mTORC1-S6K1 stimulates de novo pyrimidine synthesis by phosphorylating CAD.
| 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.1228792 · PMID 23429703 · Free full text (PMC3753690) |
Cellular growth signals stimulate anabolic processes. The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase that senses growth signals to regulate anabolic growth and proliferation. Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mTORC1 thus stimulates the production of new nucleotides to accommodate an increase in RNA and DNA synthesis needed for ribosome biogenesis and anabolic growth.
| Intervention | Biochemical/genetic (mTORC1 / S6K1) |
| Target | mTORC1 / S6K1 / CAD (pyrimidine synthesis) |
| Model | Mammalian cells |
| Effect | mTORC1 via S6K1 stimulates de novo pyrimidine synthesis (CAD phosphorylation) to support growth |