title: Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis.
abstract: 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.
authors: Biozentrum, University of Basel, Basel, Switzerland.
authors: Aaron M
authors: AM
authors: Robitaille
authors: Stefan
authors: S
authors: Christen
authors: Mitsugu
authors: M
authors: Shimobayashi
authors: Marion
authors: M
authors: Cornu
authors: Luca L
authors: LL
authors: Fava
authors: Suzette
authors: S
authors: Moes
authors: Cristina
authors: C
authors: Prescianotto-Baschong
authors: Uwe
authors: U
authors: Sauer
authors: Paul
authors: P
authors: Jenoe
authors: Michael N
authors: MN
authors: Hall
mesh_terms: D000818:Animals; D001221:Aspartate Carbamoyltransferase / Q000235:genetics / Q000378:metabolism*; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004080:Dihydroorotase / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C033626:CAD trifunctional enzyme; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D020543:Proteome; D011743:Pyrimidines; D001221:Aspartate Carbamoyltransferase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); C030986:pyrimidine