Quantitative Phosphoproteomics Reveal mTORC1 Activates de Novo Pyrimidine Synthesis
Open accessAbstract
Coordinating Metabolism: Growth factors help to coordinate metabolism with growth in part by stimulating the activity of the protein kinase mTORC1 (mechanistic target of rapamycin complex 1). Ben-Sahra et al. (p. 1323 , published online 21 February) and Robitaille et al. (p. 1320 , published online 21 February) independently identified a key target of mTORC1—carbamolyl-phosphate synthase 2, or CAD, the rate-limiting enzyme for de novo synthesis of pyrimidines. Metabolomic profiling and phosphoproteomic analyses of normal cells and cells lacking signaling by mTORC1 converged on CAD as a key point at which growth-promoting signals also ramp up production of nucleic acids.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Glutamine-induced activation of mTORC1 results in phosphorylation of CAD, which catalyzes the condensation reaction converting glutamine-derived nitrogen into the pyrimidine precursor orotate.
“Moreover, glutamine-induced activation of mTORC1 results in the phosphorylation of the enzyme complex called carbamoyl phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the condensation reaction converting glutamine-derived nitrogen into the pyrimidine precursor orotate34,35.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [35]
CAD activity is regulated via phosphorylation by MAPK and by mTORC1-dependent S6 kinase.
“Furthermore, activity of CAD enzyme is regulated via phosphorylation by MAPK and by mTORC1-dependent S6 kinase (Ben-Sahra et al., 2013; Graves et al., 2000; Robitaille et al., 2013).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Robitaille et al., 2013
Cites
Clustal W and Clustal X version 2.0
Larkin, M., Blackshields, G., Brown, N. P., Chenna, R., McGettigan, P., McWilliam, H., Valentin, F., Wallace, I. M., Wilm, A., López, R., et al. (2007) · Bioinformatics · doi:10.1093/bioinformatics/btm404 · Cited by 28,221 · see citing works
Cox, J., & Mann, M. (2008) · Nature Biotechnology · doi:10.1038/nbt.1511 · Cited by 14,855 · see citing works
WebLogo: A Sequence Logo Generator: Figure 1Preprint
Crooks, G. E., Hon, G. C., Chandonia, J., & Brenner, S. E. (2004) · Genome Research · doi:10.1101/gr.849004 · Cited by 12,433 · see citing works
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509 · see citing works
TOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787 · see citing works
Self-citationOng, S.-E., Blagoev, B., Kratchmarova, I., Kristensen, D. B., Steen, H., Pandey, A., & Mann, M. (2002) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m200025-mcp200 · Cited by 5,574 · see citing works
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083 · see citing works
Creation of human tumour cells with defined genetic elements
Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., & Weinberg, R. A. (1999) · Nature · doi:10.1038/22780 · Cited by 2,345 · see citing works
Laplante, M., & Sabatini, D. (2009) · Journal of Cell Science · doi:10.1242/jcs.051011 · Cited by 2,317 · see citing works
Activation of a metabolic gene regulatory network downstream of mTOR complex 1
Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.022 · Cited by 2,020 · see citing works
g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments
Reimand, J., Kull, M., Peterson, H., Hansen, J., & Vilo, J. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm226 · Cited by 1,525 · see citing works
Olsen, J. V., de Godoy, L. M. F., Li, G., Maček, B., Mortensen, P., Pesch, R., Makarov, A., Lange, O., Horning, S. R., & Mann, M. (2005) · Molecular & Cellular Proteomics · doi:10.1074/mcp.t500030-mcp200 · Cited by 1,513 · see citing works
Hsu, P. P., Kang, S. A., Rameseder, J., Zhang, Y., Ottina, K. A., Lim, D., Peterson, T. R., Choi, Y., Gray, N. S., Yaffe, M. B., et al. (2011) · Science · doi:10.1126/science.1199498 · Cited by 1,084 · see citing works
BioNumbers—the database of key numbers in molecular and cell biology
Milo, R., Jorgensen, P., Moran, U., Weber, G., & Springer, M. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkp889 · Cited by 1,055 · see citing works
Rapamycin passes the torch: a new generation of mTOR inhibitors
Benjamin, D., Colombi, M., Moroni, C., & Hall, M. N. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3531 · Cited by 981 · see citing works
Self-citationSchwartz, D., & Gygi, S. P. (2005) · Nature Biotechnology · doi:10.1038/nbt1146 · Cited by 879 · see citing works
Yu, Y., Yoon, S.-O., Poulogiannis, G., Yang, Q., Ma, X. M., Villén, J., Kubica, N., Hoffman, G. R., Cantley, L. C., Gygi, S. P., et al. (2011) · Science · doi:10.1126/science.1199484 · Cited by 855 · see citing works
mTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs
Dowling, R. J. O., Topisirović, I., Alain, T., Bidinosti, M., Fonseca, B. D., Petroulakis, E., Wang, X., Larsson, O. S., Selvaraj, A., Liu, Y., et al. (2010) · Science · doi:10.1126/science.1187532 · Cited by 726 · see citing works
Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling
Gao, X., Zhang, Y., Arrazola, P., Hino, O., Kobayashi, T., Yeung, R. S., Ru, B., & Pan, D. (2002) · Nature Cell Biology · doi:10.1038/ncb847 · Cited by 719 · see citing works
Activation of mTORC2 by Association with the Ribosome
Zinzalla, V., Stracka, D., Oppliger, W., & Hall, M. N. (2011) · Cell · doi:10.1016/j.cell.2011.02.014 · Cited by 648 · see citing works
Self-citationReproducible isolation of distinct, overlapping segments of the phosphoproteome
Bodenmiller, B., Mueller, L. N., Mueller, M., Domon, B., & Aebersold, R. H. (2007) · Nature Methods · doi:10.1038/nmeth1005 · Cited by 564 · see citing works
Dazert, E., & Hall, M. N. (2011) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2011.09.003 · Cited by 460 · see citing works
ScanProsite: a reference implementation of a PROSITE scanning tool.
