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: 33.12). 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.

    • "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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    • "The levels of other key metabolites have multiple effects that influence both metabolism and cell signaling in ways that we are just beginning to understand. For example, 2-oxoglutarate (2OG, also known as a-ketoglutarate) is a central intermediate in the TCA cycle, but also needed for amino acid interconversion and breakdown by transamination, which may affect the activity level of a major amino acid sensor and growth regulator, mTORC1 (Bar-Peled et al. 2012). In addition , 2OG is a critical cofactor for the Jumonji class of histone methyl-N-lysine demethylases (Hou and Yu 2010), TET family 5-methylcytosine hydroxylases (Wu and Zhang 2011), and EglN-type prolyl-4-hydroxylases (Freeman et al. 2003), all of which likely affect the level of expression of genes encoding signaling proteins. "
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    • "Multiple GAPs have also been identified for Rags including the GATOR1 complex for RagA/B (Bar-Peled et al., 2013), the FLCN-FNIP complex for RagC/D (Tsun et al., 2013), and possibly the leucyl-tRNA synthase for RagD (Han et al., 2012). In addition, the Ragulator complex functions as a GEF for RagA/B, whose activity is induced via the lysosomal v-ATPase upon amino acid stimulation (Bar-Peled et al., 2012). Finally, although GDI proteins are known to control the functions of Rho and Rab subfamilies of small GTPases (Garcia-Mata et al., 2011; Pfeffer and Aivazian, 2004), no GDIs have been described for either Rheb or Rags. "
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