Special Issue "TOR Signaling Pathway"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 May 2017)

Special Issue Editors

Guest Editor
Prof. Kazuhiro Shiozaki

1. Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma 630-0192, Nara, Japan
2. Department of Microbiology and Molecular Genetics, University of California, Davis, CA 95616, USA
Website | E-Mail
Interests: cellular signal transduction pathways in yeast and humans
Guest Editor
Prof. Ted Powers

Department of Molecular and Cellular Biology, University of California, Davis, CA95616, USA
Website | E-Mail
Interests: cellular responses to growth and stress signals in budding yeast

Special Issue Information

Dear Colleagues,

Among the numerous protein kinases that play key roles in signal transduction pathways of eukaryotic cells, Target of Rapamycin (TOR) stands out because of its unique characteristics. TOR is a serine/threonine-specific protein kinase, but it is structurally related to lipid kinases, such as PI3K. It forms at least two distinct high-molecular weight complexes, known as TOR complex 1 (TORC1) and TOR complex 2 (TORC2), with multiple regulatory subunits that determine signal inputs, substrate specificities, and intracellular localization. Rapamycin and other inhibitors of TOR affect diverse aspects of cellular physiology, such as growth, proliferation, as well as catabolic and anabolic processes, suggesting TOR functions at pivotal nodes of cellular signaling networks.

We invite contributions from researchers who have been exploring distinct aspects of this unique protein kinase through studies in diverse model organisms. Both original research articles and reviews are welcome. Together, these studies will contribute to an integrated view of the emerging TOR network, implicated in cancers, metabolic diseases and aging in humans.

Prof. Kazuhiro Shiozaki
Prof. Ted Powers
Guest Editors

Manuscript Submission Information

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Keywords

  • Target of Rapamycin
  • TOR
  • mTOR
  • rapamycin

Published Papers (7 papers)

