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Science 339 (6125): 1320-1323

Copyright © 2013 by the American Association for the Advancement of Science

Quantitative Phosphoproteomics Reveal mTORC1 Activates de Novo Pyrimidine Synthesis

Aaron M. Robitaille,1 Stefan Christen,2 Mitsugu Shimobayashi,1 Marion Cornu,1 Luca L. Fava,1,* Suzette Moes,1 Cristina Prescianotto-Baschong,1 Uwe Sauer,2 Paul Jenoe,1 Michael N. Hall1,{dagger}

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.

1 Biozentrum, University of Basel, 4056 Basel, Switzerland.
2 Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zürich, 8093 Zürich, Switzerland.

{dagger} Corresponding author. E-mail: m.hall{at}

* Present address: Biocenter, Division of Developmental Immunology, Innsbruck Medical University, A-6020 Innsbruck, Austria.

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