Coordinating cell growth with nutrient availability is critical for cell survival. The evolutionarily conserved TOR (target of rapamycin) controls cell growth in response to nutrients, in particular ...amino acids. As a central controller of cell growth, mTOR (mammalian TOR) is implicated in several disorders, including cancer, obesity, and diabetes. Here, we review how nutrient availability is sensed and transduced to TOR in budding yeast and mammals. A better understanding of how nutrient availability is transduced to TOR may allow novel strategies in the treatment for mTOR‐related diseases.
As part of our metabolism focus, this review summarizes how nutrient availability is recognized and integrated by the conserved TOR cell growth regulator.
Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino ...acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy.
More than 20 years after its discovery, our understanding of target of rapamycin (TOR) signalling continues to grow. Recent global 'omics' studies have revealed physiological roles of mammalian TOR ...(mTOR) in protein, nucleotide and lipid synthesis. Furthermore, emerging evidence provides new insight into the control of mTOR by other pathways such as Hippo, WNT and Notch signalling. Together, this progress has expanded the list of downstream effectors and upstream regulators of mTOR signalling.
Amino acids control cell growth via activation of the highly conserved kinase TORC1. Glutamine is a particularly important amino acid in cell growth control and metabolism. However, the role of ...glutamine in TORC1 activation remains poorly defined. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate. We demonstrate that glutamine in combination with leucine activates mammalian TORC1 (mTORC1) by enhancing glutaminolysis and α-ketoglutarate production. Inhibition of glutaminolysis prevented GTP loading of RagB and lysosomal translocation and subsequent activation of mTORC1. Constitutively active Rag heterodimer activated mTORC1 in the absence of glutaminolysis. Conversely, enhanced glutaminolysis or a cell-permeable α-ketoglutarate analog stimulated lysosomal translocation and activation of mTORC1. Finally, cell growth and autophagy, two processes controlled by mTORC1, were regulated by glutaminolysis. Thus, mTORC1 senses and is activated by glutamine and leucine via glutaminolysis and α-ketoglutarate production upstream of Rag. This may provide an explanation for glutamine addiction in cancer cells.
Display omitted
► Inhibition of glutaminolysis prevents mTORC1 activation by leucine and glutamine ► Enhanced glutaminolysis stimulates mTORC1 ► RagB mediates glutaminolysis-dependent activation of mTORC1 ► Activation of mTORC1 by glutaminolysis blocks autophagy and increases cell size
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.
The target of rapamycin (TOR), discovered 30 years ago, is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by ...nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2. TOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. With emphasis on mammalian TOR (mTOR), we comprehensively reviewed the literature and identified all reported direct substrates. In the context of recent structural information, we discuss how mTORC1 and mTORC2, despite having a common catalytic subunit, phosphorylate distinct substrates. We conclude that the two complexes recruit different substrates to phosphorylate a common, minimal motif.
mTOR is a central growth regulatory kinase whose function has been intensively studied, revealing a bevy of downstream effects, many of which are indirect. Here, Hall and colleagues discern which targets are validated direct substrates of its two complexes, mTORC1 and mTORC2, and propose a target motif.
The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in ...various disorders, including cancer and diabetes. Here, we investigated the upstream regulation of mTORC2. A genetic screen in yeast and subsequent studies in mammalian cells revealed that ribosomes, but not protein synthesis, are required for mTORC2 signaling. Active mTORC2 was physically associated with the ribosome, and insulin-stimulated PI3K signaling promoted mTORC2-ribosome binding, suggesting that ribosomes activate mTORC2 directly. Findings with melanoma and colon cancer cells suggest that mTORC2-ribosome association is important in oncogenic PI3K signaling. Thus, TORC2-ribosome interaction is a likely conserved mechanism of TORC2 activation that is physiologically relevant in both normal and cancer cells. As ribosome content determines growth capacity of a cell, this mechanism of TORC2 regulation ensures that TORC2 is active only in growing cells.
Display omitted
► Genetic screen in yeast reveals that the ribosome is required for TORC2 signaling ► Active mTORC2 is associated with the ribosome ► Insulin-PI3K signaling stimulates mTORC2-ribosome association ► mTORC2-ribosome interaction promotes Akt signaling in cancer cells
Where is mTOR and what is it doing there? Betz, Charles; Hall, Michael N
The Journal of cell biology,
2013-Nov-25, 2013-11-25, 20131125, Volume:
203, Issue:
4
Journal Article
Peer reviewed
Open access
Target of rapamycin (TOR) forms two conserved, structurally distinct kinase complexes termed TOR complex 1 (TORC1) and TORC2. Each complex phosphorylates a different set of substrates to regulate ...cell growth. In mammals, mTOR is stimulated by nutrients and growth factors and inhibited by stress to ensure that cells grow only during favorable conditions. Studies in different organisms have reported localization of TOR to several distinct subcellular compartments. Notably, the finding that mTORC1 is localized to the lysosome has significantly enhanced our understanding of mTORC1 regulation. Subcellular localization may be a general principle used by TOR to enact precise spatial and temporal control of cell growth.
The evolutionarily conserved target of rapamycin complex 1 （TORC1） is a master regulator of cell growth and metabolism. In mammals, growth factors and cellular energy stimulate mTORC1 activity ...through inhibition of the TSC complex （TSC1-TSC2-TBC1D7）, a negative regulator of mTORC1. Amino acids signal to mTORC1 independently of the TSC complex. Here, we review recently identified regulators that link amino acid sufficiency to mTORC1 activity and how mutations affecting these regulators cause human disease.
The AMPK (AMP-activated protein kinase) and TOR (target-of-rapamycin) pathways are interlinked, opposing signaling pathways involved in sensing availability of nutrients and energy and regulation of ...cell growth. AMPK (Yin, or the “dark side”) is switched on by lack of energy or nutrients and inhibits cell growth, while TOR (Yang, or the “bright side”) is switched on by nutrient availability and promotes cell growth. Genes encoding the AMPK and TOR complexes are found in almost all eukaryotes, suggesting that these pathways arose very early during eukaryotic evolution. During the development of multicellularity, an additional tier of cell-extrinsic growth control arose that is mediated by growth factors, but these often act by modulating nutrient uptake so that AMPK and TOR remain the underlying regulators of cellular growth control. In this review, we discuss the evolution, structure, and regulation of the AMPK and TOR pathways and the complex mechanisms by which they interact.
In this review, the authors argue that the opposing AMPK and TOR signaling pathways are the primary controllers of cell growth in eukaryotes. In Taoism, the opposing forces of Yin and Yang must always remain balanced; how AMPK and TOR maintain a similar balance in the cellular context is discussed.
PDF
