Amino acid regulation of TOR complex 1

Harvard University, Cambridge, Massachusetts, United States
AJP Endocrinology and Metabolism (Impact Factor: 3.79). 10/2008; 296(4):E592-602. DOI: 10.1152/ajpendo.90645.2008
Source: PubMed


TOR complex 1 (TORC1), an oligomer of the mTOR (mammalian target of rapamycin) protein kinase, its substrate binding subunit raptor, and the polypeptide Lst8/GbetaL, controls cell growth in all eukaryotes in response to nutrient availability and in metazoans to insulin and growth factors, energy status, and stress conditions. This review focuses on the biochemical mechanisms that regulate mTORC1 kinase activity, with special emphasis on mTORC1 regulation by amino acids. The dominant positive regulator of mTORC1 is the GTP-charged form of the ras-like GTPase Rheb. Insulin, growth factors, and a variety of cellular stressors regulate mTORC1 by controlling Rheb GTP charging through modulating the activity of the tuberous sclerosis complex, the Rheb GTPase activating protein. In contrast, amino acids, especially leucine, regulate mTORC1 by controlling the ability of Rheb-GTP to activate mTORC1. Rheb binds directly to mTOR, an interaction that appears to be essential for mTORC1 activation. In addition, Rheb-GTP stimulates phospholipase D1 to generate phosphatidic acid, a positive effector of mTORC1 activation, and binds to the mTOR inhibitor FKBP38, to displace it from mTOR. The contribution of Rheb's regulation of PL-D1 and FKBP38 to mTORC1 activation, relative to Rheb's direct binding to mTOR, remains to be fully defined. The rag GTPases, functioning as obligatory heterodimers, are also required for amino acid regulation of mTORC1. As with amino acid deficiency, however, the inhibitory effect of rag depletion on mTORC1 can be overcome by Rheb overexpression, whereas Rheb depletion obviates rag's ability to activate mTORC1. The rag heterodimer interacts directly with mTORC1 and may direct mTORC1 to the Rheb-containing vesicular compartment in response to amino acid sufficiency, enabling Rheb-GTP activation of mTORC1. The type III phosphatidylinositol kinase also participates in amino acid-dependent mTORC1 activation, although the site of action of its product, 3'OH-phosphatidylinositol, in this process is unclear.

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Available from: Angela Papageorgiou, Oct 29, 2014
    • "This dual activity of TORC1 allows the rate of translation to be coupled with the amount of ribosomes. TORC1 is modulated by cellular aminoacid levels, thereby linking nutritional status with the rate of protein synthesis (Avruch et al. 2009). The amino-acid-dependent activation of TORC1 takes place downstream of the TSC-1/2 complex and is mediated by Rag GTPase proteins. "
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    • "One mechanism requires a direct Rheb-mTORC1 interaction. When associated with GTP, Rheb binds directly to the mTOR catalytic domain, sequesters FKBP38 which otherwise associates with and suppresses mTORC1, and then activates mTORC1 (Fig. 4) (Laplante and Sabatini 2009; Joseph Avruch 2009; Oshiro et al. 2014). The other mechanism occurs though production of phosphatidic acid (PA). "
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    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.
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    • "mTORC1 senses multiple internal and external signals such as cellular energy status, the growth factors insulin and insulin-like growth factor-1 (IGF-1), and most importantly amino acid availability [7-10]. mTORC1 is activated at the lysosomal membrane in the presence of amino acids, especially by leucine and glutamine, which play a predominant role for mTORC1 activation [11-17]. Thus, there is a direct link between amino acid availability and mTORC1-driven cell growth. "
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