Gattiker, A., Gasteiger, E., & Bairoch, A. (2002) · PubMed · Cited by 432 · see citing works
Buescher, J. M., Moco, S., Sauer, U., & Zamboni, N. (2010) · Analytical Chemistry · doi:10.1021/ac100101d · Cited by 341 · see citing works
Self-citationOh, W. J., Wu, C. C., Kim, S. J., Facchinetti, V., Julien, L.-A., Finlan, M., Roux, P. P., Su, B., & Jacinto, E. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.271 · Cited by 333 · see citing works
Large-Scale Phosphorylation Analysis of α-Factor-Arrested Saccharomyces cerevisiae
Li, X., Gerber, S. A., Rudner, A. D., Beausoleil, S. A., Haas, W., Villén, J., Elias, J. E., & Gygi, S. P. (2007) · Journal of Proteome Research · doi:10.1021/pr060559j · Cited by 289 · see citing works
Soulard, A., Cremonesi, A., Moes, S., Schütz, F., Jenö, P., & Hall, M. N. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-03-0182 · Cited by 260 · see citing works
Self-citationAmino Acid Signaling in TOR Activation
Kim, J., & Guan, K. (2011) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-062209-094414 · Cited by 235 · see citing works
Regulation of carbamoyl phosphate synthetase by MAP kinase
Graves, L. M., Guy, H. I., Kozlowski, P., Huang, M., Lazarowski, E. R., Pope, R. M., Collins, M. A., Dahlstrand, E. N., Earp, H. S., & Evans, D. R. (2000) · Nature · doi:10.1038/35002111 · Cited by 232 · see citing works
Patursky-Polischuk, I., Stolovich-Rain, M., Hausner-Hanochi, M., Kasir, J., Cybulski, N., Avruch, J., Rüegg, M. A., Hall, M. N., & Meyuhas, O. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00980-08 · Cited by 135 · see citing works
Self-citationRühl, M., Rupp, B., Nöh, K., Wiechert, W., Sauer, U., & Zamboni, N. (2011) · Biotechnology and Bioengineering · doi:10.1002/bit.24344 · Cited by 97 · see citing works
Self-citationRamírez‐Valle, F., Badura, M. L., Braunstein, S. E., Narasimhan, M., & Schneider, R. J. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00322-09 · Cited by 93 · see citing works
S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy
Espeillac, C., Mitchell, C., Celton‐Morizur, S., Chauvin, C., Koka, V., Gillet, C., Albrecht, J. H., Desdouets, C., & Pende, M. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44203 · Cited by 80 · see citing works
Lee, L., Kelly, R. E., Pastra-Landis, S. C., et al. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.20.6802 · Cited by 78 · see citing works
Carrey, E. A., Campbell, D. G., & Hardie, D. G. (1985) · The EMBO Journal · doi:10.1002/j.1460-2075.1985.tb04142.x · Cited by 75 · see citing works
Patterson, D., & Carnright, D. V. (1977) · Somatic Cell and Molecular Genetics · doi:10.1007/bf01539120 · Cited by 75 · see citing works
Zhang, P., Martin, P. D., Purcărea, C., et al. (2009) · Biochemistry · doi:10.1021/bi801831r · Cited by 41 · see citing works
Analysis of the regulatory motifs in eukaryotic initiation factor 4E‐binding protein 1
Lee, V. H.-Y., Healy, T. M., Fonseca, B. D., Hayashi, A. A., & Proud, C. G. (2008) · FEBS Journal · doi:10.1111/j.1742-4658.2008.06372.x · Cited by 40 · see citing works
Nucleotide and pentose synthesis after serum‐stimulation of resting 3T6 fibroblasts
Smith, M. L., & Buchanan, J. M. (1979) · Journal of Cellular Physiology · doi:10.1002/jcp.1041010210 · Cited by 36 · see citing works
Stettler, H., Beuret, N., Prescianotto‐Baschong, C., et al. (2008) · Biochemical Journal · doi:10.1042/bj20071382 · Cited by 36 · see citing works
Self-citationInducible raptor and rictor Knockout Mouse Embryonic Fibroblasts
Cybulski, N., Zinzalla, V., & Hall, M. N. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-430-8_16 · Cited by 34 · see citing works
Self-citationMitchell, A. D., & Hoogenraad, N. J. (1975) · Experimental Cell Research · doi:10.1016/0014-4827(75)90428-0 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555 · see citing works
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · see citing works
mTOR at the nexus of nutrition, growth, ageing and disease
Liu, G. Y., & Sabatini, D. M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0199-y · Cited by 2,737 · see citing works
From Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119 · see citing works
mTOR signalling and cellular metabolism are mutual determinants in cancer
Mossmann, D., Park, S., & Hall, M. N. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0074-8 · Cited by 1,088 · see citing works
