Journal
SCIENCE
Volume 339, Issue 6125, Pages 1320-1323Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1228771
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Funding
- Werner Siemens Foundation
- Societe Francophone du Diabete-Association de Langue Francaise pour L'Etude du Diabete et des Maladies Metaboliques
- Swiss Cancer League
- Louis Jeantet Foundation
- Swiss National Science Foundation
- SystemsX.ch project YeastX
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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.
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