The amino acid sensitive TOR pathway from yeast to mammals

University of Cincinnati Genome Research Institute, 2180 East Galbraith Road, Cincinnati, OH 45237, USA.
FEBS Letters (Impact Factor: 3.34). 06/2006; 580(12):2821-9. DOI: 10.1016/j.febslet.2006.04.068
Source: PubMed

ABSTRACT The target of rapamycin (TOR) is an ancient effector of cell growth that integrates signals from growth factors and nutrients. Two downstream effectors of mammalian TOR, the translational components S6K1 and 4EBP1, are commonly used as reporters of mTOR activity. The conical signaling cascade initiated by growth factors is mediated by PI3K, PKB, TSC1/2 and Rheb. However, the process through which nutrients, i.e., amino acids, activate mTOR remains largely unknown. Evidence exists for both an intracellular and/or a membrane bound sensor for amino acid mediated mTOR activation. Research in eukaryotic models, has implicated amino acid transporters as nutrient sensors. This review describes recent advances in nutrient signaling that impinge on mTOR and its targets including hVps34, class III PI3K, a transducer of nutrient availability to mTOR.

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    ABSTRACT: L-arginine (Arg) is an indispensable amino acid in avians and is required for growth. The aim of this study was to investigate the effects of L-Arg on protein synthesis and genes expression involved in target of rapamycin (TOR) signaling pathway in chicken enterocytes. Cells were cultured for 4 days in L-Arg-free Dulbecco's modified Eagle's medium containing 10, 100, 200, 400, or 600 μM L-Arg. Cell growth, cell cycle, protein synthesis, and protein degradation as well as mRNA expression levels of TOR, ribosomal protein S6 kinase 1 (S6K1), and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) were determined. The results showed that cell viability was enhanced by L-Arg with a maximal response at 10 to 400 μM. Increasing extracellular concentrations of L-Arg from 10 to 400 μM increased the cells in S and G2/M phase to a significant extent and decreased cell numbers in G0/G1 phase. Further more, addition of 100, 200, or 400 μM L-Arg to culture medium increased protein synthesis and reduced protein degradation in chicken intestinal epithelial cells. Consistent with the data on cell growth and protein turnover, supplementation of 100, 200, or 400 μM L-Arg increased the mRNA abundances of TOR, 4E-BP1, and S6K1. It was concluded the action of L-Arg involves in upregulating the genes expression of TOR cell signaling pathway which increases protein synthesis and reduces protein degradation. © 2015 Poultry Science Association Inc.
    Poultry Science 03/2015; 94(5). DOI:10.3382/ps/pev051 · 1.54 Impact Factor
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    ABSTRACT: Mammalian target of rapamycin (mTOR), which is now referred to as mechanistic target of rapamycin, integrates many signals, including those from growth factors, energy status, stress, and amino acids, to regulate cell growth and proliferation, protein synthesis, protein degradation, and other physiological and biochemical processes. The mTOR-Rheb-TSC-TBC complex co-localizes to the lysosome and the phosphorylation of TSC-TBC effects the dissociation of the complex from the lysosome and activates Rheb. GTP-bound Rheb potentiates the catalytic activity of mTORC1. Under conditions with growth factors and amino acids, v-ATPase, Ragulator, Rag GTPase, Rheb, hVps34, PLD1, and PA have important but disparate effects on mTORC1 activation. In this review, we introduce five models of mTORC1 activation by growth factors and amino acids to provide a comprehensive theoretical foundation for future research.
    International Journal of Molecular Sciences 11/2014; 15(11):20753-20769. DOI:10.3390/ijms151120753 · 2.46 Impact Factor
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    ABSTRACT: The target of rapamycin (TOR) is an important signaling pathway on a hierarchical network of interacting pathways regulating central biological processes, such as cell growth, stress response and aging. Several lines of evidence suggest a functional link between TOR signaling and sphingolipid metabolism. Here, we report that the TORC1-Sch9p pathway is activated in cells lacking Isc1p, the yeast orthologue of mammalian neutral sphingomyelinase 2. The deletion of TOR1 or SCH9 abolishes the premature aging, oxidative stress sensitivity and mitochondrial dysfunctions displayed by isc1Δ cells and this is correlated with the suppression of the autophagic flux defect exhibited by the mutant strain. The protective effect of TOR1 deletion, as opposed to that of SCH9 deletion, is not associated with the attenuation of Hog1p hyperphosphorylation, which was previously implicated in isc1Δ phenotypes. Our data support a model in which Isc1p regulates mitochondrial function and chronological lifespan in yeast through the TORC1-Sch9p pathway although Isc1p and TORC1 also seem to act through independent pathways, as isc1Δtor1Δ phenotypes are intermediate to those displayed by isc1Δ and tor1Δ cells. We also provide evidence that TORC1 downstream effectors, the type 2A protein phosphatase Sit4p and the AGC protein kinase Sch9p, integrate nutrient and stress signals from TORC1 with ceramide signaling derived from Isc1p to regulate mitochondrial function and lifespan in yeast. Overall, our results show that TORC1-Sch9p axis is deregulated in Isc1p-deficient cells, contributing to mitochondrial dysfunction, enhanced oxidative stress sensitivity and premature aging of isc1Δ cells.


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