Chapter 3 Ribosomal Protein S6 Kinase: From TOP mRNAs to Cell Size

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Abstract

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.

Section snippets

S6 Kinases

A search for a kinase that phosphorylates ribosomal protein S6 (rpS6) yielded initially a 90-kDa polypeptide from Xenopus oocytes that was later termed p90 ribosomal protein S6 kinase (RSK, also known as p90RSK).1 However, purification of the avian and mammalian major rpS6 kinase recovered 65- to 70-kDa polypeptides2, 3 that are currently referred to as S6K. The discovery that S6K is the predominant rpS6 kinase in somatic cells4, 5 has led to a widely accepted belief that RSK, despite its name,

S6K Substrates and Interactors

The wide variety of signals that stimulate S6K activation suggests that if S6K is involved in the manifestation of at least part of the numerous different cellular responses it is likely that it operates through multiple substrates. Indeed, after more than a decade during which rpS6 was perceived as the only S6K substrate, new substrates are being identified. Presently, a total of 13 such substrates have been described, of which five are implicated in the translational machinery (Table I).

Does S6K Regulate the Translation Efficiency of TOP mRNAs?

Two lines of correlative evidence laid the ground for the hypothesis that S6K might be involved in the translational control of a subset of mRNAs: (a) rpS6 is located near the mRNA/tRNA-binding site at the interface between the small and large ribosomal subunits and potentially, this location enables rpS6 to alter translation efficiency112 and (b) inhibition of mTORC1 by rapamycin, and thereby of rpS6 phosphorylation, leads to partial repression of protein synthesis (Ref. 113 and references

Cell Size

Genetic and pharmacological manipulations in Drosophila, as well as in mammalian cells, have established all mediators along the pathway from growth factor receptors to mTOR that are involved in regulation of cell size (reviewed in Ref. 211). Accordingly, in parallel to the refutation of the role of S6K in the translational control of TOP mRNAs, it has emerged as a critical determinant of cell size. Thus, most Drosophila lacking their single S6K gene, dS6K, exhibit embryonic lethality, with the

Concluding Remarks

The preceding sections have shown that S6K is a critical determinant of cell size and affects whole animal physiology. S6K was initially implicated in translational control of TOP mRNAs, yet later studies have unequivocally shown that it exerts its effects in a TOP mRNAs-independent fashion. Nonetheless, despite extensive experimental work, many questions regarding the mode of action of S6K and the translational control of TOP mRNAs remain unresolved, including the following major issues:

  • (a)

    Which

Acknowledgments

This work was supported by grants to O.M. from United States-Israel Binational Science Foundation (BSF 2005034), the Israel Science Foundation (Grant No. 296/05), the German-Israeli Foundation (Grant No. 819/05f), and the Otto Stieber Foundation. The authors thank Robert P. Perry for his critical comments, Wayne Sossin for his comments on the response of TOP mRNAs to LTP, and Steve Marygold, Philip East, and Riu Yamashita for the provision of unpublished sequences of Drosophila and human 5′-TOP

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