Abstract
The evolutionarily conserved serine/threonine protein kinase target of rapamycin (TOR) is a master controller of cell growth. TOR controls growth by promoting anabolic processes and inhibiting catabolic processes in response to nutrient availability, growth factors and cellular energy, which can be perturbed by environmental and cellular stresses. These upstream signals are integrated by TOR, which in turn modulates protein synthesis—an energetically demanding cellular process that requires tight regulation to minimize energy expenditure. The TOR pathway plays a central role in the control of protein synthesis through the phosphorylation of numerous substrates with well-characterized functions in ribosome biogenesis and the initiation and elongation steps of protein synthesis. The role of TOR in protein synthesis has been studied in extensive detail in several eukaryotic model systems, and consequently, a great deal is now known about how TOR controls protein synthesis in eukaryotes. In this book chapter, we provide an evolutionary perspective of the TOR pathway in the control of protein synthesis and ribosome biogenesis across eukaryotes (from unicellular to multicellular organisms).
The original version of the book was revised: A spelling error in the author’s name was corrected, a figure was placed correctly, and a typographical error was corrected. The erratum to this chapter is available at 10.1007/978-3-319-39468-8_23
An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-3-319-39468-8_23
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mTOR gene has been reported to encode two isoforms resultant from an alternative splicing event. The long isoform (mTOR alpha) is 289 kDa and the short isoform (mTOR beta) is 80 kDa. Most published studies refer to the long (289 kDa) mTOR alpha isoform. Further details in Ref. [39].
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One cannot rule out, however, functional adaptation of alternative signaling pathways in the control of cell growth. A shared cellular function does not necessitate a common signaling mechanism. Convergent evolution allows for different signaling mechanisms fulfilling a shared cellular role in distinct species.
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Metazoans have evolved several cascades that control cellular and organismal growth. One major growth pathway is the insulin/mTORC1 signaling pathway, which in mammals follows the sequence: insulin, insulin receptor, PI3K, Akt, TSC1/TSC2/RHEB and mTORC1. In Drosophila melanogaster the signaling mode does not follow this linear sequence. In insects, dPI3 K and dTORC1 pathways do not crosstalk—instead, they appear to function in parallel to control cellular and organismal growth in response to environmental, endocrinological and nutritional inputs [181].
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It does not, however, affect fly viability.
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PDK1 can also phosphorylate Thr389 (Thr412 according to the p85 S6K1 isoform amino acid numbering) in vitro, albeit at rather low stoichiometry indicating that PDK1 is not the predominant Thr389-kinase in vivo [317].
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S6K1 preferentially phosphorylates another S6K substrate: IRS-1 (insulin receptor substrate-1) [332].
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Phosphorylation of RPS6 at Ser235 and Ser236 can also be catalyzed by another family of S6 kinases termed p90RSKs (short for ribosomal S6 kinases of 90 kDa). p90RSKs are not subject to regulation by the TOR pathway and are therefore not reviewed in this chapter. For additional information on p90RSKs please refer to this excellent review on the subject [333].
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Thr37, Thr46, Thr41, Thr50, Ser65 and Thr70 (but not Ser83, Ser101 and Ser112) are conserved in between mammals and insects. This suggests that the N-terminal phosphorylation residues play a conserved regulatory role in evolution.
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The following factors have been previously linked to regulation of TOP mRNA translation: ribosomal protein S6 (RPS6) and its kinases S6Ks, eukaryotic initiation factor 4E (eIF4E) and its binding partners 4E-BPs, lupus autoantigen (La) protein and the La-related protein 7, cellular nucleic acid-binding protein (CNBP) also known as zinc finger protein 9 (ZNF9), microRNAs miR-10a and miR-10b. While some of these do appear to contribute to TOP mRNA regulation on some level (e.g., TIA1/TIAR represses TOP mRNA translation in response to amino acid deprivation), definitive evidence for any these being the long-sought controller of TOP mRNA translation is lacking. Refer to the following review for an exhaustive analysis of these factors in the context of TOP mRNA regulation [386].
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Roux and colleagues proposed a different model in which LARP1 functions as an activator (rather than an inhibitor) of TOP mRNA translation. See Ref. [373] for an alternative perspective on this subject.
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The importance of the hippocampus in consolidating new memories was described in a seminal case report by the neurosurgeon William Scoville and the psychologist Brenda Milner (a former graduate student of Donald Hebb) in 1957. A historical perspective of “Patient HM,” whose hippocampi had been almost completely surgically resected has been recently published and is a highly recommended read [419].
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Acknowledgments
We wish to thank all of the scientists in the TOR field for their contributions to our present understanding of the TOR pathway. We apologize to the scientists whose work was not acknowledged or discussed in further detail, in particular those who have contributed to the elucidation of the signaling pathways up- and downstream of TOR that regulate cellular functions other than mRNA translation. The authors wish to thank the various funding agencies that have contributed to research in our laboratories over the many years of the study of TOR. The authors also wish to thank the following funding agencies that currently fund their research: A.G. and M.N.H. acknowledge support from the Louis Jeantet Foundation, the Swiss National Science Foundation and the Canton of Basel. B.D.F. and T.A. gratefully acknowledge financial support from Prostate Cancer Canada. The laboratories of C.M. and C.R. are supported by ANR grants TRANSLATOR and DECORATOR; CR is also supported by the A*MIDEX project (no. ANR-11-IDEX-0001-02).
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Fonseca, B.D. et al. (2016). Evolution of TOR and Translation Control. In: Hernández, G., Jagus, R. (eds) Evolution of the Protein Synthesis Machinery and Its Regulation. Springer, Cham. https://doi.org/10.1007/978-3-319-39468-8_15
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