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Review
. 2011 Jan;12(1):21-35.
doi: 10.1038/nrm3025. Epub 2010 Dec 15.

mTOR: from growth signal integration to cancer, diabetes and ageing

Roberto Zoncu  1 , Alejo Efeyan, David M Sabatini
Affiliations
Review

mTOR: from growth signal integration to cancer, diabetes and ageing

Roberto Zoncu et al. Nat Rev Mol Cell Biol. 2011 Jan.

Abstract

In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.

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Figures

Figure 1
Figure 1. Domain organization of mTOR and mTOR-interacting proteins
A. mTORC1 and mTORC2 have shared (mTOR, mLST8 and deptor) and unique components. Raptor and PRAS40 are unique to mTORC1 and rictor, mSin1 and Protor are specific to mTORC2. The domain organization of mTOR resembles that of other PIKK family members. At the N-terminus there is a cluster of Huntingtin, Elongation factor 3, a subunit of protein phosphatase 2A and TOR1 (HEAT) repeats, which mediate protein-protein interactions. These are followed by, a FRAP, ATM and TRRAP (FAT) domain, the FKBP12-Rapamycin Binding (FRB) domain (which mediates the inhibitory action of rapamycin), the serine/threonine kinase catalytic domain and the C-terminal FATC domain. mLST8 is highly conserved; its seven WD40 domains form a beta propeller that mediates protein-protein interactions. Deptor consists of a tandem dishevelled, egl-10, pleckstrin (DEP) domains, followed by a single postsynaptic density 95, discs large, zonula occludens-1 (PDZ) domain. The scaffolding function of raptor is reflected by its composition of protein-binding domains; it consists of several HEAT repeats, followed by seven WD40 motifs, probably arranged in a beta propeller.Rictor has no clearly identifiable domains or motifs despite its key role in mTORC2 function; likewise, Protor lacks identifiable domains or motifs, and its function awaits clarification.
Figure 2
Figure 2. The mTOR signaling pathway
mTORC1 promotes translation (A) and inhibits autophagy (B), by integrating nutrient signals generated by amino acids (C), growth factor signals relayed by the insulin and insulin-like growth factors (D), energy signals acting through AMP-activated kinase (AMPK) (E) and various stressors including hypoxia (F) and DNA damage (G). A first level of integration occurs at the level of the Tuberous Sclerosis Complex (TSC). Akt and extracellular regulated kinase (ERK) 1/2 phosphorylate and inhibit TSC, while AMPK, glycogen synthase kinase (GSK) 3-beta and hypoxic factor REDD1 activate it. A second level of integration occurs at the lysosome: the Rag GTPases (held in place by the p18/p14/MP1 ragulator) recruit mTORC1 to the lysosomal surface in response to amino acids; in turn, lysosomal recruitment enables mTORC1 to interact with GTP-bound Rheb, the end point of growth factor, energy and stress inputs. Growth factor receptors activate mTORC2, probably via Ras, near the plasma membrane, where mTORC2 may be recruited through binding of mSin1 to phospholipids. Because of its role in phosphorylating and activating Akt, mTORC2 forms a core component of the PI3K pathway.
Figure 3
Figure 3. mTOR in metabolism and insulin resistance
A. Effects of mTOR in metabolism. mTOR links nutrient abundance with growth and the accumulation of energy stores in anticipation of future nutrient shortage. Feeding triggers a raise in insulin and nutrient levels in the bloodstream; these converge as activating inputs to mTOR. In turn, mTORC1 activates protein synthesis, cell mass increase, and lipid accumulation, whereas mTORC2 promotes glucose usage by the cell by positively regulating glucose import, glycogen synthesis and by inhibiting gluconeogenesis. B. In the western diet, overabundance of nutrients leads to chronic mTOR activation, which disrupts energetic homeostasis. During chronic insulin stimulation, as occurs in over-feeding states, mTORC1 activity towards S6K inhibits insulin receptor signaling at the cellular membrane, contributing to the onset of the diabetic state. In an insulin-resistance state, phosphatidylinositol 3 kinase (PI3K) and Akt are not activated, leading to decreased glucose uptake and to hepatic gluconeogenesis, which in turn worsen hyperglycaemia. Despite decreased insulin signaling, mTORC1 remains active, maintaining the negative feedback loop to IR. The nutrient inputs to mTORC1 may explain sustained mTORC1 activity in the context of insulin insensitivity. (AA: amino acids; ins: insulin; IR: insulin receptor; IRS; insulin receptor substrate)
Figure 4
Figure 4. mTOR in cancer
A. mTOR-regulated cellular processes that play a role in cancer. mTORC1 favors tumorigenesis by driving translation of oncogenes, by inhibiting autophagy, by upregulating angiogenesis, and by enhancing the accumulation of lipids. mTORC2 plays a role in tumorigenesis by activating Akt and other AGC family proteins which promote proliferation and survival. Moreover, by promoting Akt-mediated glucose uptake, mTORC2 fuels the metabolism of cancer cells. B. Therapeutic inhibition of mTOR activity by rapamycin, mTOR catalytic inhibitors (mTOR cat inh) and dual PI3K-mTOR inhibitors (dual inh). Rapamycin only partially suppresses mTORC1 function, efficiently inhibiting S6K but not eIF4E; thus, it only partially inhibits translation. Moreover, due to the inhibition of the S6K-dependent feedback loops, rapamycin indirectly upregulates phosphatidylinositol 3 kinase (PI3K) activity and promotes cell survival. In contrast, mTOR ATP-competitive inhibitors target all known functions of mTORC1 as well as mTORC2; thus, they inhibit translation more potently. Although PI3K overactivation still occurs, Akt phosphorylation by mTORC2 is impaired. Dual PI3K/mTOR inhibitors block all functions of PI3K, including PDK1- and mTORC2-mediated activation of Akt. However, they might cause increased toxicity.
Figure 5
Figure 5. mTOR in ageing
A. mTORC1-regulated processes that promote cellular ageing. mTORC1-dependent translation may overcome the protein folding capacity of the cell, resulting in accumulation of unfolded proteins and ER stress. Stimulation of mitochondrial function may increase ROS production, resulting in oxidative damage to DNA, proteins and membranes. Inhibition of autophagy by mTORC1 reduces the turnover of cellular components and promotes the accumulation of their damaged forms (red). B. mTORC1 promotes stem cell exhaustion and tissue ageing. In young tissues, stem cells divide asymmetrically to generate new stem cells as well as postmitotic cell that replace those that have undergone turnover (left). Continued exposure to mitogens that signal through mTORC1 causes stem cell exhaustion through hyperproliferation or senescence (right); thus, in aged tissues post-mitotic cells are no longer replaced and the overall performance of the tissue is degraded. C. Inhibiting mTORC1 activity by various means allows lifespan extension in multiple organisms, and may have beneficial effects on human ageing.
Box1 Figure
Box1 Figure
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