Abstract
mTORC1 stimulates de novo pyrimidine synthesis via S6K to promote cell proliferation.
Major finding: mTORC1 stimulates de novo pyrimidine synthesis via S6K to promote cell proliferation.
Mechanism: S6K-mediated phosphorylation activates CAD, a critical enzyme in pyrimidine biosynthesis.
Impact: mTORC1 broadly regulates multiple anabolic pathways in response to growth factor stimulation.
The protein kinase mTOR complex 1 (mTORC1), which is activated in up to 80% of human cancers, senses and responds to nutrient and energy stimuli to promote cell growth through the activation of metabolic processes, including glycolysis, ribosome biogenesis, and protein and lipid synthesis. Although several mTORC1 substrates have been described, it is likely that this complex functions through additional downstream effectors to broadly control anabolic pathways. Using quantitative phosphoproteomic analysis, Robitaille and colleagues showed that mTOR complexes directly or indirectly regulated the phosphorylation of 335 proteins, many of which were previously unidentified targets, including the enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the initial steps of de novo pyrimidine biosynthesis. In a complementary study, Ben-Sahra and colleagues found that N-carbamoyl-aspartate, a product of the CAD-dependent first step of pyrimidine synthesis, was increased by mTORC1 activation and sensitive to rapamycin treatment, suggesting that mTORC1 regulates this metabolic pathway. Indeed, both groups of researchers showed that mTORC1 signaling acutely enhanced flux through the de novo pyrimidine but not through the purine synthesis pathway in response to growth factors and amino acids, independent of its delayed stimulation of the pentose phosphate pathway. This induction of pyrimidine synthesis required S6K1-mediated phosphorylation of CAD at serine 1859 downstream of mTORC1, as rapamycin or S6K inhibition decreased growth factor–stimulated pyrimidine synthesis, similar to the effects of expression of a phosphorylation-site mutant CAD protein. Furthermore, Ben-Sahra and colleagues found that mTORC1-S6K1 signaling promoted incorporation of de novo-synthesized pyrimidines into RNA and DNA, and Robitaille and colleagues showed that CAD phosphorylation increased its oligomerization and induced S-phase progression. These findings define regulation of nucleotide synthesis as an additional mechanism by which mTORC1 modulates anabolic metabolism to drivecell proliferation in response to growth-promoting stimuli.
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