Article

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: 3.17). 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.

Full-text preview

Available from: sciencedirect.com
  • Source
    • "Amino acids are not just the building blocks of proteins and the substrates of metabolic and biosynthetic reactions, but they are also the signaling molecules to regulate cellular metabolism and cell growth. One of the well-recognized cellular signaling pathways mobilized by amino acids is the mechanistic target of rapamycin (mTOR) signaling pathway (Dann and Thomas 2006; Wu 2009; Abstract Among amino acids, leucine is a potential signaling molecule to regulate cell growth and metabolism by activating mechanistic target of rapamycin complex 1 (mTORC1). To reveal the critical structures of leucine molecule to activate mTORC1, we examined the structure– activity relationships of leucine derivatives in HeLa S3 cells for cellular uptake and for the induction of phosphorylation of p70 ribosomal S6 kinase 1 (p70S6K), a downstream effector of mTORC1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Among amino acids, leucine is a potential signaling molecule to regulate cell growth and metabolism by activating mechanistic target of rapamycin complex 1 (mTORC1). To reveal the critical structures of leucine molecule to activate mTORC1, we examined the structure-activity relationships of leucine derivatives in HeLa S3 cells for cellular uptake and for the induction of phosphorylation of p70 ribosomal S6 kinase 1 (p70S6K), a downstream effector of mTORC1. The activation of mTORC1 by leucine and its derivatives was the consequence of two successive events: the cellular uptake by L-type amino acid transporter 1 (LAT1) responsible for leucine uptake in HeLa S3 cells and the activation of mTORC1 following the transport. The structural requirement for the recognition by LAT1 was to have carbonyl oxygen, alkoxy oxygen of carboxyl group, amino group and hydrophobic side chain. In contrast, the requirement for mTORC1 activation was more rigorous. It additionally required fixed distance between carbonyl oxygen and alkoxy oxygen of carboxyl group, and amino group positioned at α-carbon. L-Configuration in chirality and appropriate length of side chain with a terminal isopropyl group were also important. This confirmed that LAT1 itself is not a leucine sensor. Some specialized leucine sensing mechanism with rigorous requirement for agonistic structures should exist inside the cells because leucine derivatives not transported by LAT1 did not activate mTORC1. Because LAT1-mTOR axis is involved in the regulation of cell growth and cancer progression, the results from this study may provide a new insight into therapeutics targeting both LAT1 and leucine sensor.
    Full-text · Article · Jan 2016 · Amino Acids
  • Source
    • "Several factors involved in amino acid - MTOR sig - naling have been described in the past and have been reviewed in detail elsewhere ( Dann and Thomas 2006 ; Avruch et al . 2009 ; Meijer and Codogno 2009 ; Kim and Guan 2011 ; Laplante and Sabatini 2012 ) ( Fig . 2 ) . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amino acids not only participate in intermediary metabolism but also stimulate insulin-mechanistic target of rapamycin (MTOR)-mediated signal transduction which controls the major metabolic pathways. Among these is the pathway of autophagy which takes care of the degradation of long-lived proteins and of the elimination of damaged or functionally redundant organelles. Proper functioning of this process is essential for cell survival. Dysregulation of autophagy has been implicated in the etiology of several pathologies. The history of the studies on the interrelationship between amino acids, MTOR signaling and autophagy is the subject of this review. The mechanisms responsible for the stimulation of MTOR-mediated signaling, and the inhibition of autophagy, by amino acids have been studied intensively in the past but are still not completely clarified. Recent developments in this field are discussed.
    Full-text · Article · Jun 2014 · Amino Acids
  • Source
    • "Rapamycin is a specific inhibitor of mTOR (Dann and Thomas, 2006; Wullschleger et al., 2006). It inhibits mTOR by binding with high affinity to its internal receptor, FKBP12 [FK506-binding protein 12 (FK506 is an immunosuppressant macrolide)]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oligodendrocyte development is controlled by numerous extracellular signals that regulate a series of transcription factors that promote the differentiation of oligodendrocyte progenitor cells to myelinating cells in the central nervous system. A major element of this regulatory system that has only recently been studied is the intracellular signaling from surface receptors to transcription factors to downregulate inhibitors and upregulate inducers of oligodendrocyte differentiation and myelination. The current review focuses on one such pathway: the mammalian target of rapamycin (mTOR) pathway, which integrates signals in many cell systems and induces cell responses including cell proliferation and cell differentiation. This review describes the known functions of mTOR as they relate to oligodendrocyte development, and its recently discovered impact on oligodendrocyte differentiation and myelination. A potential model for its role in oligodendrocyte development is proposed.
    Full-text · Article · Feb 2013 · ASN Neuro
Show more