Quantitative phosphoproteomics show mTORC1 activates de novo pyrimidine synthesis.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Science |
| Year | 2013 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.1228771 · PMID 23429704 |
The Ser-Thr kinase mammalian target of rapamycin (mTOR) controls cell growth and metabolism by stimulating glycolysis and synthesis of proteins and lipids. To further understand the central role of mTOR in cell physiology, we used quantitative phosphoproteomics to identify substrates or downstream effectors of the two mTOR complexes. mTOR controlled the phosphorylation of 335 proteins, including CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). CAD catalyzes the first three steps in de novo pyrimidine synthesis. mTORC1 indirectly phosphorylated CAD-S1859 through S6 kinase (S6K). CAD-S1859 phosphorylation promoted CAD oligomerization and thereby stimulated de novo synthesis of pyrimidines and progression through S phase of the cell cycle in mammalian cells. Thus, mTORC1 also stimulates the synthesis of nucleotides to control cell proliferation.
| Intervention | Quantitative phosphoproteomics |
| Target | mTORC1 / S6K1 / CAD |
| Model | Mammalian cells |
| Effect | mTORC1 activates de novo pyrimidine synthesis (CAD phosphorylation), among 335 mTOR-controlled phosphosites |