Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control

Department of Molecular Biology and National Centers of Competence in Research and Frontiers in Genetics and Chemical Biology, University of Geneva, Geneva, CH-1211, Switzerland.
Genetics (Impact Factor: 5.96). 12/2011; 189(4):1177-201. DOI: 10.1534/genetics.111.133363
Source: PubMed


TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin used in three different therapeutic areas. The yeast Saccharomyces cerevisiae has played a prominent role in both the discovery of TOR and the elucidation of its function. Here we review the TOR signaling network in S. cerevisiae.

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Available from: Robbie Loewith, Apr 01, 2014
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    • "RESEARCH ARTICLE Journal of Cell Science (2015) 128, 2454-2467 doi:10.1242/jcs.164160 interacts and activates TORC1 (Loewith and Hall, 2011), and arv1- and sur2-null mutations had an additive effect on the EGO3 transcription (supplementary material Fig. S4I), suggesting a sphingolipid-dependent regulation of TORC1 activity. Consistent with this, we found that ARV1 deletion conferred significant hypersensitivity to rapamycin, compared with wild-type (data not shown). "
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    ABSTRACT: In eukaryotic organisms including mammals, nematodes, and yeasts, the ends of chromosomes, telomeres are clustered at the nuclear periphery. Telomere clustering is assumed to be functionally important because proper organization of chromosomes is necessary for proper genome function and stability. However, the mechanisms and physiological roles of telomere clustering remain poorly understood. In this study, we demonstrate a role for sphingolipids in telomere clustering in the budding yeast Saccharomyces cerevisiae. Because abnormal sphingolipid metabolism causes down-regulation of expression levels of genes involved in telomere organization, sphingolipids appear to control telomere clustering at the transcriptional level. Additionally, the data presented here provide evidence that telomere clustering is required to protect chromosome ends from DNA-damage checkpoint signaling. As sphingolipids are found in all eukaryotes, we speculate that sphingolipid-based regulation of telomere clustering and the protective role of telomere clusters in maintaining genome stability might be conserved in eukaryotes. © 2015. Published by The Company of Biologists Ltd.
    Journal of Cell Science 06/2015; 128(14). DOI:10.1242/jcs.164160 · 5.43 Impact Factor
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    • "The lack of a comparable TORC2-specific inhibitor has hindered its functional characterization. TORC2, via its main effector, the AGC family kinase Ypk1, regulates actin polarization, endocytosis, calcineurin activity, sphingolipid synthesis , and genome integrity, although the molecular mechanisms by which these distal effectors are regulated are not known (Roelants et al., 2011; Loewith and Hall, 2011; Niles et al., 2012; Shimada et al., 2013). "
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    ABSTRACT: Target of Rapamycin (TOR) plays central roles in the regulation of eukaryote growth as the hub of two essential multiprotein complexes: TORC1, which is rapamycin-sensitive, and the lesser characterized TORC2, which is not. TORC2 is a key regulator of lipid biosynthesis and Akt-mediated survival signaling. In spite of its importance, its structure and the molecular basis of its rapamycin insensitivity are unknown. Using crosslinking-mass spectrometry and electron microscopy, we determined the architecture of TORC2. TORC2 displays a rhomboid shape with pseudo-2-fold symmetry and a prominent central cavity. Our data indicate that the C-terminal part of Avo3, a subunit unique to TORC2, is close to the FKBP12-rapamycin-binding domain of Tor2. Removal of this sequence generated a FKBP12-rapamycin-sensitive TORC2 variant, which provides a powerful tool for deciphering TORC2 function in vivo. Using this variant, we demonstrate a role for TORC2 in G2/M cell-cycle progression. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 05/2015; 58(6). DOI:10.1016/j.molcel.2015.04.031 · 14.02 Impact Factor
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    • "TOR is highly conserved in eukaryotes and is also called mTOR (mammalian or mechanistic TOR) in various organisms (Hall, 2013). It phosphorylates a large number of targets, and its kinase activity is modulated in response to various stresses (Fig. 1) (Bar- Peled and Sabatini, 2014; Laplante and Sabatini, 2012; Loewith and Hall, 2011). The budding yeast Saccharomyces cerevisiae has two TOR-encoding genes (TOR1 and TOR2), whereas almost all other eukaryotes have a single TOR-encoding gene. "
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    ABSTRACT: Cells constantly adapt to various environmental changes and stresses. The way in which nutrient and stress levels in a cell feed back to control metabolism and growth are, unsurprisingly, extremely complex, as responding with great sensitivity and speed to the 'feast or famine, slack or stress' status of its environment is a central goal for any organism. The highly conserved target of rapamycin complex 1 (TORC1) controls eukaryotic cell growth and response to a variety of signals, including nutrients, hormones and stresses, and plays the key role in the regulation of autophagy. A lot of attention has been paid recently to the factors in this pathway functioning upstream of TORC1. In this Commentary, we focus on a major, newly discovered upstream regulator of TORC1 - the multiprotein SEA complex, also known as GATOR. We describe the structural and functional features of the yeast complex and its mammalian homolog, and their involvement in the regulation of the TORC1 pathway and TORC1-independent processes. We will also provide an overview of the consequences of GATOR deregulation in cancer and other diseases. © 2015. Published by The Company of Biologists Ltd.
    Journal of Cell Science 05/2015; 128(12). DOI:10.1242/jcs.168922 · 5.43 Impact Factor
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