Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1

Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, MA 02142, USA
Cell (Impact Factor: 32.24). 09/2012; 150(6):1196-208. DOI: 10.1016/j.cell.2012.07.032
Source: PubMed


The mTOR Complex 1 (mTORC1) pathway regulates cell growth in response to numerous cues, including amino acids, which promote mTORC1 translocation to the lysosomal surface, its site of activation. The heterodimeric RagA/B-RagC/D GTPases, the Ragulator complex that tethers the Rags to the lysosome, and the v-ATPase form a signaling system that is necessary for amino acid sensing by mTORC1. Amino acids stimulate the binding of guanosine triphosphate to RagA and RagB but the factors that regulate Rag nucleotide loading are unknown. Here, we identify HBXIP and C7orf59 as two additional Ragulator components that are required for mTORC1 activation by amino acids. The expanded Ragulator has nucleotide exchange activity toward RagA and RagB and interacts with the Rag heterodimers in an amino acid- and v-ATPase-dependent fashion. Thus, we provide mechanistic insight into how mTORC1 senses amino acids by identifying Ragulator as a guanine nucleotide exchange factor (GEF) for the Rag GTPases.

    • "ino acids, particularly the branched chain amino acid leucine, promotes the localization of mTORC1 to the lysosome . This process is mediated by the Rag family of GTPases and the Ragulator complex, which recruits mTORC1 to the lysosome and promote its interaction with the vacuolar ATPase (Sancak et al . 2008Sancak et al . , 2010Zoncu et al . 2011 ;Bar-Peled et al . 2012). The pathways that regulate the Rags and Ragulator are an area of active investigation by numerous labs. Several protein complexes that act as GAPs for the Rags have been identifi ed, including the GATOR1/2 complex, as well as a complex composed of folliculin and FNIP1/2 (Bar-Peled et al . 2013 ;Tsun et al . 2013). The amino acid trans"
    [Show abstract] [Hide abstract]
    ABSTRACT: Lipids are essential for many cellular and organismal processes, yet an excess of lipids can cause toxicity. The liver is a key organ for the maintenance of lipid homeostasis, performing lipogenesis as well as mediating the exchange of lipoproteins with peripheral tissues. In this chapter, we focus primarily on the regulation of lipogenesis in the liver by the protein kinase mTOR (mechanistic Target of Rapamycin), a central sensor of environmental cues that coordinates growth, protein synthesis and metabolism with nutrient availability. The mTOR protein kinase is found in two distinct complexes, each of which plays a role in the regulation of lipogenesis. We discuss the regulation of lipogenesis both directly by hepatic mTOR, indirectly by mTOR in other organs, and the regulation of hepatic lipogenesis by hormones and growth factors that regulate mTOR. This regulation by mTOR is an extremely complex process that we are only now beginning to fully understand.
    No preview · Chapter · Jan 2016
  • Source
    • "Moreover, rescue of both synaptic growth defects and pupal lethality by RagA QL suggest a common molecular origin for the disparate trpml 1 phenotypes. The Rag-Ragulator complex activates MTORC1 in response to an increase in amino acid levels (Bar-Peled et al., 2012) or a decrease in the activity of AMPK (Zhang et al., 2014) (Figure S1B). AMPK inhibits MTORC1 via phosphorylation and activation of the TSC1/TSC2 complex, which is a GAP for Rheb, a G protein required for MTORC1 function (Zoncu et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Here, we evaluate the mechanisms underlying the neurodevelopmental deficits in Drosophila and mouse models of lysosomal storage diseases (LSDs). We find that lysosomes promote the growth of neuromuscular junctions (NMJs) via Rag GTPases and mechanistic target of rapamycin complex 1 (MTORC1). However, rather than employing S6K/4E-BP1, MTORC1 stimulates NMJ growth via JNK, a determinant of axonal growth in Drosophila and mammals. This role of lysosomal function in regulating JNK phosphorylation is conserved in mammals. Despite requiring the amino-acid-responsive kinase MTORC1, NMJ development is insensitive to dietary protein. We attribute this paradox to anaplastic lymphoma kinase (ALK), which restricts neuronal amino acid uptake, and the administration of an ALK inhibitor couples NMJ development to dietary protein. Our findings provide an explanation for the neurodevelopmental deficits in LSDs and suggest an actionable target for treatment.
    Full-text · Article · Sep 2015 · Cell Reports
  • Source
    • "Akt and Erk, as well as RSK downstream of Erk, phosphorylate the TSC2 and thereby allow Rheb to activate mTORC1. Unlike GFs, AAs communicate to mTORC1 through the Rag GTPase complex and the Ragulator complex that anchors the Rags to the lysosome (Bar-Peled et al., 2012; Kim et al., 2008; Sancak et al., 2008, 2010). In response to AAs, the Rag GTPase complex is activated and subsequently recruits mTORC1 to the lysosome, where the Rheb GTPase is also present. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mechanistic target of rapamycin complex 1 (mTORC1) senses diverse signals to regulate cell growth and metabolism. It has become increasingly clear that mTORC1 activity is regulated in time and space inside the cell, but direct interrogation of such spatiotemporal regulation is challenging. Here, we describe a genetically encoded mTORC1 activity reporter (TORCAR) that exhibits a change in FRET in response to phosphorylation by mTORC1. Co-imaging mTORC1 activity and calcium dynamics revealed that a growth-factor-induced calcium transient contributes to mTORC1 activity. Dynamic activity maps generated with the use of subcellularly targeted TORCAR uncovered mTORC1 activity not only in cytosol and at the lysosome but also in the nucleus and at the plasma membrane. Furthermore, a wide distribution of activities was observed upon growth factor stimulation, whereas leucine ester, an amino acid surrogate, induces more compartmentalized activities at the lysosome and in the nucleus. Thus, mTORC1 activities are spatiotemporally regulated in a signal-specific manner. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Cell Reports
Show more