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.

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    • "In particular, the outer surface of the lysosomal membrane constitutes a privileged site for the detection of amino acid repletion by the so-called ''Ragulator,'' a multiprotein complex with guanine nucleotide exchange factor (GEF) activity that controls MTORC1 activation by Ras homolog enriched in brain (RHEB) (Bar-Peled et al., 2012). In the presence of amino acids, RAG GTPases are recruited to the lysosomal surface and activated by the Ragulator, resulting in optimal MTORC1 signaling and autophagy inhibition (Sancak et al., 2010). "
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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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