Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis - PubMed

Affiliations

• PMID: 23429704
• DOI: 10.1126/science.1228771

Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis

Aaron M Robitaille et al. Science. 2013.

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.

Comment in

• mTORC1 signaling aids in CADalyzing pyrimidine biosynthesis.

  Buel GR, Kim SG, Blenis J. Buel GR, et al. Cell Metab. 2013 May 7;17(5):633-5. doi: 10.1016/j.cmet.2013.04.018. Cell Metab. 2013. PMID: 23663734

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