search for its physiological role, it was proposed that S6K activation and ribosomal protein S6 (rpS6) phosphorylation account for the translational activation of a subgroup of transcripts, the TOP mRNAs. The structural hallmark of these mRNAs is an oligopyrimidine tract at their 5'-terminus, known as the 5'-TOP motif. TOP mRNAs consists of about 90 members that encode multiple components of the translational machinery, such as ribosomal proteins and translation factors. The translation efficiency of TOP mRNAs indeed correlates with S6K activation and rpS6 phosphorylation, yet recent biochemical and genetic studies have established that, although S6K and TOP mRNAs respond to similar signals and are regulated by mTOR, they maintain no cause and effect relationship. Instead, S6K is primarily involved in regulation of cell size, and affects glucose homeostasis, but is dispensable for global protein synthesis, whereas translational efficiency of TOP mRNAs is a determinant of the cellular protein synthesis capacity. Despite extensive studies of their function and mode of regulation, the mechanism underlying the effect of S6K on the cell size, as well as the trans-acting factor that mediates the translational control of TOP mRNAs, still await their identification.
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