Identifies the Rag GTPase family as the missing link that lets mTORC1 sense amino acids by controlling whether mTOR is positioned near its activator Rheb.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Human cell lines |
| Journal | Science |
| Year | 2008 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.1157535 · PMID 18497260 · Free full text (PMC2475333) |
The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins--a family of four related small guanosine triphosphatases (GTPases)--interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate-bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.
| Intervention | Genetic/biochemical (Rag GTPases) |
| Target | Rag GTPases / raptor / mTORC1 |
| Model | Human cell lines |
| Effect | Rag GTPases interact with raptor in an amino-acid-sensitive way and are necessary for amino-acid activation of mTORC1 |