Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1

By I. Ben-Sahra, Jessica J. Howell, J. Asara, B. Manning. Science, 2013

722 citations recorded by the source corpus.

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. In addition to its role in stimulating protein and lipid synthesis, the kinase mammalian target of rapamycin stimulates nucleotide biosynthesis. Cellular growth signals stimulate anabolic processes. The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase that senses growth signals to regulate anabolic growth and proliferation. Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mTORC1 thus stimulates the production of new nucleotides to accommodate an increase in RNA and DNA synthesis needed for ribosome biogenesis and anabolic growth.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/41dbd16dcd84093c0cd77fc90297ee99f805030d

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Citations in the corpus

mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “…S6K1 phosphorylates and activates carbamoyl-phosphate synthetase (CAD), a critical component of the de novo pyrimidine synthesis pathway (Ben-Sahra et al., 2013; Robitaille et al., 2013). mTORC1 also facilitates growth by promoting a shift in glucose metabolism from oxidative…”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “Additionally, S6K1 phosphorylates and activates carbamoylphosphate synthetase (CAD), a critical component of the de novo pyrimidine synthesis pathway (Ben-Sahra et al., 2013; Robataille et al., 2013).”
Fundamentals of cancer metabolism (2016, background): “The mTORC1 effector ribosomal S6K1 phosphorylates the trifunctional enzymeCAD (carbamoylphosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), which catalyzes the first three steps of pyrimidine synthesis (113).”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “74 Robitaille and colleagues have performed quantitative phosphoproteomics and identi ﬁ ed that mTOR regulates the phosphorylation of approximately 335 proteins.”
Signal transduction in cancer. (2015, neutral): “Signaling in Cancer Cite this article as Cold Spring Harb Perspect Med 2015;5:a006098 9 ysis into the Krebs cycle. mTORC1 can also stimulate pyrimidine biosynthesis via S6K1 (Ben-Sahra et al. 2013; Nakashima et al. 2013).”