Editorial GuideCell Biology

Focus Issue: Demystifying mTOR Signaling

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Sci. Signal.  21 Apr 2009:
Vol. 2, Issue 67, pp. eg5
DOI: 10.1126/scisignal.267eg5

Abstract

The mammalian target of rapamycin (mTOR) is a master integrator of cell energy state, nutrient status, and growth factor stimulation. This kinase is part of two distinct complexes, mTORC1 and mTORC2, and the network that regulates these two complexes is interconnected with distinct and overlapping inputs and outputs. Research published in Science Signaling has revealed new connections between epidermal growth factor receptors and the mTOR pathway, and new insight into the roles of mTOR signaling in vascular disease. The Perspectives in this issue highlight how new pharmacological tools and the ability to knock down the function of complex-specific subunits are providing new insight into the regulation and functions of these complexes in physiological contexts, as well as providing new avenues for therapeutic intervention in diseases associated with aberrant activity of these complexes.

The kinase mammalian target of rapamycin (mTOR) is a component of two complexes, mTORC1 and mTORC2, and together these complexes serve to integrate signals from growth factors with information about cellular energy and nutrient status. Although both complexes are activated by receptor tyrosine kinases coupled to the phosphoinositide 3-kinase (PI3K) pathway, mTORC1 is the complex responsible for responding to the cellular nutrient and energy status. The kinase Akt, which is downstream of PI3K, activates mTORC1, whereas Akt is a target of mTORC2. Because of the connections with the PI3K/Akt pathway, components of which are frequently mutated in cancer, and because genes encoding components of the mTORC1 pathway are also implicated in cancer, there is great interest in targeting this pathway therapeutically. In a Perspective, Guertin and Sabatini describe the pursuit of mTOR-targeted inhibitors as chemotherapeutic agents, starting with rapamycin, which predominantly inhibits mTORC1, then describing the newer agents that target the catalytic site of mTOR, and wrapping up with a discussion of a future generation of mTOR inhibitors.

The importance of mTOR signaling in cancer and the best approaches for therapeutic intervention are also the topics of Research Articles by Nardella et al. and Fan et al., the latter of which is highlighted in a Perspective by Vogt and Hart. Nardella et al. studied tumor initiation in mouse prostate and found that conditional inactivation of mTOR, which prevented signaling through both mTORC1 and mTORC2, had little effect on prostate development or function, but prevented tumorigenesis caused by loss of PTEN, the lipid phosphatase that terminates PI3K signaling. Fan et al. sought to understand the molecular mechanisms by which increased signaling by the epidermal growth factor receptor (EGFR) causes glioma, a common and deadly form of brain cancer. They found an unexpected path from EGFR to mTOR that relied on protein kinase C but not Akt.

The first mTOR inhibitor discovered and approved for use as an immunosuppressant by the FDA was rapamycin, which is a naturally occurring product of the bacterium Streptomyces hygroscopius. In order to inhibit mTOR—in most cell types, rapamycin is selective for mTORC1—rapamycin binds to the protein FKB12 and then this complex binds outside of the mTOR kinase domain. Although the inhibitory effects of rapamycin on the adaptive immune system through inhibition of lymphocyte proliferation are well characterized, as Janes and Fruman describe in a Perspective, rapamycin and its analogs also appear to modulate the innate immune system. By inhibiting the activation of mTORC1 downstream of Toll-like receptors (TLRs), exposure of macrophages and dendritic cells to rapamycin alters the cytokine profile produced by these cells in response to TLR ligands such that they stimulate an inflammatory response. This effect of rapamycin may have a protective effect against bacterial infection and a proinflammatory effect when used as an immunosuppressant in transplant patients. In contrast, exposure of plasmacytoid dendritic cells to rapamycin reduces the ability of these cells to stimulate T cell proliferation and cytokine production, which may increase susceptibility to viral infection. Janes and Fruman discuss the clinical implications for these diverse effects on the immune system.