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Review

Open AccessReview The TORC2‐Dependent Signaling Network in the Yeast Saccharomyces cerevisiae
Biomolecules 2017, 7(3), 66; doi:10.3390/biom7030066
Received: 2 August 2017 / Revised: 25 August 2017 / Accepted: 28 August 2017 / Published: 5 September 2017
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Abstract
To grow, eukaryotic cells must expand by inserting glycerolipids, sphingolipids, sterols, and proteins into their plasma membrane, and maintain the proper levels and bilayer distribution. A fungal cell must coordinate growth with enlargement of its cell wall. In Saccharomyces cerevisiae, a plasma
[...] Read more.
To grow, eukaryotic cells must expand by inserting glycerolipids, sphingolipids, sterols, and proteins into their plasma membrane, and maintain the proper levels and bilayer distribution. A fungal cell must coordinate growth with enlargement of its cell wall. In Saccharomyces cerevisiae, a plasma membrane‐localized protein kinase complex, Target of Rapamicin (TOR) complex‐2 (TORC2) (mammalian ortholog is mTORC2), serves as a sensor and masterregulator of these plasma membrane‐ and cell wall‐associated events by directly phosphorylating and thereby stimulating the activity of two types of effector protein kinases: Ypk1 (mammalian ortholog is SGK1), along with a paralog (Ypk2); and, Pkc1 (mammalian ortholog is PKN2/PRK2). Ypk1 is a central regulator of pathways and processes required for plasma membrane lipid and protein homeostasis, and requires phosphorylation on its T‐loop by eisosome‐associated protein kinase Pkh1 (mammalian ortholog is PDK1) and a paralog (Pkh2). For cell survival under various stresses, Ypk1 function requires TORC2‐mediated phosphorylation at multiple sites near its C terminus. Pkc1 controls diverse processes, especially cell wall synthesis and integrity. Pkc1 is also regulated by Pkh1‐ and TORC2‐dependent phosphorylation, but, in addition, by interaction with Rho1‐GTP and lipids phosphatidylserine (PtdSer) and diacylglycerol (DAG). We also describe here what is currently known about the downstream substrates modulated by Ypk1‐mediated and Pkc1‐mediated phosphorylation. Full article
(This article belongs to the Special Issue TOR Signaling Pathway)
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Open AccessReview Coupling TOR to the Cell Cycle by the Greatwall–Endosulfine–PP2A-B55 Pathway
Biomolecules 2017, 7(3), 59; doi:10.3390/biom7030059
Received: 26 June 2017 / Revised: 31 July 2017 / Accepted: 2 August 2017 / Published: 4 August 2017
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Abstract
Cell growth and division are two processes tightly coupled in proliferating cells. While Target of Rapamycin (TOR) is the master regulator of growth, the cell cycle is dictated by the activity of the cyclin-dependent kinases (CDKs). A long-standing question in cell biology is
[...] Read more.
Cell growth and division are two processes tightly coupled in proliferating cells. While Target of Rapamycin (TOR) is the master regulator of growth, the cell cycle is dictated by the activity of the cyclin-dependent kinases (CDKs). A long-standing question in cell biology is how these processes may be connected. Recent work has highlighted that regulating the phosphatases that revert CDK phosphorylations is as important as regulating the CDKs for cell cycle progression. At mitosis, maintaining a low level of protein phosphatase 2A (PP2A)-B55 activity is essential for CDK substrates to achieve the correct level of phosphorylation. The conserved Greatwall–Endosulfine pathway has been shown to be required for PP2A-B55 inhibition at mitosis in yeasts and multicellular organisms. Interestingly, in yeasts, the Greatwall–Endosulfine pathway is negatively regulated by TOR Complex 1 (TORC1). Moreover, Greatwall–Endosulfine activation upon TORC1 inhibition has been shown to regulate the progression of the cell cycle at different points: the G1 phase in budding yeast, the G2/M transition and the differentiation response in fission yeast, and the entry into quiescence in both budding and fission yeasts. In this review, we discuss the recent findings on how the Greatwall–Endosulfine pathway may provide a connection between cell growth and the cell cycle machinery. Full article
(This article belongs to the Special Issue TOR Signaling Pathway)
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Open AccessReview The TOR Signaling Network in the Model Unicellular Green Alga Chlamydomonas reinhardtii
Biomolecules 2017, 7(3), 54; doi:10.3390/biom7030054
Received: 31 May 2017 / Revised: 6 July 2017 / Accepted: 7 July 2017 / Published: 12 July 2017
Cited by 1 | PDF Full-text (508 KB) | HTML Full-text | XML Full-text
Abstract
Cell growth is tightly coupled to nutrient availability. The target of rapamycin (TOR) kinase transmits nutritional and environmental cues to the cellular growth machinery. TOR functions in two distinct multiprotein complexes, termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2). While the
[...] Read more.
Cell growth is tightly coupled to nutrient availability. The target of rapamycin (TOR) kinase transmits nutritional and environmental cues to the cellular growth machinery. TOR functions in two distinct multiprotein complexes, termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2). While the structure and functions of TORC1 are highly conserved in all eukaryotes, including algae and plants, TORC2 core proteins seem to be missing in photosynthetic organisms. TORC1 controls cell growth by promoting anabolic processes, including protein synthesis and ribosome biogenesis, and inhibiting catabolic processes such as autophagy. Recent studies identified rapamycin-sensitive TORC1 signaling regulating cell growth, autophagy, lipid metabolism, and central metabolic pathways in the model unicellular green alga Chlamydomonas reinhardtii. The central role that microalgae play in global biomass production, together with the high biotechnological potential of these organisms in biofuel production, has drawn attention to the study of proteins that regulate cell growth such as the TOR kinase. In this review we discuss the recent progress on TOR signaling in algae. Full article
(This article belongs to the Special Issue TOR Signaling Pathway)
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Open AccessReview Lysosomal Regulation of mTORC1 by Amino Acids in Mammalian Cells
Biomolecules 2017, 7(3), 51; doi:10.3390/biom7030051
Received: 1 June 2017 / Revised: 3 July 2017 / Accepted: 4 July 2017 / Published: 7 July 2017
Cited by 1 | PDF Full-text (581 KB) | HTML Full-text | XML Full-text
