Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med

Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
Trends in Molecular Medicine (Impact Factor: 9.45). 06/2012; 18(9):524-33. DOI: 10.1016/j.molmed.2012.05.007
Source: PubMed

ABSTRACT The mechanistic target of rapamycin (mTOR) kinase controls growth and metabolism, and its deregulation underlies the pathogenesis of many diseases, including cancer, neurodegeneration, and diabetes. mTOR complex 1 (mTORC1) integrates signals arising from nutrients, energy, and growth factors, but how exactly these signals are propagated await to be fully understood. Recent findings have placed the lysosome, a key mediator of cellular catabolism, at the core of mTORC1 regulation by amino acids. A multiprotein complex that includes the Rag GTPases, Ragulator, and the v-ATPase forms an amino acid-sensing machinery on the lysosomal surface that affects the decision between cell growth and catabolism at multiple levels. The involvement of a catabolic organelle in growth signaling may have important implications for our understanding of mTORC1-related pathologies.

1 Follower
19 Reads
  • Source
    • "mTORC1 plays many significant physiological and pathological implications in vivo. Its deregulation underlies the pathogenesis of many diseases (Efeyan et al. 2012). On the other hand, lysosome, a key mediator of cellular catabolism, is at the core of mTORC1 regulation by amino acids. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mammalian target of rapamycin complex 1 (mTORC1) is activated by amino acids to promote cell growth via protein synthesis. Specifically, Ras-related guanosine triphosphatases (Rag GTPases) are activated by amino acids, and then translocate mTORC1 to the surface of late endosomes and lysosomes. Ras homolog enriched in brain (Rheb) resides on this surface and directly activates mTORC1. Apart from the presence of intracellular amino acids, Rag GTPases and Rheb, other mediators involved in intracellular amino acid signaling to mTORC1 activation include human vacuolar sorting protein-34 (hVps34) and mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3). Those molecular links between mTORC1 and its mediators form a complicate signaling network that controls cellular growth, proliferation, and metabolism. Moreover, it is speculated that amino acid signaling to mTORC1 may start from the lysosomal lumen. In this review, we discussed the function of these mediators in mTORC1 pathway and how these mediators are regulated by amino acids in details.
    Amino Acids 02/2015; 47(5). DOI:10.1007/s00726-015-1937-x · 3.29 Impact Factor
  • Source
    • "These protein components and downstream targets include PI3K, Ras, Raf, Akt, Ras homolog enriched in brain (Rheb), the eukaryotic translation initiation factor 4E (eIF4E), the hypoxia-inducible factor 1-α (HIF1-α), mitochondrial succinate dehydrogenase subunits SDHB, SDHC and SDHD, the mitochondrial succinate dehydrogenase assembly factor 2 (SDHAF2), and mitochondrial fumarate hydratase FH [46] [48] [49] [50] [59] [71] [72]. In contrast, other protein components and downstream targets of this signaling network have been shown to decelerate cellular aging and to act as tumor suppressors; they include PTEN, LKB1, the tuberous sclerosis proteins 1 and 2 (TSC1 and TSC2), the Von Hippel–Lindau tumor suppressor protein VHL, Ras inhibitors NF1 and NF2, and mitochondrial isocitrate dehydrogenases IDH1 and IDH2 [46] [48] [49] [50] [59] [71] [72]. Third, certain pharmacological interventions, a caloric restriction (CR) diet and some dietary restriction (DR) regimens exhibit both anti-aging and anti-cancer effects by specifically altering information flow along the PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK/mTOR and/or LKB1/AMPK/mTOR signaling pathways as well as by modulating some of the downstream targets of these pathways. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Age is the major risk factor in the incidence of cancer, a hyperplastic disease associated with aging. Here, we discuss the complex interplay between mechanisms underlying aging and cancer as a reciprocal relationship. This relationship progresses with organismal age, follows the history of cell proliferation and senescence, is driven by common or antagonistic causes underlying aging and cancer in an age-dependent fashion, and is maintained via age-related convergent and divergent mechanisms. We summarize our knowledge of these mechanisms, outline the most important unanswered questions and suggest directions for future research.
    Aging and Disease 02/2015; 6(1):56-75. DOI:10.14336/AD.2014.0209 · 3.07 Impact Factor
  • Source
    • "Because aging-related pathways like mTOR are activated by amino acids, a diet that does not provide an overabundance of amino acids can be considered beneficial (Efeyan et al., 2012). Restricting proteins is one of the few dietary interventions that can increase lifespan in rodents (Yu et al., 1985; Leto et al., 1976; Ross, 1961; Ross & Bras, 1975). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many diets and nutritional advice are circulating, often based on short- or medium-term clinical trials and primary outcomes, like changes in LDL cholesterol or weight. It remains difficult to assess which dietary interventions can be effective in the long term to reduce the risk of aging-related disease and increase the (healthy) lifespan. At the same time, the scientific discipline that studies the aging process has identified some important nutrient-sensing pathways that modulate the aging process, such as the mTOR and the insulin/insulin-like growth factor signaling pathway. A thorough understanding of the aging process can help assessing the efficacy of dietary interventions aimed at reducing the risk of aging-related diseases. To come to these insights, a synthesis of biogerontological, nutritional, and medical knowledge is needed, which can be framed in a new discipline called 'nutrigerontology'. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 12/2014; 14(1). DOI:10.1111/acel.12284 · 6.34 Impact Factor
Show more


19 Reads