Article

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

ABSTRACT

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"
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    • "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). "
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    • "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. "
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