A potential clinical application for rapamycin or drugs that target mTORC2 was also the topic of the Research Article by Wang et al., who found that rapamycin, acting through mTORC2, prevented obesity-induced endothelial cell senescence and reduced the severity of ischemic injury. The vascular complications appeared to result from increased Akt activity caused by diet-induced obesity and rapamycin-inhibited mTORC2 activity, thus reducing Akt activity. Alessi et al. also focus on mTORC2 in a Perspective emphasizing the substrates of this mTOR complex. Whereas mTORC1 stimulates protein translation when nutrient and energy conditions are favorable by phosphorylating its substrates S6K (ribosomal S6 kinase) and 4E-BP (eukaryotic initiation factor 4E binding protein), mTORC2 does not appear to control translation and is not regulated by cellular energy or nutrient status. Instead, mTORC2 is activated by receptors coupled to PI3K and contributes to activation of Akt and serum glucocorticoid-induced kinase (SGK). Focusing on the biochemistry of substrate phosphorylation, Alessi et al. describe the motifs that are phosphorylated in response to mTOR signaling and propose several mechanisms by which mTORC2 may promote phosphorylation of sites in a turn motif. They raise the intriguing possibility that yet another mTOR complex may be involved.

With new pharmacological tools and the ability to selectively inhibit specific mTOR complexes, the functions and regulation of mTOR signaling will continue to be revealed and hopefully will lead to improved and effective therapies for diseases associated with aberrant signaling by mTOR.

Featured in This Focus Issue

Perspectives

  • D. R. Alessi, L. R. Pearce, J. M. García-Martínez, New insights into mTOR signaling: mTORC2 and beyond. Sci. Signal. 2, pe27 (2009). [Abstract] [Full Text] [PDF]

  • D. A. Guertin, D. M. Sabatini, The pharmacology of mTOR inhibition. Sci. Signal. 2, pe24 (2009). [Abstract] [Full Text] [PDF]

  • M. R. Janes, D. A. Fruman, Immune regulation by rapamycin: Moving beyond T cells. Sci. Signal. 2, pe25 (2009). [Abstract] [Full Text] [PDF]

  • P. K. Vogt, J. R. Hart, Akt demoted in glioblastoma Sci. Signal. 2, pe26 (2009). [Abstract] [Full Text] [PDF]

Related Resources

Research Articles

  • Q.-W. Fan, C. Cheng, Z. A. Knight, D. Haas-Kogan, D. Stokoe, C. D. James, F. McCormick, K. M. Shokat, W. A. Weiss, EGFR signals to mTOR through PKC and independently of Akt in glioma. Sci. Signal. 2, ra4 (2009). [Abstract] [Full Text] [PDF]

  • C. B. Marshall, J. Ho, C. Buerger, M. J. Plevin, G.-Y. Li, Z. Li, M. Ikura, V. Stambolic, Characterization of the intrinsic and TSC2-GAP–regulated GTPase activity of Rheb by real-time NMR. Sci. Signal. 2, ra3 (2009). [Abstract] [Full Text] [PDF]

  • C. Nardella, A. Carracedo, A. Alimonti, R. M. Hobbs, J. G. Clohessy, Z. Chen, A. Egia, A. Fornari, M. Fiorentino, M. Loda, S. C. Kozma, G. Thomas, C. Cordon-Cardo, P. P. Pandolfi, Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Sci. Signal. 2, ra2 (2009). [Abstract] [Full Text] [PDF]

  • C.-Y. Wang, H.-H. Kim, Y. Hiroi, N. Sawada, S. Salomone, L. E. Benjamin, K. Walsh, M. A. Moskowitz, J. K. Liao, Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR. Sci. Signal. 2, ra11 (2009). [Abstract] [Full Text] [PDF]

Editorial Guide

  • E. M. Adler, 2008: Signaling breakthroughs of the year. Sci. Signal. 2, eg1 (2009). [Abstract] [Full Text] [PDF]

Perspectives

  • J. Montagne, T. Radimerski, G. Thomas, Insulin signaling: Lessons from the Drosophila tuberous sclerosis complex, a tumor suppressor. Sci. STKE 2001, pe36 (2001). [Abstract] [Full Text] [PDF]

  • Y. Zick, Ser/Thr phosphorylation of IRS proteins: A molecular basis for insulin resistance. Sci. STKE 2005, pe4 (2005). [Abstract] [Full Text] [PDF]

Reviews

  • S. Marshall, Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel metabolism and energy homeostasis: A nutritional perspective of diabetes, obesity, and cancer. Sci. STKE 2006, re7 (2006). [Gloss] [Abstract] [Full Text] [PDF]

  • T. E. Harris, J. C. Lawrence, Jr., TOR signaling. Sci. STKE 2003, re15 (2003). [Gloss] [Abstract] [Full Text] [PDF]

Database of Cell Signaling

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