Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Jul;24(7):400-6.
doi: 10.1016/j.tcb.2014.03.003. Epub 2014 Mar 31.

Regulation of mTORC1 by amino acids

Liron Bar-Peled  1 , David M Sabatini  2
Affiliations
Review

Regulation of mTORC1 by amino acids

Liron Bar-Peled et al. Trends Cell Biol. 2014 Jul.

Abstract

The mechanistic target of rapamycin complex I (mTORC1) is a central regulator of cellular and organismal growth, and hyperactivation of this pathway is implicated in the pathogenesis of many human diseases including cancer and diabetes. mTORC1 promotes growth in response to the availability of nutrients, such as amino acids, which drive mTORC1 to the lysosomal surface, its site of activation. How amino acid levels are communicated to mTORC1 is only recently coming to light by the discovery of a lysosome-based signaling system composed of Rags (Ras-related GTPases) and Ragulator v-ATPase, GATOR (GAP activity towards Rags), and folliculin (FLCN) complexes. Increased understanding of this pathway will not only provide insight into growth control but also into the human pathologies triggered by its deregulation.

Keywords: GATOR complex; Rag GTPases; Ragulator; amino acid sensing; folliculin.

PubMed Disclaimer

Figures

Figure 1
Figure 1. The mTORC1 amino acid sensing pathway
A. Under low amino acid conditions Ragulator is found in an inhibitory state with the v-ATPase and GATOR1 exerts its GAP activity towards RagA, keeping this GTPase in the inactive GDP-bound state that is not sufficient to recruit mTORC1. Insulin signaling inhibits TSC complex translocation to the lysosomal surface where it functions as a GAP for Rheb, inactivating this G protein. B. Upon amino acid stimulation, GATOR1 may be inhibited by GATOR2 and Ragulator and v-ATPase undergo a conformational change unleashing the GEF activity of Ragulator towards RagA, while the folliculin complex promotes RagC GTP hydrolysis. The now active heterodimer, consisting of GTP-bound RagA and GDP-loaded RagC, recruits mTORC1 to the lysosomal surface, where it interacts with and is activated by Rheb.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149:274–293. published online EpubApr 13 (10.1016/j.cell.2012.03.017) - PMC - PubMed
    1. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, Marto JA, Sabatini DM. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332:1317–1322. published online EpubJun 10 (10.1126/science.1199498) - PMC - PubMed
    1. Yu Y, Yoon SO, Poulogiannis G, Yang Q, Ma XM, Villen J, Kubica N, Hoffman GR, Cantley LC, Gygi SP, Blenis J. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 2011;332:1322–1326. published online EpubJun 10 (10.1126/science.1199484) - PMC - PubMed
    1. Yip CK, Murata K, Walz T, Sabatini DM, Kang SA. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell. 2010;38:768–774. published online EpubJun 11 (10.1016/j.molcel.2010.05.017) - PMC - PubMed
    1. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110:163–175. published online EpubJul 26 ( - PubMed

Publication types

Substances