Self-citationMaking new contacts: the mTOR network in metabolism and signalling crosstalk
Shimobayashi, M., & Hall, M. N. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3757 · Cited by 1,053 · see citing works
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle
Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M., & Manning, B. D. (2016) · Science · doi:10.1126/science.aad0489 · Cited by 795 · see citing works
AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control
González, A., Hall, M. N., Lin, S.-C., & Hardie, D. G. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.01.015 · Cited by 797 · see citing works
Self-citationCancer cell metabolism: the essential role of the nonessential amino acid, glutamine
Zhang, J., Pavlova, N. N., & Thompson, C. B. (2017) · The EMBO Journal · doi:10.15252/embj.201696151 · Cited by 651 · see citing works
mTOR coordinates protein synthesis, mitochondrial activity and proliferation
Morita, M., Gravel, S.-P., Hulea, L., Larsson, O., Pollak, M., St-Pierre, J., & Topisirovic, I. (2015) · Cell Cycle · doi:10.4161/15384101.2014.991572 · Cited by 552 · see citing works
Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis
Rabinovich, S., Adler, L., Yizhak, K., Sarver, A., Silberman, A., Agron, S., Stettner, N., Sun, Q., Brandis, A., Helbling, D., et al. (2015) · Nature · doi:10.1038/nature15529 · Cited by 382 · see citing works
Oncogenic Roles of the PI3K/AKT/mTOR axis
Aoki, M., & Fujishita, T. (2017) · Current topics in microbiology and immunology · doi:10.1007/82_2017_6 · Cited by 355 · see citing works
mTOR signaling in cellular and organismal energetics
Albert, V., & Hall, M. N. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2014.12.001 · Cited by 304 · see citing works
Self-citationmTORC1 signaling controls multiple steps in ribosome biogenesis
Iadevaia, V., Liu, R., & Proud, C. G. (2014) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2014.08.004 · Cited by 248 · see citing works
Brown, K. K., Spinelli, J. B., Asara, J. M., & Toker, A. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0611 · Cited by 198 · see citing works
Role of mTORC1 in mechanically induced increases in translation and skeletal muscle mass
Goodman, C. A. (2019) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01011.2018 · Cited by 133 · see citing works
A nexus for cellular homeostasis: the interplay between metabolic and signal transduction pathways
Gomes, A. P., & Blenis, J. (2015) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2014.12.007 · Cited by 112 · see citing works
The evolution of genome-scale models of cancer metabolism
Lewis, N. E., & Abdel-Haleem, A. M. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00237 · Cited by 87 · see citing works
Dutchak, P. A., Estill-Terpack, S. J., Plec, A. A., Zhao, X., Yang, C., Chen, J., Ko, B., Deberardinis, R. J., Yu, Y., & Tu, B. P. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.04.058 · Cited by 53 · see citing works
- Authors
- Robitaille, A. M., Christen, S., Shimobayashi, M., Cornu, M., Fava, L. L., Moes, S., Prescianotto-Baschong, C., Sauer, U., Jenoe, P., & Hall, M. N.
- Affiliations
- University of Basel (CH)
- ETH Zurich (CH)
- Biozentrum, University of Basel, 4056 Basel, Switzerland.
- Corresponding author
- Fava, Luca L.
- Hall, Michael N.
- ORCID
- Venue
- Science
- Published
- 2013-03-15
- Volume
- 339
- Issue
- 6125
- Pages
- 1320-1323
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2057650061
- Cited by
- 525
- References
- 42
- Citations by year
- 2026: 30 · 2025: 33 · 2024: 26 · 2023: 32 · 2022: 45 · 2021: 50 · 2020: 43 · 2019: 37 · 2018: 38 · 2017: 46 · 2016: 39 · 2015: 46 · 2014: 38 · 2013: 22
- FWCI
- 21.52
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- edoc (University of Basel) (acceptedVersion)
- Iris (University of Trento) (submittedVersion)
- edoc (University of Basel)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- mTORC1, de novo pyrimidine biosynthesis, aspartate transcarbamylase, dihydroorotase, S6 kinase, protein phosphorylation, S phase progression, nucleotide synthesis, cell proliferation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Aspartate Carbamoyltransferase, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Cells, Cultured, Dihydroorotase, HeLa Cells, Humans, Phosphoproteins, Pyrimidines, Mice, Knockout, Proteome, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review