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


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.

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    • "It was recently demonstrated in non-muscle cells that amino acids regulate the association of mTOR with LEL structures via a mechanism that is dependent on the Rag family of GTPases [118] [119] [120]. Specifically, amino acid stimulation increases the association of mTOR with LEL structures by regulating the activity/GTP-loading state of the Rag GTPases [121]. Based on these data, it has been suggested that amino acid–induced changes in mTORC1 signaling are primarily regulated by spatially controlling the ability of mTOR to interact with the LEL-associated activator, Rheb. "
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    • "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. "
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