Ragulator is the guanine-nucleotide exchange factor activating the Rag GTPases on the lysosome.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Cell |
| Year | 2012 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.cell.2012.07.032 · PMID 22980980 · Free full text (PMC3517996) |
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.
| Intervention | Biochemical/genetic (Ragulator) |
| Target | Ragulator / Rag GTPases / mTORC1 |
| Model | Mammalian cells |
| Effect | Ragulator is a GEF for RagA/B, activating the Rags to signal amino-acid levels to mTORC1 at the lysosome |