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth in eukaryotic cells. The active mTORC1 promotes cellular anabolic processes including protein, pyrimidine, and lipid biosynthesis, and inhibits catabolic processes such as autophagy. Consistent with its growth-promoting functions,
[...] Read more.
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth in eukaryotic cells. The active mTORC1 promotes cellular anabolic processes including protein, pyrimidine, and lipid biosynthesis, and inhibits catabolic processes such as autophagy. Consistent with its growth-promoting functions, hyper-activation of mTORC1 signaling is one of the important pathomechanisms underlying major human health problems including diabetes, neurodegenerative disorders, and cancer. The mTORC1 receives multiple upstream signals such as an abundance of amino acids and growth factors, thus it regulates a wide range of downstream events relevant to cell growth and proliferation control. The regulation of mTORC1 by amino acids is a fast-evolving field with its detailed mechanisms currently being revealed as the precise picture emerges. In this review, we summarize recent progress with respect to biochemical and biological findings in the regulation of mTORC1 signaling on the lysosomal membrane by amino acids. Full article
(This article belongs to the Special Issue TOR Signaling Pathway)
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Open AccessReview Regulation of Autophagy through TORC1 and mTORC1
Biomolecules 2017, 7(3), 52; doi:10.3390/biom7030052
Received: 1 June 2017 / Revised: 1 July 2017 / Accepted: 4 July 2017 / Published: 7 July 2017
Cited by 1 | PDF Full-text (878 KB) | HTML Full-text | XML Full-text
Abstract
Autophagy is an intracellular protein-degradation process that is conserved across eukaryotes including yeast and humans. Under nutrient starvation conditions, intracellular proteins are transported to lysosomes and vacuoles via membranous structures known as autophagosomes, and are degraded. The various steps of autophagy are regulated
[...] Read more.
Autophagy is an intracellular protein-degradation process that is conserved across eukaryotes including yeast and humans. Under nutrient starvation conditions, intracellular proteins are transported to lysosomes and vacuoles via membranous structures known as autophagosomes, and are degraded. The various steps of autophagy are regulated by the target of rapamycin complex 1 (TORC1/mTORC1). In this review, a history of this regulation and recent advances in such regulation both in yeast and mammals will be discussed. Recently, the mechanism of autophagy initiation in yeast has been deduced. The autophagy-related gene 13 (Atg13) and the unc-51 like autophagy activating kinase 1 (Ulk1) are the most crucial substrates of TORC1 in autophagy, and by its dephosphorylation, autophagosome formation is initiated. Phosphorylation/dephosphorylation of Atg13 is regulated spatially inside the cell. Another TORC1-dependent regulation lies in the expression of autophagy genes and vacuolar/lysosomal hydrolases. Several transcriptional and post-transcriptional regulations are controlled by TORC1, which affects autophagy activity in yeast and mammals. Full article
(This article belongs to the Special Issue TOR Signaling Pathway)
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Open AccessReview TORC1-Dependent Phosphorylation Targets in Fission Yeast
Biomolecules 2017, 7(3), 50; doi:10.3390/biom7030050
Received: 2 June 2017 / Revised: 27 June 2017 / Accepted: 28 June 2017 / Published: 3 July 2017
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Abstract
Target of rapamycin (TOR) kinase controls cell metabolism and growth in response to environmental cues such as nutrients, growth factors, and stress. TOR kinase is widely conserved across eukaryotes. As in other organisms, the fission yeast Schizosaccharomyces pombe has two types of TOR
[...] Read more.
Target of rapamycin (TOR) kinase controls cell metabolism and growth in response to environmental cues such as nutrients, growth factors, and stress. TOR kinase is widely conserved across eukaryotes. As in other organisms, the fission yeast Schizosaccharomyces pombe has two types of TOR complex, namely TOR complex 1 (TORC1) and TORC2. It is interesting that the two TOR complexes in S. pombe have opposite roles in sexual differentiation, which is induced by nutrient starvation. TORC1, which contains Tor2 as a catalytic subunit, promotes vegetative growth and represses sexual differentiation in nutrient-rich conditions, while TORC2 is required for the initiation of sexual differentiation. Multiple targets of TORC1 have been identified. Some of these, such as S6 kinase and an autophagy regulator Atg13, are known targets in other organisms. In addition, there is a novel group of TORC1 targets involved in the regulation of sexual differentiation. Here, we review recent findings on phosphorylation targets of TORC1 in S. pombe. Furthermore, we briefly report a novel S. pombe target of TORC1. Full article
(This article belongs to the Special Issue TOR Signaling Pathway)
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Open AccessReview The Architecture of the Rag GTPase Signaling Network
Biomolecules 2017, 7(3), 48; doi:10.3390/biom7030048
Received: 23 May 2017 / Revised: 22 June 2017 / Accepted: 27 June 2017 / Published: 30 June 2017
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Abstract
The evolutionarily conserved target of rapamycin complex 1 (TORC1) couples an array of intra- and extracellular stimuli to cell growth, proliferation and metabolism, and its deregulation is associated with various human pathologies such as immunodeficiency, epilepsy, and cancer. Among the diverse stimuli impinging
[...] Read more.
The evolutionarily conserved target of rapamycin complex 1 (TORC1) couples an array of intra- and extracellular stimuli to cell growth, proliferation and metabolism, and its deregulation is associated with various human pathologies such as immunodeficiency, epilepsy, and cancer. Among the diverse stimuli impinging on TORC1, amino acids represent essential input signals, but how they control TORC1 has long remained a mystery. The recent discovery of the Rag GTPases, which assemble as heterodimeric complexes on vacuolar/lysosomal membranes, as central elements of an amino acid signaling network upstream of TORC1 in yeast, flies, and mammalian cells represented a breakthrough in this field. Here, we review the architecture of the Rag GTPase signaling network with a special focus on structural aspects of the Rag GTPases and their regulators in yeast and highlight both the evolutionary conservation and divergence of the mechanisms that control Rag GTPases. Full article
(This article belongs to the Special Issue TOR Signaling Pathway)
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