Glutamine activates mTORC1 via a Rag-independent, Arf1-dependent route distinct from leucine.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Science |
| Year | 2015 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.1259472 · PMID 25567907 · Free full text (PMC4384888) |
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates environmental and intracellular signals to regulate cell growth. Amino acids stimulate mTORC1 activation at the lysosome in a manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and the vacuolar H(+)-adenosine triphosphatase (v-ATPase). We report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms, respectively. Glutamine promoted mTORC1 translocation to the lysosome in RagA and RagB knockout cells and required the v-ATPase but not the Ragulator. Furthermore, we identified the adenosine diphosphate ribosylation factor-1 GTPase to be required for mTORC1 activation and lysosomal localization by glutamine. Our results uncover a signaling cascade to mTORC1 activation independent of the Rag GTPases and suggest that mTORC1 is differentially regulated by specific amino acids.
| Intervention | Biochemical/genetic |
| Target | mTORC1 / Rag GTPases |
| Model | Mammalian cells |
| Effect | Leucine activates mTORC1 via the Rags; glutamine activates it Rag-independently – differential regulation |